US 20150258104A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0258104 A1 Friedhoff (43) Pub. Date: Sep. 17, 2015

(54) USE OF NORIBOGAINE FOR THE Publication Classification TREATMENT OF PAN (51) Int. Cl. (71) Applicant: psy Rx. Inc., Fort Lauderdale, FL A613 L/55 (2006.01) (52) U.S. Cl. (72) Inventor: Lawrence Friedhoff, River Vale, NJ CPC ...... A6 IK3I/55 (2013.01) (US) (73) Assignee: DemeRX, Inc., Fort Lauderdale, FL (US) (57) ABSTRACT (21) Appl. No.: 14/624,276 (22) Filed: Feb. 17, 2015 This invention is directed tO methods of treating pain in O O patients comprising treating patients with noribogaine at a Related U.S. Application Data dosage that provides an average serum concentration of 50 (60) Provisional application No. 61/952,738, filed on Mar. ng/mL to 180 ng/mL, including under conditions where the 13, 2014, provisional application No. 62/005,855, QT interval prolongation does not exceed about 50 millisec filed on May 30, 2014. onds. Patent Application Publication Sep. 17, 2015 Sheet 1 of 9 US 2015/0258104 A1

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Patent Application Publication Sep. 17, 2015 Sheet 7 of 9 US 2015/0258104 A1

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USE OF NORIBOGAINE FOR THE nociceptors are stimulated and Subsequently transmit signals TREATMENT OF PAN through sensory neurons in the spinal cord. The signals are then transmitted to the brain, at which point the individual CROSS-REFERENCE TO RELATED becomes aware of the pain. APPLICATIONS 0007. There are a number of pain categories and classifi 0001. This application claims benefit from U.S. Provi cations, which for example, can be grouped into four catego sional Application No. 61/952,738, filed Mar. 13, 2014, and ries according to the source and related nociceptors: (1) cuta U.S. Provisional Application No. 62/005,855, filed May 30, neous pain; (2) Somatic pain; (3) visceral pain; and (4) 2014, which are hereby incorporated by reference in their neuropathic pain. Other pain classifications include acute entirety. pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain FIELD OF THE INVENTION indicates present damage to tissue or disease and may be “fast' and “sharp' followed by aching pain. Acute pain is 0002 This invention is directed to methods of treating centralized in one area before becoming somewhat spread pain in patients comprising treating patients with nori out. Acute pain generally responds well to medications (e.g., bogaine, noribogaine derivative, or pharmaceutically accept morphine). able salt and/or Solvate thereof at a dosage that provides a 0008 Chronic pain may be medically defined as pain that therapeutic serum concentration. In one embodiment, the has lasted six months or longer. This constant or intermittent average serum concentration is 50 ng/mL to 180 ng/mL, pain has often outlived its purpose because it does not help the including under conditions where the QT interval prolonga body to prevent injury. It is often more difficult to treat than tion does not exceed about 50 milliseconds, and preferably acute pain. Expert care is generally necessary to treat any pain about 30 milliseconds. that has become chronic. In addition, stronger medications are typically used for extended periods in an attempt to con STATE OF THE ART trol the pain. This can lead to drug dependency. For example, 0003) Noribogaine is sometimes referred to as 12-hy opioids are used in some instances for prolonged periods to droxyibogaine. U.S. Pat. No. 2,813,873 claims noribogaine control chronic pain. Drug tolerance, chemical dependency, albeit as “12-O-demethylibogaine' while providing an incor and even psychological addiction may occur. rect structural formula for ibogaine. Noribogaine can be 0009 Debilitating chronic pain affects tens of millions of depicted by the following formula: people annually and costs hundreds of millions of dollars in terms of medication, physical therapy, and lost production. The current methods for treating chronic pain have a limited Success rate and in some cases may result in chemical depen dency. HO C2H5. 0010 Numerous treatments have been developed in N attempts to ameliorate pain in its various categories. How N ever, in many cases, treatment requires the use of addictive or H habit-forming Substances (e.g., morphine or methadone). While the prior art suggests that ibogaine at higher doses is 0004 Noribogaine and its pharmaceutically acceptable useful as a treatment for pain, use of ibogaine is associated salts have recently received significant attention as a non with hallucinations and other negative side effects. In the addictive alkaloid useful in treating drug dependency (U.S. United States, ibogaine is classified as a Schedule I controlled Pat. No. 6,348,456) and as a potent analgesic (U.S. Pat. No. Substance. 7.220,737). Such treatment generally requires administration 0011 Noribogaine is a metabolite of ibogaine found in of high doses of noribogaine, typically 0.1 mg to 100 mg per human, dog, rat and monkey. However, the therapeutic dosing kg body weight. of noribogaine for treating pain in humans has not previously 0005 Noribogaine is a metabolite of ibogaine found in been addressed, especially as it relates to dosing protocols human, dog, rat and monkey. While the prior art Suggests that that are effective, as well as safe. Indeed, prior to the instant ibogaine at higher doses is useful as a treatment for addiction, invention, it was uncertainas to whethernoribogaine could be use of ibogaine is associated with hallucinations and other administered at a dose which was therapeutic while at the negative side effects. In the United States, ibogaine is classi same time safe for patients. fied as a Schedule I controlled substance. Noribogaine has 0012. Accordingly, there is a significant need for effective, been Suggested to have a greater and longer lasting activity in non-addictive treatment for pain, such as chronic, debilitat humans than ibogaine for reducing craving for addictive Sub ing, nociceptive pain, that reduces the need for habit-forming stances and treating chemical dependency. U.S. Pat. No. pain relieving drugs. 6,348,456, incorporated by reference herein in its entirety, discloses highly purified noribogaine and teaches that it SUMMARY OF THE INVENTION should be provided at dosages from about 0.01 to about 100 0013 While noribogaine has been disclosed for treatment mg per kg body weight per day to treat addiction, although no of pain, its use in humans is complicated by the fact that the human data was provided showing an effective dose to treat ranges in the prior art are exceptionally broad (0.01 to 1000 drug addiction. mg/kg body weight). Furthermore, human clinical studies 0006 Pain is broadly defined as an unpleasant sensory demonstrate that the lower dosing of noribogaine has minimal experience associated with actual or potential tissue damage, impact on the alleviation of pain in patients. Thus, the previ or described in terms of such damage. The interpretation of ously disclosed broad range has now been found to be insuf sensory pain occurs when peripheral nerve endings called ficient for human therapy at the lower end of this range. US 2015/0258 104 A1 Sep. 17, 2015

0014 Moreover, the use of noribogaine imparts a dose 0019. In some embodiments, the dose of noribogaine, dependent prolongation of the treated patient’s QT interval, noribogaine derivative, or pharmaceutically acceptable salt rendering higher dosing of noribogaine unacceptable. A pro and/or solvate thereof administered to the patient is sufficient longed QT interval is a marker of potential ventricular tach to provide an average serum concentration of 50 ng/mL to 180 yarrhythmia which can result in death. ng/mL or any Subrange or subvalue there between. In a pre 0015 The current invention is predicated on the surprising ferred embodiment, the dose of noribogaine, noribogaine discovery that treatment with a narrow dosage range of nori derivative, or pharmaceutically acceptable salt and/or Solvate bogaine, noribogaine derivative, or pharmaceutically accept thereof administered to the patient provides an average serum able salt and/or solvate thereof, between 0.1 mg/kg body concentration of 80 ng/mL to 100 ng/mL. weight and 4 mg/kg body weight, provides a therapeutic 0020. In some embodiments, the dose of noribogaine, alleviation of pain. Preferably, the dose range that provides noribogaine derivative, or pharmaceutically acceptable salt both therapeutic results and an acceptable QT interval pro and/or Solvate thereof that provides an average serum con longation of less than 50 milliseconds in humans is between centration of 50 ng/mL to 180 ng/mL is administered as a 0.1 mg per kg body weight and no more than 3 mg per kg body single dose. In some embodiments, the dose of noribogaine, weight and, more preferably between 0.7 mg per kg body noribogaine derivative, or pharmaceutically acceptable salt weight and no more than 2 mg per kg body weight, or any and/or Solvate thereof that provides an average serum con Subrange or Subvalue within the aforementioned ranges. centration of 50 ng/mL to 180 ng/mL is administered as 0016. In some embodiments, the dose that provides both multiple doses. In some embodiments, the aggregate dose of therapeutic results and an acceptable QT interval prolonga noribogaine, noribogaine derivative, or pharmaceutically tion of less than 50 milliseconds is about 120 mg. In some acceptable salt and/or solvate thereof is from 0.1 mg/kg to 4 embodiments, the dose that provides both therapeutic results mg/kg. In some embodiments, the aggregate dose of nori and an acceptable QT interval prolongation of less than 50 bogaine, noribogaine derivative, or pharmaceutically accept milliseconds is about 100 mg. In some embodiments, the dose able salt and/or Solvate thereof is from 1 mg/kg to 4 mg/kg. In that provides both therapeutic results and an acceptable QT one embodiment, the aggregate dose of noribogaine, nori interval prolongation of less than 50 milliseconds is about 1.5 bogaine derivative, or pharmaceutically acceptable salt and/ mg/kg body weight. In some embodiments, the dose that or Solvate thereof is from 0.1 mg/kg to 3 mg/kg. In one provides both therapeutic results and an acceptable QT inter embodiment, the aggregate dose of noribogaine, noribogaine Val prolongation of less than 50 milliseconds is about 2 mg/kg derivative, or pharmaceutically acceptable salt and/or Solvate body weight. thereof is from 0.1 mg/kg to 2 mg/kg. In another embodiment, the aggregate dose of noribogaine, noribogaine derivative, or 0017. In some embodiments, the patient is administered pharmaceutically acceptable salt and/or Solvate thereof is an initial dose of noribogaine, noribogaine derivative, or from 0.7 mg/kg to 1.5 mg/kg. pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, the 0021. In some embodiments, the serum concentration is initial dose is from 75 mg to 120 mg. In one embodiment, the Sufficient to alleviate or inhibit said pain while maintaining a one or more additional doses are lower than the initial dose. In QT interval of less than 500 milliseconds (ms) during said one embodiment, the one or more additional doses are from 5 treatment. In some embodiments, the therapeutic dose of mg to 50 mg. In one embodiment. Such a dosing regimen noribogaine, noribogaine derivative, or pharmaceutically provides an average serum concentration of noribogaine of 50 acceptable salt and/or Solvate thereof provides prolongation ng/mL to 180 ng/mL. In one embodiment, the one or more of the QT interval of less than 80 ms. In a preferred embodi additional doses maintain an average serum concentration of ment, the dose of noribogaine, noribogaine derivative, or 50 ng/mL to 180 ng/mL over a period of time. In one embodi pharmaceutically acceptable salt and/or Solvate thereof pro ment, the one or more additional doses are administered vides prolongation of the QT interval of less than 50 ms. In periodically. Some embodiments, the dose or therapeutic dose of nori bogaine, noribogaine derivative, or pharmaceutically accept 0018. In a preferred embodiment, the narrow therapeutic able salt and/or solvate thereof provides prolongation of the doses of noribogaine, noribogaine derivative, or pharmaceu QT interval of less than 30 ms. In a preferred embodiment, the tically acceptable salt and/or solvate described above do not dose of noribogaine, noribogaine derivative, or pharmaceuti prolong the QT interval to unacceptable levels in human cally acceptable salt and/or solvate thereof provides prolon patients. In some embodiments, patients are administered gation of the QT interval of less than 20 ms. In one embodi therapeutic doses of noribogaine, noribogaine derivative, or ment, the patient is tested to determine QT interval before pharmaceutically acceptable salt and/or Solvate thereof in a treatment with noribogaine, and if the clinician determines clinical setting with cardiac monitoring. In some embodi that the QT prolongation poses an unacceptable risk, nori ments, the patient will be pre-screened to evaluate tolerance bogaine therapy will be contraindicated. for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with noribogaine. In one BRIEF DESCRIPTION OF THE FIGURES embodiment, a patient who exhibits a QT interval prolonga tion of less than about 20 ms after treatment with one or more 0022 FIG. 1 represents mean noribogaine concentration therapeutic doses of noribogaine, noribogaine derivative, or time profiles in healthy patients after single oral dosing with pharmaceutically acceptable salt and/or solvate thereof will 3, 10, 30 or 60 mg doses. Inset: Individual concentration-time not require further clinical monitoring. In one embodiment, profiles from 0-12 h after a 10 mg dose. the patient is not monitored after administration of nori 0023 FIG. 2 represents mean plasma noribogaine glucu bogaine, noribogaine derivative, or pharmaceutically accept ronide concentration-time profiles in healthy patients after able salt and/or solvate thereof. single oral 30 or 60 mg doses. US 2015/0258 104 A1 Sep. 17, 2015

0024 FIG. 3 illustrates the mean noribogaine concentra disclosure found in any section may be combined with that in tion-time profile in opioid-addicted patients after a single oral another section. Unless defined otherwise, all technical and 60 mg (diamonds), 120 mg (squares), or 180 mg (triangles) Scientific terms used herein have the same meaning as com dose of noribogaine. monly understood by one of ordinary skill in the art to which 0025 FIG. 4 illustrates hours to resumption of opioid sub this invention belongs. stitution treatment (OST) for each patient given placebo 0037. It must be noted that as used herein and in the (circles), or a single oral dose of noribogaine (60 mg. Squares; appended claims, the singular forms “a”, “an', and “the 120 mg. triangles; 180 mg, inverted triangles). Center hori include plural referents unless the context clearly dictates Zontal line represents mean. Error bars represent standard otherwise. Thus, for example, reference to “a compound deviation. includes a plurality of compounds. 0026 FIG.5 illustrates results of noribogaine treatment on final COWS scores before resumption of OST. Boxes include I. Definitions values representing 25%-7.5% quartiles. Diamonds represent 0038. Unless defined otherwise, all technical and scien the median, crossbars represent mean. Whiskers represent tific terms used herein have the same meaning as commonly values within one standard deviation of mid-quartiles. No understood by one of ordinary skill in the art to which this outliers were present. invention belongs. As used herein the following terms have 0027 FIG. 6A illustrates of the mean change in total the following meanings COWS scores over the first 6 hours following dosing of 0039. The term “about when used before a numerical noribogaine (60 mg, squares; 120 mg. triangles: 180 mg. designation, e.g., temperature, time, amount, concentration, diamonds) or placebo (circles). Data is given relative to base and Such other, including a range, indicates approximations line COWS Score. which may vary by (+) or (-) 20%, 10%, 5%, 1%, or any 0028 FIG. 6B illustrates the mean area under the curve subrange or subvalue there between. Preferably, the term (AUC) over the initial 6 hour period after administration of “about when used with regard to a dose amount means that noribogaine or placebo, based on the COWS score data given the dose may vary by +/-20%. For example, “about 2 mg/kg in FIG. 6A. A negative change in score indicates that with noribogaine' indicates that a patient may be administered a drawal symptoms Subsided over the period. dose of noribogaine between 1.6 mg/kg and 2.4 mg/kg. In 0029 FIG. 7A illustrates of the mean change in total another example, about 120 mg per unit dose of noribogaine OOWS scores over the first 6 hours following dosing of indicates that the unit dose may range from 96 mg to 144 mg. noribogaine (60 mg, squares; 120 mg. triangles: 180 mg. 0040 Administration” refers to introducing an agent, diamonds) or placebo (circles). Data is given relative to base Such as noribogaine, into a patient. Typically, an effective line OOWS Score. amount is administered, which amount can be determined by 0030 FIG. 7B illustrates the mean area under the curve the treating physician or the like. Any route of administration, (AUC) over the initial 6 hour period after administration of Such as oral, topical, Subcutaneous, peritoneal, intra-arterial, noribogaine or placebo, based on the OOWS score data given inhalation, vaginal, rectal, nasal, introduction into the cere in FIG. 7A. A negative change in score indicates that with broSpinal fluid, or instillation into body compartments can be drawal symptoms Subsided over the period. used. The agent, Such as noribogaine, may be administered by 0031 FIG. 8A illustrates of the mean change in total direct blood stream delivery, e.g. Sublingual, buccal, intrana SOWS scores over the first 6 hours following dosing of nori sal, or intrapulmonary administration. bogaine (60 mg, squares; 120 mg. triangles; 180 mg. dia 0041. The related terms and phrases “administering and monds) or placebo (circles). Data is given relative to baseline “administration of, when used in connection with a com SOWS Score. pound or pharmaceutical composition (and grammatical 0032 FIG. 8B illustrates the mean area under the curve equivalents) refer both to direct administration, which may be (AUC) over the initial 6 hour period after administration of administration to a patient by a medical professional or by noribogaine or placebo, based on the SOWS score data given self-administration by the patient, and/or to indirect admin in FIG. 8A. A negative change in score indicates that with istration, which may be the act of prescribing a drug. For drawal symptoms Subsided over the period. example, a physician who instructs a patient to self-adminis 0033 FIG. 9A illustrates the average change in QT inter ter a drug and/or provides a patient with a prescription for a Val (AQTc1) for each cohort (60 mg, squares; 120 mg. tri drug is administering the drug to the patient. angles; 180 mg. diamonds) or placebo (circles) over the first 0042 “Periodic administration” or “periodically adminis 24 hours post administration. tering refers to multiple treatments that occur on a daily, 0034 FIG.9B illustrates the correlation between serum weekly, or monthly basis. Periodic administration may also noribogaine concentration and AQTcl for each patient over refer to administration of an agent, such as noribogaine, nori time. The equation of the line is given. bogaine derivative, or salt or solvate thereof one, two, three, or more times per day. Administration may be via transdermal DETAILED DESCRIPTION OF THE INVENTION patch, gum, lozenge, Sublingual tablet, intranasal, intrapul 0035. It is to be understood that this invention is not lim monary, oral administration, or other administration. ited to particular embodiments described, as such may, of 0043 “Comprising or “comprises” is intended to mean course, vary. It is also to be understood that the terminology that the compositions and methods include the recited ele used herein is for the purpose of describing particular ments, but not excluding others. “Consisting essentially of embodiments only, and is not intended to be limiting, since when used to define compositions and methods, shall mean the scope of this invention will be limited only by the excluding other elements of any essential significance to the appended claims. combination for the stated purpose. Thus, a composition con 0036. The detailed description of the invention is divided sisting essentially of the elements as defined herein would not into various sections only for the reader's convenience and exclude other materials or steps that do not materially affect US 2015/0258 104 A1 Sep. 17, 2015

the basic and novel characteristic(s) of the claimed invention. cycloalkylthio. Substituted cycloalkylthio, cycloalkenyl, Sub “Consisting of shall mean excluding more than trace ele stituted cycloalkenyl, cycloalkenyloxy, Substituted cycloalk ments of other ingredients and Substantial method steps. enyloxy, cycloalkenylthio. Substituted cycloalkenylthio. Embodiments defined by each of these transition terms are guanidino, Substituted guanidino, halo, hydroxy, heteroaryl, within the scope of this invention. substituted heteroaryl, heteroaryloxy, substituted heteroary 0044 As used herein, the term “alkyl refers to monova loxy, heteroarylthio, substituted heteroarylthio, heterocyclic, lent saturated aliphatic hydrocarbyl groups having from 1 to substituted heterocyclic, heterocyclyloxy, substituted hetero 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 cyclyloxy, heterocyclylthio, substituted heterocyclylthio. carbon atoms, and more preferably 1 to 3 carbon atoms. This nitro, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, term includes, by way of example, linear and branched hydro thiol, alkylthio, and substituted alkylthio, wherein said sub carbyl groups such as methyl (CH ), ethyl (CHCH ), stituents are defined herein and with the proviso that any n-propyl (CHCH2CH2—), isopropyl ((CH3)2CH ), n-bu hydroxy or thiol substitution is not attached to a vinyl (unsat tyl (CHCHCHCH ), isobutyl ((CH3)2CHCH ), sec urated) carbon atom. butyl ((CH)(CHCH)CH ), t-butyl ((CH),C ), n-penty1 0049 “Substituted alkynyl refers to alkynyl groups hav (CHCH2CH2CHCH ), and neopentyl ((CH),CCH3). ing from 1 to 3 substituents, and preferably 1 to 2 substituents, The term “C, alkyl” refers to an alkyl group having x carbon selected from the group consisting of alkoxy, Substituted atoms, wherein X is an integer, for example, C refers to an alkoxy, acyl, acylamino, acyloxy, amino, Substituted amino, alkyl group having 3 carbon atoms. aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, 0045 “Alkenyl refers to straight or branched hydrocarbyl aminothiocarbonylamino, aminocarbonyloxy, aminosulfo groups having from 2 to 6 carbonatoms and preferably 2 to 4 nyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, carbonatoms and having at least 1 and preferably from 1 to 2 Substituted aryl, aryloxy, Substituted aryloxy, arylthio. Sub sites of vinyl (>C=C-) unsaturation. Such groups are exem stituted arylthio, carboxyl, carboxyl ester, (carboxyl ester) plified, for example, by vinyl, allyl, and but-3-en-1-yl. amino, (carboxyl ester)oxy, cyano, cycloalkyl, Substituted Included within this term are the cis and trans isomers or cycloalkyl, cycloalkyloxy, Substituted cycloalkyloxy, mixtures of these isomers. cycloalkylthio. Substituted cycloalkylthio, cycloalkenyl, Sub 0046 “Alkynyl refers to straight or branched monovalent stituted cycloalkenyl, cycloalkenyloxy, Substituted cycloalk hydrocarbyl groups having from 2 to 6 carbon atoms and enyloxy, cycloalkenylthio. Substituted cycloalkenylthio. preferably 2 to 3 carbon atoms and having at least 1 and guanidino, Substituted guanidino, halo, hydroxy, heteroaryl, preferably from 1 to 2 sites of acetylenic (-C=C- ) unsat substituted heteroaryl, heteroaryloxy, substituted heteroary uration. Examples of Such alkynyl groups include acetylenyl loxy, heteroarylthio, substituted heteroarylthio, heterocyclic, ( C=CH), and propargyl ( CHC=CH). substituted heterocyclic, heterocyclyloxy, substituted hetero 0047 “Substituted alkyl refers to an alkyl group having cyclyloxy, heterocyclylthio, substituted heterocyclylthio. from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 nitro, SOH, substituted sulfonyl, sulfonyloxy, thioacyl, Substituents selected from the group consisting of alkoxy, thiol, alkylthio, and substituted alkylthio, wherein said sub Substituted alkoxy, acyl, acylamino, acyloxy, amino, Substi stituents are defined herein and with the proviso that any tuted amino, aminocarbonyl, aminothiocarbonyl, aminocar hydroxy or thiol Substitution is not attached to an acetylenic bonylamino, aminothiocarbonylamino, aminocarbonyloxy, carbon atom. aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, 0050 “Alkoxy” refers to the group – O-alkyl wherein amidino, aryl, Substituted aryl, aryloxy, Substituted aryloxy, alkyl is defined herein. Alkoxy includes, by way of example, arylthio, substituted arylthio, carboxyl, carboxyl ester, (car methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, boxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, sec-butoxy, and n-pentoxy. Substituted cycloalkyl, cycloalkyloxy, Substituted cycloalky 0051. “Substituted alkoxy' refers to the group —O-(sub loxy, cycloalkylthio. Substituted cycloalkylthio, cycloalk stituted alkyl) wherein substituted alkyl is defined herein. enyl, Substituted cycloalkenyl, cycloalkenyloxy, Substituted 0052 “Acyl” refers to the groups H C(O) , alkyl-C cycloalkenyloxy, cycloalkenylthio. Substituted cycloalk (O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substi enylthio, guanidino, Substituted guanidino, halo, hydroxy, tuted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl heteroaryl, substituted heteroaryl, heteroaryloxy, substituted C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, heteroaryloxy, heteroarylthio, substituted heteroarylthio, het cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, erocyclic, Substituted heterocyclic, heterocyclyloxy, Substi aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, tuted heterocyclyloxy, heterocyclylthio, substituted hetero substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and cyclylthio, nitro, SOH, substituted sulfonyl, sulfonyloxy, substituted heterocyclic-C(O)—, wherein alkyl, substituted thioacyl, thiol, alkylthio, and substituted alkylthio, wherein alkyl, alkenyl, Substituted alkenyl, alkynyl, Substituted alky said substituents are defined herein. nyl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substi 0048 “Substituted alkenyl refers to alkenyl groups hav tuted cycloalkenyl, aryl, Substituted aryl, heteroaryl, Substi ing from 1 to 3 substituents, and preferably 1 to 2 substituents, tuted heteroaryl, heterocyclic, and substituted heterocyclic selected from the group consisting of alkoxy, Substituted are as defined herein. Acyl includes the “acetyl group CHC alkoxy, acyl, acylamino, acyloxy, amino, Substituted amino, (O)—. aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, 0053 “Acylamino” refers to the groups - NRC(O) aminothiocarbonylamino, aminocarbonyloxy, aminosulfo alkyl, - NRC(O)substituted alkyl, - NRC(O)cy nyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, cloalkyl, - NRC(O)substituted cycloalkyl, - NRC(O) Substituted aryl, aryloxy, Substituted aryloxy, arylthio. Sub cycloalkenyl, -NRC(O)substituted cycloalkenyl, stituted arylthio, carboxyl, carboxyl ester, (carboxyl ester) - NRC(O)alkenyl, - NRC(O)substituted alkenyl, amino, (carboxyl ester)oxy, cyano, cycloalkyl, Substituted - NRC(O)alkynyl, - NRC(O)substituted alkynyl, cycloalkyl, cycloalkyloxy, Substituted cycloalkyloxy, NRC(O)aryl, NRC(O)substituted aryl, NRC US 2015/0258 104 A1 Sep. 17, 2015

(O)heteroaryl, - NRC(O)substituted heteroaryl, - NRC cycloalkenyl, aryl. Substituted aryl, heteroaryl, Substituted (O)heterocyclic, and NRC(O)substituted heterocyclic heteroaryl, heterocyclic, and Substituted heterocyclic are as wherein R is hydrogen or alkyl and wherein alkyl, substi defined herein. tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted 0058 “Aminothiocarbonyl refers to the group - C(S) alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, NR'R' where R'' and Rare independently selected from Substituted cycloalkenyl, aryl, Substituted aryl, heteroaryl, the group consisting of hydrogen, alkyl, Substituted alkyl, substituted heteroaryl, heterocyclic, and substituted hetero alkenyl, Substituted alkenyl, alkynyl. Substituted alkynyl, cyclic are as defined herein. aryl, Substituted aryl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, heteroaryl, Substi 0054 Acyloxy' refers to the groups alkyl-C(O)O sub tuted heteroaryl, heterocyclic, and substituted heterocyclic stituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alk and where R'' and Rare optionally joined together with the enyl-C(O)O—, alkynyl-C(O)O— substituted alkynyl-C(O) nitrogen bound thereto to form a heterocyclic or substituted O—, aryl-C(O)O— substituted aryl-C(O)O—, cycloalkyl-C heterocyclic group, and wherein alkyl, Substituted alkyl, alk (O)O— substituted cycloalkyl-C(O)O—, cycloalkenyl-C enyl, Substituted alkenyl, alkynyl, Substituted alkynyl, (O)O— substituted cycloalkenyl-C(O)O heteroaryl-C cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted (O)O— substituted heteroaryl-C(O)O—, heterocyclic-C(O) cycloalkenyl, aryl. Substituted aryl, heteroaryl, Substituted O—, and substituted heterocyclic-C(O)O wherein alkyl, heteroaryl, heterocyclic, and Substituted heterocyclic are as substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub defined herein. stituted alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalk enyl, Substituted cycloalkenyl, aryl, Substituted aryl, het 0059 Aminocarbonylamino” refers to the group eroaryl, substituted heteroaryl, heterocyclic, and substituted NRC(O)NR'R' where R is hydrogen oralkyland R' heterocyclic are as defined herein. and Rare independently selected from the group consisting of hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alk 0055 “Amino” refers to the group —NH. enyl, alkynyl. Substituted alkynyl, aryl, Substituted aryl, 0056 “Substituted amino” refers to the group - NR'R'' cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted where RandR'' are independently selected from the group cycloalkenyl, heteroaryl, Substituted heteroaryl, heterocyclic, consisting of hydrogen, alkyl, Substituted alkyl, alkenyl, Sub and substituted heterocyclic and where R'' and R' are stituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substituted optionally joined together with the nitrogen bound thereto to aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, Substi form a heterocyclic or substituted heterocyclic group, and tuted cycloalkenyl, heteroaryl, substituted heteroaryl, hetero wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, cyclic, Substituted heterocyclic. —SO-alkyl, -SO-substi alkynyl. Substituted alkynyl, cycloalkyl, Substituted tuted alkyl, -SO-alkenyl, -SO-substituted alkenyl, cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, aryl, Sub —SO-cycloalkyl, -SO-substituted cylcoalkyl, -SO-cy stituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, cloalkenyl, -SO-substituted cylcoalkenyl, -SO-aryl, and substituted heterocyclic are as defined herein. —SO-substituted aryl, -SO-heteroaryl, -SO-substi 0060 Aminothiocarbonylamino” refers to the group tuted heteroaryl, -SO-heterocyclic, and—SO-substituted NRC(S)NR'R' where R is hydrogen oralkyl and R' heterocyclic and wherein R and R' are optionally joined, and Rare independently selected from the group consisting together with the nitrogen bound thereto to form a heterocy of hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted alk clic or substituted heterocyclic group, provided that Rand enyl, alkynyl. Substituted alkynyl, aryl, Substituted aryl, R" are both not hydrogen, and wherein alkyl, substituted cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substituted alky cycloalkenyl, heteroaryl, Substituted heteroaryl, heterocyclic, nyl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substi and substituted heterocyclic and where R'' and R' are tuted cycloalkenyl, aryl, Substituted aryl, heteroaryl, Substi optionally joined together with the nitrogen bound thereto to tuted heteroaryl, heterocyclic, and substituted heterocyclic form a heterocyclic or substituted heterocyclic group, and are as defined herein. When R is hydrogen and R' is alkyl, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, the Substituted amino group is sometimes referred to hereinas alkynyl. Substituted alkynyl, cycloalkyl, Substituted alkylamino. When R and R' are alkyl, the substituted cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, aryl, Sub amino group is sometimes referred to hereinas dialkylamino. stituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, When referring to a monosubstituted amino, it is meant that and substituted heterocyclic are as defined herein. either R or R' is hydrogen but not both. When referring to 0061 “Aminocarbonyloxy' refers to the group —O C a disubstituted amino, it is meant that neither R nor R' are (O)NR'R' where R' and Rare independently selected hydrogen. from the group consisting of hydrogen, alkyl, Substituted 0057 “Aminocarbonyl refers to the group –C(O) alkyl, alkenyl, Substituted alkenyl, alkynyl, Substituted alky NR'R' where R'' and Rare independently selected from nyl, aryl, Substituted aryl, cycloalkyl, Substituted cycloalkyl, the group consisting of hydrogen, alkyl, Substituted alkyl, cycloalkenyl, Substituted cycloalkenyl, heteroaryl, Substi alkenyl, Substituted alkenyl, alkynyl. Substituted alkynyl, tuted heteroaryl, heterocyclic, and substituted heterocyclic aryl, Substituted aryl, cycloalkyl, Substituted cycloalkyl, and where R'' and Rare optionally joined together with the cycloalkenyl, Substituted cycloalkenyl, heteroaryl, Substi nitrogen bound thereto to form a heterocyclic or substituted tuted heteroaryl, heterocyclic, and substituted heterocyclic heterocyclic group, and wherein alkyl, Substituted alkyl, alk and where R'' and Rare optionally joined together with the enyl, Substituted alkenyl, alkynyl, Substituted alkynyl, nitrogen bound thereto to form a heterocyclic or substituted cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted heterocyclic group, and wherein alkyl, Substituted alkyl, alk cycloalkenyl, aryl. Substituted aryl, heteroaryl, Substituted enyl, Substituted alkenyl, alkynyl, Substituted alkynyl, heteroaryl, heterocyclic, and Substituted heterocyclic are as cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted defined herein. US 2015/0258 104 A1 Sep. 17, 2015

0062 “Aminosulfonyl refers to the group matic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3 (4H)- —SONR'R' where R' and R are independently one-7-yl, and the like) provided that the point of attachment is selected from the group consisting of hydrogen, alkyl, Sub at an aromatic carbon atom. Preferred aryl groups include stituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substi phenyl and naphthyl. tuted alkynyl, aryl, Substituted aryl, cycloalkyl, Substituted 0067 “Substituted aryl” refers to aryl groups which are cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, het substituted with 1 to 5, preferably 1 to 3, or more preferably eroaryl, substituted heteroaryl, heterocyclic, and substituted 1 to 2 substituents selected from the group consisting of alkyl, heterocyclic and where R' and R' are optionally joined substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub together with the nitrogen bound thereto to form a heterocy stituted alkynyl, alkoxy, Substituted alkoxy, acyl, acylamino, clic or Substituted heterocyclic group, and wherein alkyl, acyloxy, amino, Substituted amino, aminocarbonyl, ami substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub nothiocarbonyl, aminocarbonylamino, aminothiocarbony stituted alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalk lamino, aminocarbonyloxy, aminosulfonyl, aminosulfony enyl, Substituted cycloalkenyl, aryl, Substituted aryl, het loxy, aminosulfonylamino, amidino, aryl, Substituted aryl, eroaryl, substituted heteroaryl, heterocyclic, and substituted aryloxy, substituted aryloxy, arylthio, substituted arylthio. heterocyclic are as defined herein. carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl 0063 “Aminosulfonyloxy' refers to the group ester)oxy, cyano, cycloalkyl, Substituted cycloalkyl, —O SO.NR'R' where R'' and R' are independently cycloalkyloxy, Substituted cycloalkyloxy, cycloalkylthio. selected from the group consisting of hydrogen, alkyl, Sub substituted cycloalkylthio, cycloalkenyl, substituted stituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substi cycloalkenyl, cycloalkenyloxy, Substituted cycloalkenyloxy, tuted alkynyl, aryl, Substituted aryl, cycloalkyl, Substituted cycloalkenylthio. Substituted cycloalkenylthio, guanidino, cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, het Substituted guanidino, halo, hydroxy, heteroaryl, Substituted eroaryl, substituted heteroaryl, heterocyclic, and substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, het heterocyclic and where R'' and R' are optionally joined eroarylthio, substituted heteroarylthio, heterocyclic, substi together with the nitrogen bound thereto to form a heterocy tuted heterocyclic, heterocyclyloxy, substituted heterocycly clic or Substituted heterocyclic group, and wherein alkyl, loxy, heterocyclylthio. Substituted heterocyclylthio, nitro, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub SOH, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alky stituted alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalk lthio, and substituted alkylthio, wherein said substituents are enyl, Substituted cycloalkenyl, aryl, Substituted aryl, het defined herein. eroaryl, substituted heteroaryl, heterocyclic, and substituted 0068 "Aryloxy” refers to the group —O-aryl, where aryl heterocyclic are as defined herein. is as defined herein, that includes, by way of example, phe 0064 “Aminosulfonylamino” refers to the group noxy and naphthoxy. - NR SONR'R' where R is hydrogen or alkyl and 0069. “Substituted aryloxy' refers to the group —O-(sub R'' and Rare independently selected from the group con stituted aryl) where substituted aryl is as defined herein. sisting of hydrogen, alkyl, Substituted alkyl, alkenyl, Substi (0070 "Arylthio” refers to the group – S-aryl, where aryl tuted alkenyl, alkynyl, Substituted alkynyl, aryl, Substituted is as defined herein. aryl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substi (0071. “Substituted arylthio” refers to the group - S-(sub tuted cycloalkenyl, heteroaryl, substituted heteroaryl, hetero stituted aryl), where substituted aryl is as defined herein. cyclic, and substituted heterocyclic and where R'' and Rare (0072 “Carbonyl refers to the divalent group –C(O)— optionally joined together with the nitrogen bound thereto to which is equivalent to —C(=O)—. form a heterocyclic or substituted heterocyclic group, and (0073. “Carboxy” or “carboxyl refers to -COOH or salts wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, thereof. alkynyl. Substituted alkynyl, cycloalkyl, Substituted (0074 “Carboxyl ester” or “carboxy ester” refers to the cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, aryl, Sub groups —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O) stituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl, and substituted heterocyclic are as defined herein. —C(O)C)-substituted alkynyl, —C(O)O-aryl, —C(O)O-sub 0065 “Amidino” refers to the group –C(=NR) stituted aryl, —C(O)O-cycloalkyl, —C(O)O-substituted NR'R' where R', R', and Rare independently selected cycloalkyl, —C(O)O-cycloalkenyl, —C(O)O-substituted from the group consisting of hydrogen, alkyl, Substituted cycloalkenyl, —C(O)O-heteroaryl, —C(O)O-substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, Substituted alky heteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted nyl, aryl, Substituted aryl, cycloalkyl, Substituted cycloalkyl, heterocyclic wherein alkyl, substituted alkyl, alkenyl, substi cycloalkenyl, Substituted cycloalkenyl, heteroaryl, Substi tuted alkenyl, alkynyl, Substituted alkynyl, cycloalkyl, Sub tuted heteroaryl, heterocyclic, and substituted heterocyclic stituted cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, and where R'' and Rare optionally joined together with the aryl, substituted aryl, heteroaryl, substituted heteroaryl, het nitrogen bound thereto to form a heterocyclic or substituted erocyclic, and Substituted heterocyclic are as defined herein. heterocyclic group, and wherein alkyl, Substituted alkyl, alk (0075 “(Carboxyl ester)amino” refers to the group enyl, Substituted alkenyl, alkynyl, Substituted alkynyl, - NR C(O)O-alkyl, - NR C(O)O-substituted alkyl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted - NR C(O)O-alkenyl, -NR C(O)O-substituted alk cycloalkenyl, aryl. Substituted aryl, heteroaryl, Substituted enyl, - NR C(O)O-alkynyl, - NR C(O)O-substi heteroaryl, heterocyclic, and Substituted heterocyclic are as tuted alkynyl, - NR C(O)O-aryl, -NR C(O)C)-sub defined herein. stituted aryl, - NR C(O)O-cycloalkyl, - NR C(O) 0066 “Aryl or 'Ar' refers to a monovalent aromatic car O-substituted cycloalkyl, - NR C(O)C)-cycloalkenyl, bocyclic group of from 6 to 14 carbon atoms having a single - NR C(O)O-substituted cycloalkenyl, -NR C(O) ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl O-heteroaryl, - NR C(O)O-substituted heteroaryl, or anthryl) which condensed rings may or may not be aro - NR C(O)O-heterocyclic, and NR C(O)C)-sub US 2015/0258 104 A1 Sep. 17, 2015

stituted heterocyclic wherein R is alkyl or hydrogen, and I0084) “Substituted cycloalkylthio’ refers to S-(substi wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, tuted cycloalkyl). alkynyl. Substituted alkynyl, cycloalkyl, Substituted I0085 “Cycloalkenyloxy” refers to -O-cycloalkenyl. cycloalkyl, cycloalkenyl, Substituted cycloalkenyl, aryl, Sub I0086. “Substituted cycloalkenyloxy' refers to —O-(sub stituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, stituted cycloalkenyl). and substituted heterocyclic are as defined herein. I0087. “Cycloalkenylthio” refers to S-cycloalkenyl. 0076 “(Carboxyl ester)oxy” refers to the group - O C I0088. “Substituted cycloalkenylthio” refers to S-(sub (O)O-alkyl, substituted —O C(O)O-alkyl, —O C(O)O- stituted cycloalkenyl). alkenyl, —O C(O)O-substituted alkenyl, —O C(O)O- I0089) “Guanidino” refers to the group - NHC(=NH) alkynyl, —O C(O)O-substituted alkynyl, —O—C(O)O- NH. aryl, —O C(O)O-substituted aryl, —O—C(O)O- 0090 “Substituted guanidino” refers to NRC(=NR) cycloalkyl, —O C(O)O-substituted cycloalkyl, —O—C N(R), where each R is independently selected from the (O)O-cycloalkenyl, O—C(O)O-substituted cycloalkenyl, group consisting of hydrogen, alkyl, Substituted alkyl, aryl, —O C(O)O-heteroaryl, —O C(O)O-substituted het substituted aryl, heteroaryl, substituted heteroaryl, heterocy eroaryl, —O C(O)O-heterocyclic, and —O—C(O)O-sub clic, and substituted heterocyclic and two R' groups attached stituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, to a common guanidino nitrogen atom are optionally joined Substituted alkenyl, alkynyl, Substituted alkynyl, cycloalkyl, together with the nitrogen bound thereto to form a heterocy Substituted cycloalkyl, cycloalkenyl, Substituted cycloalk clic or Substituted heterocyclic group, provided that at least enyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, one R is not hydrogen, and wherein said substituents areas heterocyclic, and substituted heterocyclic are as defined defined herein. herein. (0091) “Halo' or “halogen” refers to fluoro, chloro, bromo 0077 “Cyano” refers to the group –CN. and iodo and preferably is fluoro or chloro. 0078 “Cycloalkyl refers to cyclic alkyl groups of from 3 0092 “Haloalkyl refers to alkyl groups substituted with 1 to 10 carbon atoms having single or multiple cyclic rings to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are including fused, bridged, and spiro ring systems. One or more as defined herein. of the rings can be aryl, heteroaryl, or heterocyclic provided 0093. “Haloalkoxy' refers to alkoxy groups substituted that the point of attachment is through the non-aromatic, with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkoxy and non-heterocyclic ring carbocyclic ring. Examples of Suitable halo are as defined herein. cycloalkyl groups include, for instance, adamantyl, cyclopro I0094 "Haloalkylthio” refers to alkylthio groups substi pyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples tuted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein of cycloalkyl groups include bicycle 2.2.2. octanyl, nor alkylthio and halo are as defined herein. bornyl, and spirobicyclo groups such as Spiro4.5 dec-8-yl. (0095) “Hydroxy” or “hydroxyl refers to the group –OH. 0079. “Cycloalkenyl refers to non-aromatic cyclic alkyl 0096 “Heteroaryl” refers to an aromatic group of from 1 groups of from 3 to 10 carbonatoms having single or multiple to 10 carbon atoms and 1 to 4 heteroatoms selected from the cyclic rings and having at least one >C=C- ring unsaturation group consisting of oxygen, nitrogen and Sulfur within the and preferably from 1 to 2 sites of C=C- ring unsaturation. ring. Such heteroaryl groups can have a single ring (e.g., 0080 “Substituted cycloalkyl and “substituted cycloalk pyridyl, pyridinyl or furyl) or multiple condensed rings (e.g., enyl refers to a cycloalkyl or cycloalkenyl group having indolizinyl or benzothienyl) wherein the condensed rings from 1 to 5 or preferably 1 to 3 substituents selected from the may or may not be aromatic and/or contain a heteroatom group consisting of oxo, thione, alkyl, Substituted alkyl, alk provided that the point of attachment is through an atom of the enyl, Substituted alkenyl, alkynyl, Substituted alkynyl, aromatic heteroaryl group. In one embodiment, the nitrogen alkoxy, Substituted alkoxy, acyl, acylamino, acyloxy, amino, and/or the Sulfur ring atom(s) of the heteroaryl group are Substituted amino, aminocarbonyl, aminothiocarbonyl, ami optionally oxidized to provide for the N-oxide (N->O), sulfi nocarbonylamino, aminothiocarbonylamino, aminocarbony nyl, and/or sulfonyl moieties. Preferred heteroaryls include loxy, aminosulfonyl, aminosulfonyloxy, aminosulfony pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. lamino, amidino, aryl, Substituted aryl, aryloxy, Substituted (0097 “Substituted heteroaryl” refers to heteroaryl groups aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl that are substituted with from 1 to 5, preferably 1 to 3, or more ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, preferably 1 to 2 substituents selected from the group con cycloalkyl, Substituted cycloalkyl, cycloalkyloxy, Substituted sisting of the same group of Substituents defined for Substi cycloalkyloxy, cycloalkylthio. Substituted cycloalkylthio. tuted aryl. cycloalkenyl, Substituted cycloalkenyl, cycloalkenyloxy, (0098 “Heteroaryloxy” refers to O-heteroaryl. substituted cycloalkenyloxy, cycloalkenylthio, substituted (0099. “Substituted heteroaryloxy” refers to the group cycloalkenylthio, guanidino, Substituted guanidino, halo, —O-(substituted heteroaryl). hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, 0100 “Heteroarylthio’ refers to the group—S-heteroaryl. substituted heteroaryloxy, heteroarylthio. Substituted het 0101. “Substituted heteroarylthio” refers to the group eroarylthio, heterocyclic, substituted heterocyclic, heterocy —S-(substituted heteroaryl). clyloxy, substituted heterocyclyloxy, heterocyclylthio. Sub 0102) “Heterocycle” or “heterocyclic” or "heterocy stituted heterocyclylthio, nitro, SOH, substituted sulfonyl, cloalkyl or "heterocyclyl refers to a saturated or partially sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alky saturated, but not aromatic, group having from 1 to 10 ring lthio, wherein said substituents are defined herein. carbonatoms and from 1 to 4 ring heteroatoms selected from I0081) “Cycloalkyloxy” refers to O-cycloalkyl. the group consisting of nitrogen, Sulfur, or oxygen. Hetero 0082 “Substituted cycloalkyloxy” refers to —O-(substi cycle encompasses single ring or multiple condensed rings, tuted cycloalkyl). including fused bridged and spiro ring systems. In fused ring I0083) “Cycloalkylthio” refers to S-cycloalkyl. systems, one or more the rings can be cycloalkyl, aryl, or US 2015/0258 104 A1 Sep. 17, 2015 heteroaryl provided that the point of attachment is through the substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub non-aromatic heterocyclic ring. In one embodiment, the stituted alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalk nitrogen and/or Sulfur atom(s) of the heterocyclic group are enyl, Substituted cycloalkenyl, aryl, Substituted aryl, het optionally oxidized to provide for the N-oxide, sulfinyl, and/ eroaryl, substituted heteroaryl, heterocyclic, and substituted or Sulfonyl moieties. heterocyclic are as defined herein. (0103 “Substituted heterocyclic” or “substituted heterocy 0115 “Thioacyl refers to the groups H C(S)—, alkyl cloalkyl or “substituted heterocyclyl refers to heterocyclyl C(S)—, substituted alkyl-C(S)—, alkenyl-C(S)—, substi groups that are substituted with from 1 to 5 or preferably 1 to tuted alkenyl-C(S)—, alkynyl-C(S)—, substituted alkynyl-C 3 of the same substituents as defined for substituted (S)- cycloalkyl-C(S)—, substituted cycloalkyl-C(S) , cycloalkyl. cycloalkenyl-C(S)—, substituted cycloalkenyl-C(S)—, aryl 0104. “Heterocyclyloxy' refers to the group —O-hetero C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—, substi cycyl. tuted heteroaryl-C(S)—, heterocyclic-C(S)—, and substi 0105. “Substituted heterocyclyloxy” refers to the group tuted heterocyclic-C(S) , wherein alkyl, substituted alkyl, —O-(substituted heterocycyl). alkenyl, Substituted alkenyl, alkynyl. Substituted alkynyl, 0106 “Heterocyclylthio’ refers to the group —S-hetero cycloalkyl, Substituted cycloalkyl, cycloalkenyl, Substituted cycyl. cycloalkenyl, aryl. Substituted aryl, heteroaryl, Substituted 0107 “Substituted heterocyclylthio” refers to the group heteroaryl, heterocyclic, and Substituted heterocyclic are as —S-(substituted heterocycyl). defined herein. 0108 Examples of heterocycle and heteroaryls include, 0116 “Thiol” refers to the group -SH. but are not limited to, aZetidine, pyrrole, imidazole, pyrazole, 0117 “Thiocarbonyl refers to the divalent group pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoin —C(S)— which is equivalent to —C(=S)—. dole, indole, dihydroindole, indazole, purine, quinolizine, 0118 “Thione” refers to the atom (—S). isoquinoline, quinoline, phthalazine, naphthylpyridine, qui 0119) “Alkylthio’ refers to the group —S-alkyl wherein noxaline, quinazoline, cinnoline, pteridine, carbazole, carbo alkyl is as defined herein. line, phenanthridine, acridine, phenanthroline, isothiazole, I0120 "Substituted alkylthio’ refers to the group —S- phenazine, isoxazole, phenoxazine, phenothiazine, imidazo (substituted alkyl) wherein substituted alkyl is as defined lidine, imidazoline, piperidine, piperazine, indoline, phthal herein. imide, 1.2.3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahy I0121 “Compound' or “compounds' as used herein is drobenzobthiophene, thiazole, thiazolidine, thiophene, meant to include the stereoiosmers and tautomers of the indi benzobthiophene, morpholinyl, thiomorpholinyl (also cated formulas. referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, 0.122 "Stereoisomer' or “stereoisomers’ refer to com piperidinyl, pyrrolidine, and tetrahydrofuranyl. pounds that differ in the chirality of one or more stereo 0109) “Nitro” refers to the group - NO. centers. Stereoisomers include enantiomers and diastere 0110 “Oxo” refers to the atom (=O) or (-O). OS. 0111. “Spiro ring systems’ refers to bicyclic ring systems I0123 “Tautomer refer to alternate forms of a compound that have a single ring carbon atom common to both rings. that differ in the position of a proton, such as enol-keto and 0112 “Sulfonyl refers to the divalent group —S(O)—. imine-enamine tautomers, or the tautomeric forms of het 0113 “Substituted sulfonyl refers to the group —SO eroaryl groups containing a ring atom attached to both a ring alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-sub —NH-moiety and a ring =N-moiety such as pyrazoles, stituted alkenyl, -SO-cycloalkyl, -SO-substituted cyl imidazoles, benzimidazoles, triazoles, and tetrazoles. coalkyl, —SO-cycloalkenyl, —SO-substituted 0.124. As used herein, the term “phosphate ester refers to cylcoalkenyl, -SO-aryl, -SO-substituted aryl, -SO any one of the mono-, di- or triphosphate esters of nori heteroaryl, —SO-substituted heteroaryl, -SO-heterocy bogaine, wherein the mono-, di- or triphosphate ester moiety clic. —SO-substituted heterocyclic, wherein alkyl, substi is bonded to the 12-hydroxy group and/or the indole nitrogen tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted of noribogaine. alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, 0.125. As used herein, the term “phosphate ester refers to Substituted cycloalkenyl, aryl, Substituted aryl, heteroaryl, any one of the mono-, di- or triphosphate esters of nori substituted heteroaryl, heterocyclic, and substituted hetero bogaine, wherein the mono-, di- or triphosphate ester moiety cyclic are as defined herein. Substituted sulfonyl includes is bonded to the 12-hydroxy group and/or the indole nitrogen groups such as methyl-SO , phenyl-SO , and 4-meth of noribogaine. ylphenyl-SO . The term “alkylsulfonyl refers to —SO I0126. As used herein, the term “monophosphate” refers to alkyl. The term “haloalkylsulfonyl refers to —SO-ha the group —P(O)(OH). loalkyl where haloalkyl is defined herein. The term I0127. As used herein, the term "diphosphate” refers to the “(substituted sulfonyl)amino” refers to —NH(substituted group -P(O)(OH)–OP(O)(OH). sulfonyl), and the term “(substituted sulfonyl)aminocarbo I0128. As used herein, the term “triphosphate” refers to the nyl refers to —C(O)NH(substituted sulfonyl), wherein sub group -P(O)(OH)–(OP(O)(OH))OH. stituted sulfonyl is as defined herein. 0129. As used herein, the term “ester” as it refers to esters 0114 “Sulfonyloxy” refers to the group —OSO-alkyl, of the mono-, di- or triphosphate group means esters of the —OSO-substituted alkyl, —OSO-alkenyl, —OSO-sub monophosphate can be represented by the formula - P(O) stituted alkenyl, —OSO-cycloalkyl, OSO-substituted (OR), where each R" is independently hydrogen, C-C, cylcoalkyl, —OSO-cycloalkenyl, —OSO-substituted cyl alkyl, C-C cycloalkyl, C-C aryl, heteroaryl of 1 to 10 coalkenyl, —OSO-aryl, —OSO-substituted aryl, —OSO carbon atoms and 1 to 4 optionally oxidized heteroatoms heteroaryl, —OSO-substituted heteroaryl, —OSO-hetero selected from the group consisting of oxygen, nitrogen, and cyclic. —OSO-substituted heterocyclic, wherein alkyl, sulfur and the like, provided that at least one R is not US 2015/0258 104 A1 Sep. 17, 2015 hydrogen. Likewise, exemplary esters of the di- or triphos bogaine polymorphs), and U.S. patent application Ser. No. phate can be represented by the formulas - P(O)(OR")— 13/593.454, each of which is incorporated herein by refer OP(O)(OR), and P(O)(OR) (OP(O)(OR)),OR, ence in its entirety. where R is as defined above. 0.133 “Noribogaine derivatives” refer to, without limita 0130. As used herein, the term “hydrolyzable group' tion, esters or O-carbamates of noribogaine, or pharmaceuti refers to a group that can be hydrolyzed to release the free cally acceptable salts and/or solvates of each thereof. Also hydroxy group under hydrolysis conditions. Examples of encompassed within this invention are derivatives of nori hydrolysable group include, but are not limited to those bogaine that act as prodrug forms of noribogaine. A prodrug defined for R above. Preferred hydrolysable groups include is a pharmacological Substance administered in an inactive carboxyl esters, phosphates and phosphate esters. The (or significantly less active) form. Once administered, the hydrolysis may be done by chemical reactions conditions prodrug is metabolized in vivo into an active metabolite. Such as base hydrolysis or acid hydrolysis or may be done in Noribogaine derivatives include, without limitation, those Vivo by biological processes, such as those catalyzed by a compounds set forth in U.S. Pat. Nos. 6,348,456 and 8.362, phosphate hydrolysis enzyme. Nonlimiting examples of 007; as well as in U.S. patent application Ser. No. 13/165,626; hydrolysable group include groups linked with an ester-based and US Patent Application Publication Nos. US2013/ linker (—C(O)O— or —OC(O)—), an amide-based linker 0131046; US2013/0165647; US2013/0165425; and ( C(O)NR' or - NRC(O) ), or a phosphate-linker US2013/0165414; all of which are incorporated herein by ( P(O)(OR) O - O P(S)(OR) O - O P reference. Non-limiting examples of noribogaine derivatives (S)(SR) O S P(O)(OR)- O - O P(O) encompassed by this invention are given in more detail in the (OR) S , -S P(O)(OR) S , - O P(S) “Compositions of the Invention' section below. (OR) S – S P(S)(OR) O - O P(O)(R)- I0134. In some embodiments, the methods of the present O - O P(S)(R)- O -, - S -P(O)(R') O , disclosure entail the administration of a prodrug of nori -S P(S)(R) O. , S P(O)(R) S , or - O P bogaine that provides the desired maximum serum concen (S)(R) S ) where R' can be hydrogen or alkyl. trations and efficacious average noribogaine serum levels. A 0131 Substituted groups of this invention, as set forth prodrug of noribogaine refers to a compound that metabo above, do not include polymers obtained by an infinite chain lizes, in Vivo, to noribogaine. In some embodiments, the of Substituted groups. At most, any Substituted group can be prodrug is selected to be readily cleavable either by a cleav substituted up to five times. able linking arm or by cleavage of the prodrug entity that 0132) “Noribogaine” refers to the compound: binds to noribogaine such that noribogaine is generated in vivo. In one preferred embodiment, the prodrug moiety is selected to facilitate binding to the Land/or K receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the Land/or HO C2H5, K receptors. Examples of prodrugs of noribogaine are pro N vided in U.S. patent application Ser. No. 13/165.626, the N entire content of which is incorporated herein by reference. H 0.135 This invention is not limited to any particular chemi cal form of noribogaine or noribogaine derivative, and the as well as noribogaine derivatives or pharmaceutically drug may be given to patients either as a free base, Solvate, or acceptable salts and/or pharmaceutically acceptable Solvates as a pharmaceutically acceptable acid addition salt. In the thereof. It should be understood that where “noribogaine' is latter case, the hydrochloride salt is generally preferred, but mentioned herein, one more polymorphs of noribogaine can other salts derived from organic or inorganic acids may also be utilized and are contemplated. In some embodiments, nori be used. Examples of Such acids include, without limitation, bogaine is noribogaine glucuronide. Noribogaine can be pre those described below as “pharmaceutically acceptable salts' pared by demethylation of naturally occurring ibogaine: and the like. 0.136 “Pharmaceutically acceptable composition” refers to a composition that is suitable for administration to a mam mal, preferably a human. Such compositions include various HCO CH5 excipients, diluents, carriers, and Such other inactive agents well known to the skilled artisan. N 0.137 “Pharmaceutically acceptable salt” refers to phar N maceutically acceptable salts, including pharmaceutically H acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions which is isolated from Tabernanth iboga, a shrub of West well known in the art and include, by way of example only, Africa. Demethylation may be accomplished by conventional hydrochloric acid, hydrobromic acid, phosphoric acid, Sulfu techniques such as by reaction with boron tribromide/meth ric acid, methane Sulfonic acid, phosphorous acid, nitric acid, ylene chloride at room temperature followed by conventional perchloric acid, acetic acid, tartaric acid, lactic acid, Succinic purification. See, for example, Huffman, et al., J. Org. Chem. acid, citric acid, malic acid, maleic acid, aconitic acid, Sali 50: 1460 (1985), which incorporated herein by reference in its cylic acid, thalic acid, embonic acid, enanthic acid, oxalic entirety. Noribogaine can be synthesized as described, for acid and the like, and when the molecule contains an acidic example in U.S. Patent Pub. Nos. 2013/0165647, 2013/ functionality, include, by way of example only, Sodium, O303756, and 2012/0253037, PCT Patent Publication No. potassium, calcium, magnesium, ammonium, tetraalkylam WO 2013/04.0471 (includes description of making nori monium, and the like. US 2015/0258 104 A1 Sep. 17, 2015

0138 A “pharmaceutically acceptable solvate” or control (placebo), at least about 5 hours beyond control, and “hydrate' of a compound of the invention means a solvate or preferably at least about 10 hours beyond control. hydrate complex that is pharmaceutically acceptable and that 0.141. The therapeutically effective amount of the com possesses the desired pharmacological activity of the parent pound may be higher or lower, depending on the route of compound, and includes, but is not limited to, complexes of a administration used. For example, when direct blood admin compound of the invention with one or more solvent or water istration (e.g., Sublingual, pulmonary and intranasal delivery) molecules, or 1 to about 100, or 1 to about 10, or one to about is used, a lower dose of the compound may be administered. 2, 3 or 4, solvent or water molecules. In one aspect, a therapeutically effective amount of nori bogaine or derivative is from about 50 ng to less than 100 g 0139. As used herein the term “solvate” is taken to mean per kg of body weight. Where other routes of administration that a solid-form of a compound that crystallizes with one or are used, a higher dose of the compound may be administered. more molecules of solvent trapped inside. A few examples of In one embodiment, the therapeutically effective amount of Solvents that can be used to create Solvates, such as pharma the compound is from greater than about 1 mg to about 8 mg ceutically acceptable Solvates, include, but are certainly not per kg of body weight per day. limited to, water, methanol, ethanol, isopropanol, butanol, 0142. A “therapeutic level of a drug is an amount of C1-C6 alcohols in general (and optionally substituted), tet noribogaine, noribogaine derivative, or pharmaceutical salt rahydrofuran, acetone, ethylene glycol, propylene glycol, or solvate thereof that is sufficient to treat patients suffering acetic acid, formic acid, water, and solvent mixtures thereof. from pain or to treat, prevent, or alleviate acute pain Symp Other such biocompatible solvents which may aid in making toms, but not high enough to pose any significant risk to the a pharmaceutically acceptable solvate are well known in the patient. Therapeutic levels of drugs can be determined by art and applicable to the present invention. Additionally, vari tests that measure the actual concentration of the compound ous organic and inorganic acids and bases can be added or in the blood of the patient. This concentration is referred to as even used alone as the solvent to create a desired solvate. Such the "serum concentration.” Where the serum concentration of acids and bases are known in the art. When the solvent is noribogaine is mentioned, it is to be understood that the term water, the solvate can be referred to as a hydrate. Further, by "noribogaine' encompasses any form of noribogaine, includ being left in the atmosphere or recrystallized, the compounds ing derivatives thereof. of the present invention may absorb moisture, may include 0.143 A “sub-therapeutic level of noribogaine or phar one or more molecules of water in the formed crystal, and thus maceutical salt and/or solvate thereof that is less than the become a hydrate. Even when such hydrates are formed, they therapeutic level described above. For example, the Sub are included in the term "solvate”. Solvate also is meant to therapeutic level of noribogaine may be e.g., 80%, 70%. 60%, include such compositions where another compound or com 50%, 40%, 30%, 20%, or 10% less than a therapeutically plex co-crystallizes with the compound of interest. The term effective amount (e.g., 120 mg) of noribogaine, or any Sub “solvate” as used herein refers to complexes with solvents in value or subrange there between. Sub-therapeutic levels of which noribogaine is reacted or from which noribogaine is noribogaine may coincide with “maintenance amounts of precipitated or crystallized. For example, a complex with noribogaine which are amounts, less than the therapeutically water is known as a “hydrate”. Solvates of noribogaine are effective amount, that provide some attenuation and/or pre within the scope of the invention. It will be appreciated by vention of post-acute withdrawal syndrome in a patient. The those skilled in organic chemistry that many organic com maintenance amount of the compound is expected to be less pounds can exist in more than one crystalline form. For than the therapeutically effective amount. example, crystalline form may vary based on the Solvate used. 0144. As defined herein, a “prophylactically effective Thus, all crystalline forms of noribogaine or the pharmaceu amount of a drug is an amount, typically less than the thera tically acceptable solvates thereofare within the scope of the peutically effective amount, that provides attenuation and/or present invention. prevention of a disease or disorder or symptoms of a disease 0140. “Therapeutically effective amount’ or “therapeutic or disorder in a patient. For example, the prophylactically amount refers to an amount of a drug or an agent that, when effective amount of the compound is expected to be less than administered to a patient Suffering from a condition, will have the therapeutically effective amount because the level of inhi the intended therapeutic effect, e.g., alleviation, amelioration, bition does not need to be as high in a patient who no longer palliation or elimination of one or more manifestations of the has a disease or disorder or symptoms of a disease or disorder condition in the patient. The therapeutically effective amount (e.g., no longer physically addicted to nicotine). For example, will vary depending upon the patient and the condition being a prophylactically effective amount is preferably 90%, 80%, treated, the weight and age of the subject, the severity of the 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a thera condition, the salt, Solvate, or derivative of the active drug peutically effective amount. However, a prophylactically portion chosen, the particular composition or excipient cho effective amount may be the same as the therapeutically sen, the dosing regimen to be followed, timing of administra effective amount, for example when a patient who is physi tion, the manner of administration and the like, all of which cally addicted to nicotine is administered noribogaine to can be determined readily by one of ordinary skill in the art. attenuate cravings for a period of time when nicotine use is The full therapeutic effect does not necessarily occur by not feasible. The prophylactically effective amount may vary administration of one dose, and may occur only after admin for different a diseases or disorders or symptoms of different istration of a series of doses. Thus, a therapeutically effective diseases or disorders. amount may be administered in one or more administrations. (0145 As defined herein, a “maintenance amount of a For example, and without limitation, a therapeutically effec drug or an agent is an amount, typically less than the thera tive amount of noribogaine, in the context of treating pain, peutically effective amount that provides attenuation and/or refers to an amount of noribogaine that provides immediate prevention of syndrome disease or disorder or symptoms of a and/or sustained pain relief for at least about 2 hours beyond disease or disorder in a patient. The maintenance amount of US 2015/0258 104 A1 Sep. 17, 2015 the compound is expected to be less than the therapeutically tion. Example injuries that produce cutaneous pain include effective amount because the level of inhibition does not need paper cuts, minor burns (e.g., first degree burns) and Superfi to be as high inapatient who is no longer physically manifests cial lacerations. a disease or disorder or symptoms of a disease or disorder. For 0153. Second, Somatic pain originates from ligaments, example, a maintenance amount is preferably 90%. 80%, tendons, bones, blood vessels, and even nerves themselves, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a thera and is detected with Somatic nociceptors. The scarcity of peutically effective amount, or any Subvalue or Subrange nociceptors in these areas produces a sharp, aching, pain of there between. longer duration than cutaneous pain and somewhat less local 0146 The term "dose” refers to a range of noribogaine, ized. Examples include a sprained ankle or broken bones. noribogaine derivative, or pharmaceutical salt or Solvate 0154) Third, visceral pain originates from body organs. thereofthat provides atherapeutic serum level of noribogaine Visceral nociceptors are located within body organs and inter when given to a patient in need thereof. The dose is recited in nal cavities. Similar to somatic pain, a scarcity of nociceptors a range, for example from 20 mg to 120 mg, and can be in these areas produces a pain usually more aching and of a expressed either as milligrams or as mg/kg body weight. The longer duration than Somatic pain. Visceral pain may be more attending clinician will select an appropriate dose from the difficult to localize. Injuries to visceral tissue may exhibit range based on the patient's weight, age, type and degree of “referred pain, where the sensation is localized to an area pain, health, and other relevant factors, all of which are well completely unrelated to the site of injury. Myocardial within the skill of the art. ischaemia (i.e., the loss of blood flow to a part of the heart 0147 The term “unit dose” refers to a dose of drug that is muscle tissue) is an example of referred pain; the sensation given to the patient to provide therapeutic results, indepen can occur in the upper chest as a restricted feeling, or as an dent of the weight of the patient. In Such an instance, the unit ache in the left shoulder, arm, or hand. Another example of dose is sold in a standard form (e.g., 20 mg tablet). The unit referred pain is phantom limb pain. Phantom limb pain is the dose may be administered as a single dose or a series of sensation of pain from a limb that a person no longer has or Subdoses. In some embodiments, the unit dose provides a from which the person no longer receives physical signals. standardized level of drug to the patient, independent of This phenomena—also known as deafferentation pain is weight of patient. Many medications are sold based on a dose almost universally reported by amputees and quadriplegics. that is therapeutic to all patients based on a therapeutic win 0155 Fourth, neuropathic pain (e.g., “neuralgia”) can dow. In Such cases, it is not necessary to titrate the dosage occur as a result of injury or disease to the nerve tissue itself. amount based on the weight of the patient. The injury or disease can disrupt the ability of the sensory 0148 “Treatment,” “treating,” and “treat are defined as nerves to transmit correct information to the thalamus or acting upon a disease, disorder, or condition with an agent, cortex. Consequently, the brain interprets painful stimuli even Such as noribogaine, to reduce or ameliorate harmful or any though there is no obvious or documented physiologic cause other undesired effects of the disease, disorder, or condition for the pain. and/or its symptoms. “Treatment, as used herein, covers the 0156. Other pain classifications include acute pain and treatment of a human patient, and includes: (a) reducing the chronic pain. Acute pain is defined as short-term pain or pain risk of occurrence of the condition in a patient determined to with an easily identifiable cause. Acute pain indicates present be predisposed to the condition but not yet diagnosed as damage to tissue or disease and may be “fast' and “sharp' having the condition, (b) impeding the development of the followed by aching pain. Acute pain is centralized in one area condition, and/or (c) relieving the condition, i.e., causing before becoming somewhat spread out. Acute pain generally regression of the condition and/or relieving one or more responds well to medications (e.g., morphine). symptoms of the condition. “Treating or “treatment of a 0157 Chronic pain may be medically defined as pain that condition or patient refers to taking steps to obtain beneficial has lasted six months or longer. This constant or intermittent or desired results, including clinical results such as the reduc pain has often outlived its purpose because it does not help the tion of symptoms. For purposes of this invention, beneficial or body to prevent injury. It is often more difficult to treat than desired clinical results include, but are not limited to: pain acute pain. Expert care is generally necessary to treat any pain relief in all categories and classifications of pain; treating, that has become chronic. In addition, stronger medications alleviating and/or preventing acute and/or chronic pain; treat are typically used for extended periods in an attempt to con ing, alleviating and/or preventing cutaneous, Somatic, vis trol the pain. This can lead to drug dependency. For example, ceral and/or neuropathic pain; and preventing the recurrence opioids are used in some instances for prolonged periods to of long-term pain. control chronic pain. Drug tolerance, chemical dependency, 0149. As used herein, the term “patient” refers to mam and even psychological addiction may occur. mals and includes humans and non-human mammals. 0158 “Nociceptive pain” refers to pain that is sensed by 0150. As used herein, the term “QT interval” refers to the nociceptors, which are the nerves that sense and respond to measure of the time between the start of the Q wave and the parts of the body suffering from a damage. The nociceptors end of the T wave in the electrical cycle of the heart. Prolon can signal tissue irritation, impending injury, or actual injury. gation of the QT interval refers to an increase in the QT When activated, they transmit pain signals (via the peripheral interval. nerves as well as the spinal cord) to the brain. Nociceptive 0151. As used herein, the term “pain” refers to the all pain is typically well localized, constant, and often has an categories and classifications of pain, which are summarized aching or throbbing quality. A Subtype of nociceptive pain below for purposes of illustration. includes visceral pain and involves the internal organs. Vis 0152 First, cutaneous pain is caused by injury to the skin ceral paintends to be episodic and poorly localized. Nocice or Superficial tissues. Cutaneous nociceptors terminate just ptive pain may be time limited; when the tissue damage heals, below the skin, and due to the high concentration of nerve the pain typically resolves. However, nociceptive pain related endings, produce a well-defined, localized pain of short dura to arthritis or cancer may not be time limited. Nociceptive US 2015/0258 104 A1 Sep. 17, 2015 pain tends to respond to treatment with opiate analgesics, day. In another embodiment, the therapeutically effective Such as, for example, buprenorphin, codeine, hydrocodone, amount of the compound is from about 0.5 mg to about 1 mg oxycodone, morphine, and the like. Examples of nociceptive per kg body weight per day. The ranges include both extremes pain include, without limitation, pains from sprains, bone as well as any Subranges there between. fractures, burns, bumps, bruises, inflammatory pain from an 0162. In one embodiment, the therapeutically effective infection or arthritic disorder, pains from obstructions, cancer amount of the compound is about 3 mg/kg body weight per pain, and myofascial pain related to abnormal muscle day. In one embodiment, the therapeutically effective amount StreSSes. of the compound is about 2 mg/kg body weight per day. In one 0159) “Neuropathic pain” refers to chronic pain, often due embodiment, the therapeutically effective amount of the to tissue injury. Neuropathic pain is generally caused by compound is about 1.5 mg/kg body weight per day. In one injury or damage to nerve fibers. It may include burning or embodiment, the therapeutically effective amount of the coldness, “pins and needles' sensations, numbness and/or compound is about 1.4 mg/kg body weight per day. In one itching. It may be continuous and/or episodic. Neuropathic embodiment, the therapeutically effective amount of the pain is difficult to treat, but opioids, including, without limi compound is about 1.3 mg/kg body weight per day. In one tation, methadone, tramadol, tapentadol, oxycodone, metha embodiment, the therapeutically effective amount of the done, morphine, levorphanol, and the like. Causes of neuro compound is about 1.2 mg/kg body weight per day. In one pathic pain include, without limitation, alcoholism; embodiment, the therapeutically effective amount of the amputation; back, leg, and hip problems; chemotherapy; dia compound is about 1.1 mg/kg body weight per day. In one betes; facial nerve problems; HIV/AIDS; multiple sclerosis: embodiment, the therapeutically effective amount of the shingles; spine Surgery; trigeminal neuralgia; fibromyalgia; compound is about 1 mg/kg body weight per day. In one and the like. In some cases, the cause of neuropathic pain may embodiment, the therapeutically effective amount of the be unclear or unknown. compound is about 0.9 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the II. Compositions compound is about 0.8 mg/kg body weight per day. In one 0160. As will be apparent to the skilled artisan upon read embodiment, the therapeutically effective amount of the ing this disclosure, this invention provides compositions for compound is about 0.7 mg/kg body weight per day. In one treating pain in a Subject, comprising noribogaine, nori embodiment, the therapeutically effective amount of the bogaine derivatives, prodrugs of noribogaine, pharmaceuti compound is about 0.6 mg/kg body weight per day. In one cally acceptable salts and/or solvates of each thereof. This embodiment, the therapeutically effective amount of the invention further provides compositions for treating, attenu compound is about 0.5 mg/kg body weight per day. In one ating, or preventing symptoms of pain in a Subject, compris embodiment, the therapeutically effective amount of the ing noribogaine, noribogaine derivatives, prodrugs of nori compound is about 0.4 mg/kg body weight per day. In one bogaine, pharmaceutically acceptable salts and/or Solvates of embodiment, the therapeutically effective amount of the each thereof. compound is about 0.3 mg/kg body weight per day. In one 0161 In some embodiments, the composition is formu embodiment, the therapeutically effective amount of the lated for oral, transdermal, internal, pulmonary, rectal, nasal, compound is about 0.2 mg/kg body weight per day. In one vaginal, lingual, intravenous, intraarterial, intramuscular, embodiment, the therapeutically effective amount of the intraperitoneal, intracutaneous or Subcutaneous delivery. In compound is about 0.1 mg/kg body weight per day. one embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 4 mg per kg body Compounds Utilized weight per day. In another embodiment, the therapeutically 0163. In one embodiment, the noribogaine derivative is effective amount of the compound is from about 0.1 mg to represented by Formula I: about 3 mg per kg body weight per day. In another embodi ment, the therapeutically effective amount of the compound is from about 0.1 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 1.5 mg per kg body weight per day. In another embodiment, the therapeuti cally effective amount of the compound is from about 0.1 mg CHCH to about 1 mg per kg body weight per day. In another embodi ment, the therapeutically effective amount of the compound is from about 0.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 2 mg per kg or a pharmaceutically acceptable salt and/or Solvate thereof, body weight per day. In another embodiment, the therapeuti wherein R is hydrogen orahydrolyzable group Such as hydro cally effective amount of the compound is from about 0.5 mg lyzable esters of from about 1 to 12 carbons. to about 1.5 mg per kg body weight per day. In another 0164 Generally, in the above formula, R is hydrogen or a embodiment, the therapeutically effective amount of the group of the formula: compound is from about 0.5 mg to about 1.3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.2 mg per kg body weight per day. In another embodi ment, the therapeutically effective amount of the compound is from about 0.5 mg to about 1.1 mg per kg body weight per US 2015/0258 104 A1 Sep. 17, 2015

wherein X is a C-C group, which is unsubstituted or Sub 0173 m is 0, 1, or 2: stituted. For example, X may be a linear alkyl group Such as methyl, ethyl, n-propyl. n-butyl, n-pentyl, n-hexyl, n-heptyl, 0174 L is a bond or C-C alkylene; n-octyl, n-nonyl, n -decyl. n-undecyl or n-dodecyl, or a (0175 R is selected from the group consisting of hydro branched alkyl group, Such as i-propyl or sec-butyl. Also, X gen, C-C alkyl substituted with 1 to 5 R', C-C alkenyl may be a phenyl group or benzyl group, either of which may substituted with 1 to 5 R', X-R7. —CX' Y), X be substituted with lower alkyl groups or lower alkoxy groups. Generally, the lower alkyl and/or alkoxy groups have R7, -SONR7R, O C(O)R, C(O)OR, C(O) from 1 to about 6 carbons. For example, the group R may be NR7R, NR7R, NHC(O)R’, and NR7C(O)R’; acetyl, propionyl or benzoyl. However, these groups are only (0176) each R is independently selected from the group exemplary. consisting of hydrogen, C-C alkyl, C-C alkenyl, 0.165 Generally, for all groups X, they may either be C-C alkynyl, Co-Co aryl, C-C heteroaryl having 1 unsubstituted or substituted with lower alkyl or lower alkoxy to 4 heteroatoms, and C-C heterocycle having 1 to 4 groups. For example, Substituted X may be o-, m- or p-methyl heteroatoms, and wherein the alkyl, alkenyl, alkynyl, or methoxybenzyl groups. aryl, heteroaryl, and heterocycle are optionally Substi 0166 C-C groups include C-C alkyl, C-C2 tuted with 1 to 5 R': cycloalkyl, C-C aryl, C7-Carylalkyl, wherein C, indi cates that the group contains X carbon atoms. Lower alkyl (0177 X" is selected from the group consisting of O and refers to C-C alkyl and lower alkoxy refers to C-C alkoxy. S; 0167. In one embodiment, the noribogaine derivative is 0.178 Y is C-C alkylene or C-C arylene, or a com represented by Formula II: bination thereof; 0179 n is 1, 2, or 3:

II 0180 R and Rare each independently selected from the group consisting of hydrogen, C-C alkyl option ally substituted with 1 to 5 R', C-C heterocycle hav ing 1 to 4 heteroatoms and which is optionally Substi tuted with 1 to 5 R', C.-Co cycloalkyl optionally substituted with 1 to 5 R', Co-Co aryl optionally sub stituted with 1 to 5R'' and C-C heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R': or a pharmaceutically acceptable salt and/or Solvate thereof, 0181 R is selected from the group consisting of C-C, wherein alkyl optionally substituted with 1 to 5 R', C-C het (0168 r is a single or double bond; erocycle having 1 to 4 heteroatoms optionally Substi (0169) R' is halo, OR, or C-C alkyl optionally sub tuted with 1 to 5 R', C-C cycloalkyl optionally sub stituted with 1 to 5 R': stituted with 1 to 5 R', Co-Co aryl optionally (0170 R is hydrogen or a hydrolysable group selected substituted with 1 to 5R'' and C-C heteroaryl having from the group consisting of C(O)R. —C(O)OR and 1 to 4 heteroatoms optionally substituted with 1 to 5 —C(O)N(R') where each R is selected from the group R10); consisting of C-C alkyl optionally substituted with 1 to 0182) R' is selected from the group consisting of C-C, 5 R', and each R" is independently selected from the alkyl, phenyl, halo, -OR'', CN, -COR'', group consisting of hydrogen, C-C alkyl optionally COR'', C(O)NHR'', NR'R'', C(O) substituted with 1 to 5 R', C-C aryl optionally sub NR'R'', C(O)NHNHR'', C(O)NR''NHR'', stituted with 1 to 5 R', C.-Co cycloalkyl optionally C(O)NR''NR'R'', C(O)NHNRC(O)R'', substituted with 1 to 5R', C.-Coheteroaryl having 1 to C(O)NHNHC(O) R'', SONR'R'', C(O) 4 heteroatoms and which is optionally substituted with 1 to 5 R', C.-Coheterocyclic having 1 to 4 heteroatoms NR''NRC(O)R'', and C(O)NR''NHC(O)R''; and and which is optionally substituted with 1 to 5 R', and 0183) R' is independently hydrogen or C-C alkyl: where each R', together with the nitrogen atom bound thereto form a C-C heterocyclic having 1 to 4 heteroa 0184 provided that: toms and which is optionally substituted with 1 to 5 R' 0185 when L is a bond, then R is not hydrogen; or a C-C heteroaryl having 1 to 4 heteroatoms and 0186 when "" is a double bond, R is an ester hydro which is optionally substituted with 1 to 5 R'; lyzable group, Rand Rare both hydrogen, then-L-R (0171 R is selected from the group consisting of hydro is not ethyl: gen, C-C alkyl optionally substituted with 1 to 5 R', aryl optionally substituted with 1 to 5 R', C(O)R. 0187 when r is a double bond, R is -OH, halo or C(O)NR'R'' and C(O)CR: C-C alkyl optionally substituted with 1 to 5 R', then (0172 R is selected from the group consisting of hydro R" is hydrogen; and gen, -(CH), OR, —CR" (OH)R, -(CH2)CN, 0188 when - is a double bond, R' is OR, R is —(CH2)COR. -(CH2)CO.R. —(CH),C(O) hydrogen, -L-R is ethyl, then R is not a hydrolyzable NR7R, -(C H),C(O)NR'NRR, -(CH),C(O) group selected from the group consisting of an ester, NR'NRC(O)R’, and (CH)NR'R'': amide, carbonate and carbamate. US 2015/0258 104 A1 Sep. 17, 2015

0189 In one embodiment, the noribogaine derivative is (0202 when T is a double bond, R'' is hydrogen, R' represented by Formula III: is O-L-R, O-L-R, O-L-R, and L' is alkylene, then -O-L-R, O-L'-R''. -O-L-R are not methoxy; III 0203 when -" is a double bond, R'' is hydrogen, R is O, L' is C(O)-alkylene. —C(O)-arylene. —C(O)C- arylene. —C(O)O-alkylene. —C(O)NR'-alkylene, or —C(O)NR'-arylene, then none of R', R' or Rare hydrogen. 0204. In one embodiment, the noribogaine derivative is represented by Formula IV: or a pharmaceutically acceptable salt and/or Solvate thereof, wherein (0190. " is a single or double bond; IV (0191) R' is halo, -OH, -SH, -NH, -S(O)N (R'7), R-L-R, R-L-R, R-Li-R20 O R-L-CHR'R'', where R is O, S or NR7; (0192 L' is alkylene, arylene. —C(O)-alkylene, y —C(O)-arylene. —C(O)O-arylene. —C(O)O-alkylene, —C(O)NR'-alkylene, —C(O)NR'-arylene, C(NR')NR'-alkylene or C(NR)NR'-arylene, ls wherein L' is configured such that—O-L'-R' is —OC (O)-alkylene-R', OC(O)C-arylene-R', OC(O) O-alkylene-R', OC(O)-arylene-R', OC(O) NR'-alkylene-R, OC(O)NR'-arylene-R, OC (NRNR-alkylene-R' or OC(NR)NR 0205 or a pharmaceutically acceptable salt and/or solvate arylene-R', and wherein the alkylene and arylene are optionally substituted with 1 to 2 R'; thereof, (0193 R' is hydrogen, -S(O),OR, S(O),R, 0206 wherein C(O)R', C(O)NR'R'', C(O)OR', C-C, 0207 R’ is selected from the group consisting of hydro alkyl optionally substituted with 1 to 5 R', C-C, alkenyl optionally substituted with 1 to 5 R', or aryl gen, a hydrolysable group selected from the group consisting optionally substituted with 1 to 5 R'; of C(O)R’, C(O)NR'R'' and C(O)OR, where R (0194 R'' is hydrogen, halo, -OR'7, CN, C-C, is selected from the group consisting of hydrogen, alkyl, alkyl, C-C alkoxy, aryl or aryloxy, where the alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, alkynyl and alkoxy, aryl, and aryloxy are optionally Substituted with substituted alkynyl, R and Rare independently selected 1 to 5 R; from the group consisting of hydrogen, alkyl, Substituted (0195 each R' is independently selected from the alkyl, alkenyl, Substituted alkenyl, alkynyl, Substituted alky group consisting of hydrogen, C-C2 alkyl, C2-C2 alk nyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, enyl, C-C alkynyl, aryl, heteroaryl, and heterocycle, heterocyclic and substituted heterocyclic, R is selected and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, from the group consisting of alkyl, Substituted alkyl, alkenyl, and heterocycle are optionally substituted with 1 to 5 R16, Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substi (0196) R' is selected from the group consisting of phe tuted aryl, heteroaryl, substituted heteroaryl, heterocyclic and nyl, halo, -OR'7, CN, COR'7, COR'7, substituted heterocyclic, provided that R is not a saccharide NR7R 7, NR7C(O)R'7, NR C(O)NR'7R'7, or an oligosaccharide; C(O)NR''NR7R'7, SONR7R7 and C(O) (0208 L is selected from the group consisting of a cova NR7NR7C(O)R 7: lent bond and a cleavable linker group; (0197) each R'' is independently hydrogen or C-C, alkyl optionally substituted with from 1 to 3 halo; (0209 R’ is selected from the group consisting of hydro (0198 R' is hydrogen, C(O)R’, C(O)OR, gen, alkyl, Substituted alkyl, alkenyl, Substituted alkenyl, C(O)N(R'), or N(R)C(O)R’: R is hydrogen, alkynyl. Substituted alkynyl, aryl, Substituted aryl, cycloalkyl, N(R°), C(O)N(R°), C(NRO)N(R), substituted cycloalkyl, heteroaryl, substituted heteroaryl, het C(NSOR)N(R), NRC(O)N(R), erocyclic, and substituted heterocyclic, provided that R is not NRC(S)N(R), NRC(NRO)N(R), a saccharide or an oligosaccharide; NRC(NSOR)N(R), or tetrazole; and (0210 provided that when L is a covalent bond and R’ is (0199 each R' is independently selected from the hydrogen, then R is selected from the group consisting of group consisting of hydrogen, C-C alkyl and aryl; C(O)NR'R'' and C(O)OR; and (0200 provided that: (0211 further provided that when R is hydrogen or 0201 when "" is a double bond and R'' and R'' are —C(O)R’ and L is a covalent bond, then R’ is not hydro hydrogen, then R' is not hydroxy: gen. US 2015/0258 104 A1 Sep. 17, 2015 15

0212. In one embodiment, the noribogaine derivative is 0226. In one aspect, this invention relates to treatment of represented by Formula V: pain in a patient Suffering from pain comprising administra tion of a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof. 0227. In one aspect, this invention relates to a method for treating pain in a patient Suffering from pain, comprising administering to the patient a dosage of noribogaine, nori bogaine derivative, or pharmaceutically acceptable salt and/ or Solvate thereof that provides an average serum concentra tion of 20 ng/mL to 180 ng/mL, said concentration being Sufficient to inhibit or ameliorate said pain while maintaining a QT interval of less than about 500 ms during said treatment. or a pharmaceutically acceptable salt and/or Solvate thereof, In one embodiment, the concentration is sufficient to inhibit wherein: or ameliorate said pain while maintaining a QT interval pro 0213 4 refers to a single or a double bond provided that longation of less than about 20 ms during said treatment. when a is a single bond, Formula V refers to the corre 0228. In one aspect, this invention relates to a method for sponding dihydro compound; attenuating pain in a human patient, comprising administer 0214) R7 is hydrogen or SOOR: ing to the patient a dosage of noribogaine, noribogaine deriva 0215 R is hydrogen or SOOR: tive, or pharmaceutically acceptable Salt and/or Solvate 0216) R’ is hydrogen or C-C alkyl: thereof that provides an average serum concentration of 20 0217 provided that at least one of R7 and R is not ng/mL to 180 ng/mL said concentration being Sufficient to hydrogen. attenuate said symptoms while maintaining a QT interval of 0218. In one embodiment, the noribogaine derivative is less than about 500 ms during said treatment. In some represented by Formula VI: embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is

VI Sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is Sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. 0229. In one aspect, this invention relates to a method for attenuating pain in a human patient Susceptible to such symp toms, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically or a pharmaceutically acceptable salt and/or Solvate thereof, acceptable salt and/or Solvate thereofthat provides an average wherein: serum concentration of 50 ng/mL to 180 ng/mL, said concen 0219 1 refers to a single or a double bond provided that tration being sufficient to attenuate said symptoms while when 4 is a single bond, Formula VI refers to the corre maintaining a QT interval of less than about 500 ms during sponding vicinal dihydro compound; said treatment. In some embodiments, the concentration is 0220) R' is hydrogen, a monophosphate, a diphosphate or Sufficient to attenuate said symptoms while maintaining a QT a triphosphate; and interval of less than about 470 ms during treatment. Prefer 0221) R' is hydrogen, a monophosphate, a diphosphate or ably, the concentration is Sufficient to attenuate said symp a triphosphate: toms while maintaining a QT interval of less than about 450 0222 provided that both RandR are not hydrogen; ms during treatment. In one embodiment, the concentration is wherein one or more of the monophosphate, diphosphate and Sufficient to attenuate said symptoms while maintaining a QT triphosphate groups of R' and R are optionally esterified interval of less than about 420 ms during treatment. with one or more C-C alkyl esters. 0230. In one aspect, this invention relates to a method for 0223 Noribogaine as utilized herein, can be replaced by a attenuating pain in a human patient Susceptible to such symp noribogaine derivative or a salt of noribogaine or the nori toms, comprising administering to the patient a dosage of bogaine derivative or a Solvate of each of the foregoing. noribogaine, noribogaine derivative, or pharmaceutically 0224. In a preferred embodiment, the compound utilized acceptable salt and/or Solvate thereofthat provides an average herein is noribogaine or a salt thereof. In a more preferred serum concentration of 80 ng/mL to 100 ng/mL, said concen tration being sufficient to attenuate said symptoms while embodiment, the compound utilized herein is noribogaine. maintaining a QT interval of less than about 500 ms during III. Methods of the Invention said treatment. In some embodiments, the concentration is Sufficient to attenuate said symptoms while maintaining a QT 0225. As will be apparent to the skilled artisan upon read interval of less than about 470 ms during treatment. Prefer ing this disclosure, the present invention provides a method ably, the concentration is Sufficient to attenuate said symp for treating pain in a patient by alleviating and/or inhibiting toms while maintaining a QT interval of less than about 450 pain in said patient, comprising administering to the patient a ms during treatment. In one embodiment, the concentration is dosage of noribogaine, noribogaine derivative, or pharma Sufficient to attenuate said symptoms while maintaining a QT ceutically acceptable salt and/or solvate thereof. interval of less than about 420 ms during treatment. US 2015/0258 104 A1 Sep. 17, 2015

0231. In one embodiment, the average serum concentra embodiment, the therapeutically effective amount of the tion of noribogaine is from 50 ng/mL to 180 ng/mL, or 20 compound is about 0.8 mg/kg body weight per day. In one ng/mL to 180 ng/mL. In one embodiment, the average serum embodiment, the therapeutically effective amount of the concentration of noribogaine is from 50 ng/mL to 150 ng/mL, compound is about 0.7 mg/kg body weight per day. In one or 20 ng/mL to 150 ng/mL. In one embodiment, the average embodiment, the therapeutically effective amount of the serum concentration of noribogaine is from 50 ng/mL to 100 compound is about 0.6 mg/kg body weight per day. In one ng/mL, or 20 ng/mL to 100 ng/mL. In one embodiment, the embodiment, the therapeutically effective amount of the average serum concentration of noribogaine is from 80 compound is about 0.5 mg/kg body weight per day. In one ng/mL to 100 ng/mL. The ranges include both extremes as embodiment, the therapeutically effective amount of the well as any Subranges between. compound is about 0.4 mg/kg body weight per day. In one 0232. In one embodiment, the dosage or aggregate dosage embodiment, the therapeutically effective amount of the of noribogaine, noribogaine derivative, or salt and/or Solvate compound is about 0.3 mg/kg body weight per day. In one thereof is from 0.1 mg/kg to 4 mg/kg body weight per day. embodiment, the therapeutically effective amount of the The aggregate dosage is the combined dosage, for example compound is about 0.2 mg/kg body weight per day. In one the total amount of noribogaine, noribogaine derivative, or embodiment, the therapeutically effective amount of the pharmaceutically acceptable salt and/or Solvate thereof compound is about 0.1 mg/kg body weight per day. administered over a 24-hour period where Smaller amounts 0234. In one embodiment, the dosage or aggregate dosage are administered more than once per day. In another embodi of noribogaine or salt or solvate thereof is between 60 mg and ment, the therapeutically effective amount of the compound is 150 mg. In one embodiment, the dosage or aggregate dosage from 0.1 mg to 3 mg per kg body weight per day. In another of noribogaine or salt or solvate thereof is between 70 mg and embodiment, the therapeutically effective amount of the 150 mg. In one embodiment, the dosage or aggregate dosage compound is from 0.1 mg to 2 mg per kg body weight per day. of noribogaine or salt or solvate thereof is between 80 mg and In another embodiment, the therapeutically effective amount 140 mg. In one embodiment, the dosage or aggregate dosage of the compound is from 0.1 mg to 1.5 mg per kg body weight of noribogaine or salt or solvate thereof is between 90 mg and per day. In another embodiment, the therapeutically effective 140 mg. In one embodiment, the dosage or aggregate dosage amount of the compound is from 0.1 mg to 1 mg per kg body of noribogaine or salt or solvate thereof is between 90 mg and weight per day. In another embodiment, the therapeutically 130 mg. In one embodiment, the dosage or aggregate dosage effective amount of the compound is from 0.5 mg to 3 mg per of noribogaine or salt or solvate thereof is between 100 mg kg body weight per day. In another embodiment, the thera and 130 mg. In one embodiment, the dosage or aggregate peutically effective amount of the compound is from 0.5 mg dosage of noribogaine or salt or Solvate thereof is between to 2 mg per kg body weight per day. In another embodiment, 110 mg and 130 mg. the therapeutically effective amount of the compound is from 0235 Inanother embodiment, there is provided a unit dose 0.5 mg to 1.5 mg per kg body weight per day. In another of noribogaine or salt or solvate thereof which is about 120 embodiment, the therapeutically effective amount of the mg per dose. It being understood that the term “unit dose” compound is from 0.5 mg to 1.3 mg per kg body weight per means a dose sufficient to provide therapeutic results whether day. In another embodiment, the therapeutically effective given all at once or serially over a period of time. amount of the compound is from 0.5 mg to 1.2 mg per kg body 0236. In one embodiment, the dosage or aggregate dosage weight per day. In another embodiment, the therapeutically of noribogaine or salt or solvate thereof is between 10 mg and effective amount of the compound is from 0.5 mg to 1.1 mg 100 mg. In one embodiment, the dosage or aggregate dosage per kg body weight per day. In another embodiment, the of noribogaine or salt or solvate thereof is between 50 mg and therapeutically effective amount of the compound is from 0.5 100 mg. In one embodiment, the dosage or aggregate dosage mg to 1 mg per kg body weight per day. In another embodi of noribogaine or salt or solvate thereof is between 60 mg and ment, the therapeutically effective amount of the compound is 100 mg. In one embodiment, the dosage or aggregate dosage from 0.7 mg to 1.5 mg per kg body weight per day. The ranges of noribogaine or salt or solvate thereof is between 60 mg and include both extremes as well as any Subranges there 90 mg. In one embodiment, the dosage or aggregate dosage of between. noribogaine or salt or solvate thereof is between 60mg and 80 0233. In one embodiment, the therapeutically effective mg. In one embodiment, the dosage or aggregate dosage of amount of the compound is about 3 mg/kg body weight per noribogaine or salt or solvate thereof is between 60mg and 70 day. In one embodiment, the therapeutically effective amount ng. of the compound is about 2 mg/kg body weight per day. In one 0237. In some embodiments, the patient is administered embodiment, the therapeutically effective amount of the an initial dose of noribogaine, noribogaine derivative, or compound is about 1.5 mg/kg body weight per day. In one pharmaceutically acceptable salt or solvate thereof, followed embodiment, the therapeutically effective amount of the by one or more additional doses. In one embodiment. Such a compound is about 1.4 mg/kg body weight per day. In one dosing regimen provides an average serum concentration of embodiment, the therapeutically effective amount of the noribogaine of 50 ng/mL to 180 ng/mL. In one embodiment, compound is about 1.3 mg/kg body weight per day. In one the one or more additional doses maintain an average serum embodiment, the therapeutically effective amount of the concentration of 50 ng/mL to 180 ng/mL over a period of compound is about 1.2 mg/kg body weight per day. In one time. embodiment, the therapeutically effective amount of the 0238. In some embodiments, the initial dose of nori compound is about 1.1 mg/kg body weight per day. In one bogaine, noribogaine derivative, or salt or Solvate thereof is embodiment, the therapeutically effective amount of the from about 60 mg to about 120 mg. In some embodiments, the compound is about 1 mg/kg body weight per day. In one initial dose of noribogaine, noribogaine derivative, or salt or embodiment, the therapeutically effective amount of the solvate thereof is from about 75 mg to about 120 mg. In one compound is about 0.9 mg/kg body weight per day. In one embodiment, the initial dose is about 75 mg. In one embodi US 2015/0258 104 A1 Sep. 17, 2015

ment, the initial dose is about 80 mg. In one embodiment, the lower therapeutic dose. In some embodiments, three tapered initial dose is about 85 mg. In one embodiment, the initial doses are given to achieve the desired lower therapeutic dose. dose is about 90 mg. In one embodiment, the initial dose is In some embodiments, four or more tapered doses are given to about 95 mg. In one embodiment, the initial dose is about 100 achieve the desired lower therapeutic dose. Determination of mg. In one embodiment, the initial dose is about 105 mg. In the tapered doses, number of tapered doses, and the like can one embodiment, the initial dose is about 110 mg. In one be readily made a qualified clinician. embodiment, the initial dose is about 115 mg. In one embodi ment, the initial dose is about 120 mg. Maintenance Administration 0239. In some embodiments, the one or more additional 0243 In one aspect, this invention relates to treatment or doses are lower than the initial dose. In one embodiment, the attenuation of post-acute withdrawal from opioids or opioid one or more additional doses are from 5 mg to 50 mg. In one like drug in an addicted patient with a maintenance amount of embodiment, the one or more additional doses may or may noribogaine, noribogaine derivative, or pharmaceutically not comprise the same amount of noribogaine, noribogaine acceptable salt or solvate thereof. derivative, or salt or solvate thereof. In one embodiment, at 0244. In some aspects, this invention relates to a method to least one additional dose is about 5 mg. In one embodiment, prevent relapse of opioid or opioid-like drug abuse in an at least one additional dose is about 10 mg. In one embodi addicted patient treated to ameliorate said abuse, said method ment, at least one additional dose is about 15 mg. In one comprising periodically administering to said patient a main embodiment, at least one additional dose is about 20 mg. In tenance dosage of noribogaine. one embodiment, at least one additional dose is about 25 mg. 0245. In some embodiments, the patient undergoes long In one embodiment, at least one additional dose is about 30 term (e.g., one year or longer) treatment with maintenance mg. In one embodiment, at least one additional dose is about doses of noribogaine, noribogaine derivative, or salt or Sol 35 mg. In one embodiment, at least one additional dose is vate thereof. In some embodiments, the patient is treated for about 40 mg. In one embodiment, at least one additional dose acute withdrawal with therapeutic doses of noribogaine as is about 45 mg. In one embodiment, at least one additional described above, and then the amount of noribogaine is dose is about 50 mg. reduced to maintenance levels after acute withdrawal Symp toms would be expected to have subsided. Acute withdrawal Tapered Dosing symptoms generally are the most pronounced in the first 48 to 0240. In some embodiments, the therapeutic dose of nori 72 hours after cessation of the drug of addiction, although bogaine, noribogaine derivative, or salt or solvate thereofisa acute withdrawal may last as long as a week or more. tapered dosing over a period of time, during which the patient 0246. In some embodiments, the patient is administered a is detoxified, for example, without Suffering significant acute high (therapeutic) dose of noribogaine, noribogaine deriva withdrawal symptoms. Without being bound by theory, it is tive, or pharmaceutically acceptable salt or solvate thereof for believed that tapering will allow the full therapeutic effect of a period of time to ameliorate the most significant withdraw noribogaine with less prolongation of the QT interval. Taper symptoms, and then is administered a lower (maintenance) ing involves administration of one or more Subsequently dose to prevent relapse to opioid or opioid-like drug use. In lower doses of noribogaine over time. For example, in some Some embodiments, the patient is administered a therapeutic embodiments, the first tapered dose is 50% to 95% of the first dose of noribogaine, noribogaine derivative, or pharmaceuti or original dose. In some embodiments, the second tapered cally acceptable salt or solvate thereof for a period of time to dose is 40% to 90% of the first or original dose. In some ameliorate the most significant withdraw symptoms, and then embodiments, the third tapered dose is 30% to 85% of the first is administered a decreasing (tapered) amount of nori or original dose. In some embodiments, the fourth tapered bogaine, noribogaine derivative, or pharmaceutically accept dose is 20% to 80% of the first or original dose. In some able salt or solvate thereof over time until the maintenance embodiments, the fifth tapered dose is 10% to 75% of the first dose is reached. or original dose. 0247. In some embodiments, the maintenance dose of 0241. In some embodiments, the first tapered dose is given noribogaine, noribogaine derivative, or pharmaceutically after the first dose of noribogaine. In some embodiments, the acceptable salt or solvate thereof is 70% of the therapeutic first tapered dose is given after the second, third, or a Subse dose. In some embodiments, the maintenance dose is 60% of quent dose of noribogaine. The first tapered dose may be the therapeutic dose. In some embodiments, the maintenance administered at any time after the previous dose of nori dose is 50% of the therapeutic dose. In some embodiments, bogaine. The first tapered dose can be given once, for the maintenance dose is 40% of the therapeutic dose. In some example, followed by subsequent further tapered doses, or it embodiments, the maintenance dose is 30% of the therapeutic can be given multiple times with or without Subsequent, fur dose. In some embodiments, the maintenance dose is 20% of ther tapered doses (e.g., second, third, fourth, etc. tapered the therapeutic dose. In some embodiments, the maintenance doses), which likewise can be given once or over multiple dose is 10% of the therapeutic dose. administrations, for example. In some embodiments, the first 0248. In some embodiments, the maintenance average tapered dose is administered about one hour, 6 hours, 12 serum level of noribogaine is about 70% of the therapeutic hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after average serum level of noribogaine. In some embodiments, the previous dose of noribogaine. Similarly, second, third, the maintenance average serum level of noribogaine is about fourth, etc. tapered doses, if given, can be given about one 60% of the therapeutic average serum level of noribogaine. In hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 Some embodiments, the maintenance average serum level of hours, or more after the previous dose of noribogaine. noribogaine is about 50% of the therapeutic average serum 0242. In some embodiments, one tapered dose is given to level of noribogaine. In some embodiments, the maintenance achieve the desired lower therapeutic dose. In some embodi average serum level of noribogaine is about 40% of the thera ments, two tapered doses are given to achieve the desired peutic average serum level of noribogaine. In some embodi US 2015/0258 104 A1 Sep. 17, 2015 ments, the maintenance average serum level of noribogaine is dosage or aggregate dosage of noribogaine, noribogaine about 30% of the therapeutic average serum level of nori derivative, or salt or solvate thereof is between about 30 mg bogaine. In some embodiments, the maintenance average and about 100 mg. In one embodiment, the dosage or aggre serum level of noribogaine is about 20% of the therapeutic gate dosage of noribogaine, noribogaine derivative, or salt or average serum level of noribogaine. In some embodiments, solvate thereof is between about 40 mg and about 100 mg. In the maintenance average serum level of noribogaine is about one embodiment, the dosage or aggregate dosage of nori 10% of the therapeutic average serum level of noribogaine. bogaine, noribogaine derivative, or salt or Solvate thereof is 0249. In some embodiments, the maintenance Cmax of between about 50 mg and about 100 mg. In one embodiment, noribogaine is about 70% of the therapeutic Cmax of nori the dosage or aggregate dosage of noribogaine, noribogaine bogaine. In some embodiments, the maintenance Cmax of derivative, or salt or solvate thereof is between about 60 mg noribogaine is about 60% of the therapeutic Cmax of nori and about 100 mg. In one embodiment, the dosage or aggre bogaine. In some embodiments, the maintenance Cmax of gate dosage of noribogaine, noribogaine derivative, or salt or noribogaine is about 50% of the therapeutic Cmax of nori solvate thereof is between about 60 mg and about 90 mg. In bogaine. In some embodiments, the maintenance Cmax of one embodiment, the dosage or aggregate dosage of nori noribogaine is about 40% of the therapeutic Cmax of nori bogaine, noribogaine derivative, or salt or Solvate thereof is bogaine. In some embodiments, the maintenance Cmax of between about 60 mg and about 80 mg. In one embodiment, noribogaine is about 30% of the therapeutic Cmax of nori the dosage or aggregate dosage of noribogaine, noribogaine bogaine. In some embodiments, the maintenance Cmax of derivative, or salt or solvate thereof is between about 60 mg noribogaine is about 20% of the therapeutic Cmax of nori and about 70 mg. bogaine. In some embodiments, the maintenance Cmax of noribogaine is about 10% of the therapeutic Cmax of nori Periodic Dosing bogaine. 0254. In one embodiment, the one or more additional 0250. In some embodiments, the maintenance AUC/24h doses are administered periodically. In one embodiment, the of noribogaine is about 70% of the therapeutic AUC/24 h of one or more additional doses are administered every 4 hours. noribogaine. In some embodiments, the maintenance AUC/ In one embodiment, the one or more additional doses are 24h of noribogaine is about 60% of the therapeutic AUC/24 administered every 6 hours. In one embodiment, the one or h of noribogaine. In some embodiments, the maintenance more additional doses are administered every 8 hours. In one AUC/24 h of noribogaine is about 50% of the therapeutic embodiment, the one or more additional doses are adminis AUC/24 h of noribogaine. In some embodiments, the main tered every 10 hours. In one embodiment, the one or more tenance AUC/24 h of noribogaine is about 40% of the thera additional doses are administered every 12 hours. In one peutic AUC/24 h of noribogaine. In some embodiments, the embodiment, the one or more additional doses are adminis maintenance AUC/24 h of noribogaine is about 30% of the tered every 18 hours. In one embodiment, the one or more therapeutic AUC/24h of noribogaine. In some embodiments, additional doses are administered every 24 hours. In one the maintenance AUC/24h of noribogaine is about 20% of the embodiment, the one or more additional doses are adminis therapeutic AUC/24h of noribogaine. In some embodiments, tered every 36 hours. In one embodiment, the one or more the maintenance AUC/24h of noribogaine is about 10% of the additional doses are administered every 48 hours. therapeutic Cmax AUC/24 h of noribogaine. 0255 In one embodiment, the dosage or aggregate dosage 0251. In one embodiment, the therapeutic dose is tapered of noribogaine, noribogaine derivative, or salt and/or Solvate over time until the desired maintenance dose is reached. For thereof is from 1.3 mg/kg to 4 mg/kg body weight. In one example, in some embodiments, the first tapered dose is 50% embodiment, the dosage or aggregate dosage of noribogaine, to 95% of the therapeutic dose. In some embodiments, the noribogaine derivative, or salt and/or solvate thereof is from second tapered dose is 40% to 90% of the therapeutic dose. In 1.3 mg/kg to 3 mg/kg body weight. In one embodiment, the some embodiments, the third tapered dose is 30% to 85% of dosage or aggregate dosage of noribogaine, noribogaine the therapeutic dose. In some embodiments, the fourth derivative, or salt and/or solvate thereof is from 1.3 mg/kg to tapered dose is 20% to 80% of the therapeutic dose. In some 2 mg/kg body weight. In one embodiment, the dosage or embodiments, the fifth tapered dose is 10% to 75% of the aggregate dosage of noribogaine, noribogaine derivative, or therapeutic dose. In some embodiments, one tapered dose is salt and/or Solvate thereof is from 1.5 mg/kg to 3 mg/kg body given to achieve the maintenance dose. In some embodi weight. In one embodiment, the dosage or aggregate dosage ments, two tapered doses are given to achieve the mainte of noribogaine, noribogaine derivative, or salt and/or Solvate nance dose. In some embodiments, three tapered doses are thereof is from 1.7 mg/kg to 3 mg/kg body weight. In one given to achieve the maintenance dose. In some embodi embodiment, the dosage or aggregate dosage of noribogaine, ments, four or more tapered doses are given to achieve the noribogaine derivative, or salt and/or solvate thereof is from 2 maintenance dose. Determination of the tapered doses, num mg/kg to 4 mg/kg body weight. In one embodiment, the ber of tapered doses, and the like can be readily made a dosage or aggregate dosage of noribogaine, noribogaine qualified clinician. derivative, or salt and/or solvate thereof is from 2 mg/kg to 3 0252. In one embodiment, the QT interval is not prolonged mg/kg body weight. In one embodiment, the dosage or aggre more than about 30 ms. In a preferred embodiment, the QT gate dosage of noribogaine, noribogaine derivative, or salt interval is not prolonged more than about 20 ms. and/or solvate thereof is about 2 mg/kg body weight. The 0253. In one embodiment, the dosage or aggregate dosage ranges include both extremes as well as any Subranges there of noribogaine, noribogaine derivative, or salt or Solvate between. thereof is between about 10 mg and about 100 mg. In one 0256 In one embodiment, the QT interval is not prolonged embodiment, the dosage or aggregate dosage of noribogaine, more than about 50 ms. In one embodiment, the QT interval noribogaine derivative, or salt or solvate thereof is between is not prolonged more than about 40 ms. In one embodiment, about 20 mg and about 100 mg. In one embodiment, the the QT interval is not prolonged more than about 30 ms. In US 2015/0258 104 A1 Sep. 17, 2015

one embodiment, the QT interval is not prolonged more than cal salt and/or Solvate thereof is not monitored in a clinical about 20 ms. In one embodiment, the QT interval is not setting. In one embodiment, a patient receiving noribogaine prolonged more than about 10 ms. treatment is monitored periodically, for example daily, 0257. In some embodiments, the patient is administered weekly, monthly, or occasionally. In one embodiment, the periodically, Such as once, twice, three time, four times or five patient is not monitored. times daily with noribogaine, noribogaine derivative, or a 0263. In one aspect, this invention relates to a method for pharmaceutically acceptable salt and/or Solvate thereof. In treating pain and/or symptoms of pain in a patient, compris Some embodiments, the administration is once daily, or once ing selecting a patient Suffering from pain who is prescreened every second day, once every third day, three times a week, to evaluate the patient’s expected tolerance for prolongation twice a week, or once a week. The dosage and frequency of of QT interval, administering to the patient a dosage of nori the administration depends on the route of administration, bogaine, noribogaine derivative, or pharmaceutically accept dosage, age and body weight of the patient, condition of the able salt and/or Solvate thereofthat provides an average serum patient, without limitation. Determination of dosage and fre concentration of about 50 ng/mL to 180 ng/mL, said concen quency Suitable for the present technology can be readily tration being sufficient to inhibit or ameliorate said abuse or made a qualified clinician. symptoms while maintaining a QT interval of less than about 0258 Noribogaine, noribogaine derivative, or a pharma 500 ms during said treatment. In some embodiments, the ceutically acceptable salt and/or solvate thereof, suitable for concentration is sufficient to attenuate said abuse or symp administration in accordance with the methods provide toms while maintaining a QT interval of less than about 470 herein, can be suitable for a variety of delivery modes includ ms during treatment. Preferably, the concentration is suffi ing, without limitation, oral and transdermal delivery. Com cient to attenuate said abuse or symptoms while maintaining positions suitable for internal, pulmonary, rectal, nasal, vagi a QT interval of less than about 450 ms during treatment. In nal, lingual, intravenous, intra-arterial, intramuscular, one embodiment, the concentration is sufficient to attenuate intraperitoneal, intracutaneous and Subcutaneous routes may said abuse or symptoms while maintaining a QT interval of also be used. Possible dosage forms include tablets, capsules, less than about 420 ms during treatment. pills, powders, aerosols, suppositories, parenterals, and oral 0264. In one embodiment, prescreening of the patient liquids, including Suspensions, solutions and emulsions. Sus comprises ascertaining that noribogaine treatment will not tained release dosage forms may also be used. All dosage result in a maximum QT interval over about 500 ms. In one forms may be prepared using methods that are standard in the embodiment, prescreening of the patient comprises ascertain art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., ing that noribogaine treatment will not result in a maximum A. Oslo editor, Easton Pa. 1980). QT interval over about 470 ms. In one embodiment, pre 0259. In a preferred embodiment, noribogaine, nori screening comprises ascertaining that noribogaine treatment bogaine derivative, or a pharmaceutically acceptable Salt and/ will not result in a maximum QT interval over about 450 ms. or solvate thereof is administered orally, which may conve In one embodiment, prescreening comprises ascertaining that niently be provided in tablet, caplet, Sublingual, liquid or noribogaine treatment will not result in a maximum QT inter capsule form. In certain embodiments, the noribogaine is val over about 420 ms. In one embodiment, prescreening provided as noribogaine HCl, with dosages reported as the comprises determining the patient’s pre-treatment QT inter amount of free base noribogaine. In some embodiments, the val noribogaine HCl is provided in hard gelatin capsules contain 0265. As it relates to pre-screening or pre-selection of ing only noribogaine HCl with no excipients. patients, patients may be selected based on any criteria as determined by the skilled clinician. Such criteria may Patient Pre-Screening and Monitoring include, by way of non-limiting example, pre-treatment QT 0260 Pre-screening of patients before treatment with interval, pre-existing cardiac conditions, risk of cardiac con noribogaine, noribogaine derivative, or pharmaceutical salt ditions, age, sex, general health, and the like. The following and/or Solvate thereof and/or monitoring of patients during are examples of selection criteria for disallowing noribogaine noribogaine treatment may be required to ensure that QT treatment or restricting dose of noribogaine administered to interval is not prolonged beyond a certain value. For example, the patient: high QT interval before treatment (e.g., such that QT interval greater than about 500 ms can be considered there is a risk of the patient’s QT interval exceeding about 500 dangerous for individual patients. Pre-screening and/or ms during treatment); congenital long QT syndrome; brady monitoring may be necessary at high levels of noribogaine cardia; hypokalemia or hypomagnesemia; recent acute myo treatment. Pre-screening of patients may not be necessary at cardial infarction; uncompensated heart failure; and taking lower doses of noribogaine treatment. other drugs that increase QT interval. In some embodiments, 0261. In one embodiment, apatient receiving atherapeutic the methods can include selecting and/or administering/pro dose of noribogaine, noribogaine derivative, or pharmaceuti viding noribogaine to a patient that lacks one more of Such cal salt and/or Solvate thereof is monitored in a clinical set criteria. ting. Monitoring may be necessary to ensure the QT interval 0266. In one embodiment, this invention relates to pre is not prolonged to an unacceptable degree. A “clinical set screening a patient to determine if the patient is at risk for ting refers to an inpatient setting (e.g., inpatient clinic, hos prolongation of the QT interval beyond a safe level. In one pital, rehabilitation facility) or an outpatient setting with fre embodiment, a patient at risk for prolongation of the QT quent, regular monitoring (e.g., outpatient clinic that is interval beyond a safe level is not administered noribogaine. visited daily to receive dose and monitoring). Monitoring In one embodiment, a patient at risk for prolongation of the includes monitoring of QT interval. Methods for monitoring QT interval beyond a safe level is administered noribogaine at of QT interval are well-known in the art, for example by ECG. a limited dosage. 0262. In one embodiment, a patient receiving atherapeutic 0267. In one embodiment, this invention relates to moni dose of noribogaine, noribogaine derivative, or pharmaceuti toring a patient who is administered a therapeutic dose of US 2015/0258 104 A1 Sep. 17, 2015 20 noribogaine, noribogaine derivative, or pharmaceutically can be administered. Delivery vehicles may be intended for acceptable salt and/or solvate thereof. In one embodiment, the administration by oral, inhaled, injected, or any other means. dose of noribogaine, noribogaine derivative, or pharmaceuti 0271 The term “readable medium' as used herein refers cally acceptable salt and/or solvate thereof is reduced if the to a representation of data that can be read, for example, by a patient has one or more adverse side effects. In one embodi human or by a machine. Non-limiting examples of human ment, the noribogaine treatment is discontinued if the patient readable formats include pamphlets, inserts, or other written has one or more adverse side effects. In one embodiment, the forms. Non-limiting examples of machine-readable formats adverse side effect is a QT interval that is prolonged beyond include any mechanism that provides (i.e., Stores and/or a safe level. The determination of a safe level of prolongation transmits) information in a form readable by a machine (e.g., is within the skill of a qualified clinician. a computer, tablet, and/or Smartphone). For example, a machine-readable medium includes read-only memory Kit of Parts (ROM); random access memory (RAM); magnetic disk stor age media; optical storage media; and flash memory devices. 0268 One aspect of this invention is directed to a kit of In one embodiment, the machine-readable medium is a CD parts for the treatment of pain and/or symptoms of post-acute ROM. In one embodiment, the machine-readable medium is and/or chronic pain in a patient, wherein the kit comprises a a USB drive. In one embodiment, the machine-readable composition comprising noribogaine, noribogaine derivative, medium is a Quick Response Code (QR Code) or other matrix or salt and/or Solvate thereof and a means for administering barcode. the composition to a patient in need thereof. The means for 0272. In some aspects, the machine-readable medium administration to a patient can include, for example, any one comprises Software that contains information regarding dos or combination of noribogaine, oranoribogaine derivative, or ing schedules for the unit dose form of noribogaine, nori a pharmaceutically acceptable salt and/or Solvate thereof, a bogaine derivative, or pharmaceutically acceptable salt and/ transdermal patch, a syringe, a needle, an IV bag comprising or Solvate thereof and optionally other drug information. In the composition, a vial comprising the composition, an Some embodiments, the software may be interactive, Such inhaler comprising the composition, etc. In one embodiment, that the attending clinician or other medical professional can the kit of parts further comprises instructions for dosing and/ enter patient information. In a non-limiting example, the or administration of the composition. medical professional may enter the weight and sex of the 0269. In some aspects, the invention is directed to a kit of patient to be treated, and the Software program provides a parts for administration of noribogaine, noribogaine deriva recommended dosing regimen based on the information tive, or pharmaceutically acceptable Salt and/or Solvate entered. The amount and timing of noribogaine recom thereof, the kit comprising multiple delivery vehicles, mended to be delivered will be within the dosages that result wherein each delivery vehicle contains a discrete amount of in the serum concentrations as provided herein. noribogaine, noribogaine derivative, or pharmaceutically 0273. In some embodiments, the kit of parts comprises acceptable salt and/or solvate thereof and further wherein multiple delivery vehicles in a variety of dosing options. For each delivery vehicle is identified by the amount of nori example, the kit of parts may comprise pills or tablets in bogaine, noribogaine derivative, or pharmaceutically accept multiple dosages, such as 240 mg, 120 mg. 90 mg, 60 mg, 30 able salt and/or solvate thereof provided therein; and option mg, 20 mg, 10 mg, and/or 5 mg of noribogaine, noribogaine ally further comprising a dosing treatment schedule in a derivative, or pharmaceutically acceptable salt and/or Solvate readable medium. In some embodiments, the dosing treat thereof per pill. Each pill is labeled such that the medical ment schedule includes the amount of noribogaine, nori professional and/or patient can easily distinguish different bogaine derivative, or pharmaceutically acceptable salt and/ dosages. Labeling may be based on printing or embossing on or Solvate thereof required to achieve each average serum the pill, shape of the pill, color of pill, the location of the pill level is provided. In some embodiments, the kit of parts in a separate, labeled compartment within the kit, and/or any includes a dosing treatment schedule that provides an attend other distinguishing features of the pill. In some embodi ing clinician the ability to select a dosing regimen of nori ments, all of the delivery vehicles within a kit are intended for bogaine, noribogaine derivative, or pharmaceutically accept one patient. In some embodiments, the delivery vehicles able salt and/or solvate thereof based on the sex of the patient, within a kit are intended for multiple patients. mass of the patient, and the serum level that the clinician 0274. One aspect of this invention is directed to a kit of desires to achieve. In some embodiments, the dosing treat parts for the treatment of pain, including symptoms of post ment schedule further provides information corresponding to acute and chronic pain in a patient, wherein the kit comprises the Volume of blood in a patient based upon weight (or mass) a unit dose form of noribogaine, noribogaine derivative, or and sex of the patient. In an embodiment, the storage medium salt and/or solvate thereof. The unit dose form provides a can include an accompanying pamphlet or similar written patient with an average serum level of noribogaine of from information that accompanies the unit dose form in the kit. In about 50 ng/mL to about 180 ng/mL or about 60 ng/mL to an embodiment, the storage medium can include electronic, about 180 ng/mL. optical, or other data storage. Such as a non-volatile memory, 0275. In some embodiments, the unit dose form comprises for example, to store a digitally-encoded machine-readable one or multiple dosages to be administered periodically, Such representation of Such information. as once, twice, three time, four times or five time daily with (0270. The term “delivery vehicle' as used herein refers to noribogaine, noribogaine derivative, or pharmaceutically any formulation that can be used for administration of nori acceptable salt and/or Solvate thereof, or its prodrug. In some bogaine, noribogaine derivative, or pharmaceutically accept embodiments, the administration is once daily, or once every able salt and/or solvate thereof to a patient. Non-limiting, second day, once every third day, three times a week, twice a exemplary delivery vehicles include caplets, pills, capsules, week, or once a week. The dosage and frequency of the tablets, powder, liquid, or any other form by which the drug administration depends on criteria including the route of US 2015/0258 104 A1 Sep. 17, 2015 administration, content of composition, age and body weight maceutically acceptable salt and/or solvate thereof is suffi of the patient, condition of the patient, sex of the patient, cient to provide an average serum concentration of 80 ng/mL without limitation, as well as by the severity of the addiction. to 100 ng/mL when administered to a patient. Determination of the unit dose form providing a dosage and 0282. In some embodiments, the unit dose of unit dose of frequency Suitable for a given patient can readily be made by noribogaine, noribogaine derivative, or pharmaceutically a qualified clinician. acceptable salt and/or solvate thereof, wherein the amount of 0276. In some embodiments, the initial unit dose and one noribogaine, noribogaine derivative, or pharmaceutically or more additional doses of noribogaine, noribogaine deriva acceptable salt and/or solvate thereof is sufficient to provide tive, or salt or solvate thereofare provided as one or multiple an average serum concentration of about 20 ng/mL to about dosages to be administered periodically, such as once, twice, 180 ng/mL administered to a patient. In a preferred embodi three times, four times or five times daily with noribogaine or ment, the amount of noribogaine, noribogaine derivative, or its prodrug. In some embodiments, the administration is once pharmaceutically acceptable salt and/or Solvate thereof is daily, or once every second day, once every third day, three Sufficient to provide an average serum concentration of about times a week, twice a week, or once a week. The dosage and 80 ng/mL to about 100 ng/mL when administered to a patient. frequency of the administration depends on criteria including 0283. In some embodiments, the unit dose of noribogaine, the route of administration, content of composition, age and noribogaine derivative, or pharmaceutically acceptable salt body weight of the patient, condition of the patient, sex of the and/or Solvate thereof is administered in one or more dosings. patient, without limitation, as well as by the severity of the 0284. In one embodiment, the amount of noribogaine is addiction. Determination of the unit dose form providing a Sufficient to provide an average serum concentration of nori dosage and frequency Suitable for a given patient can readily bogaine from about 50 ng/mL to about 180 ng/mL, or about be made by a qualified clinician. 60 ng/mL to about 180 ng/mL. In one embodiment, the 0277. In one aspect, provided herein is a kit of parts com amount of noribogaine is Sufficient to provide an average prising two or more doses of noribogaine, noribogaine deriva serum concentration of noribogaine from about 50 ng/mL to tive, or pharmaceutically acceptable salt or Solvate thereof, about 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In wherein the two or more doses comprise an amount of nori one embodiment, the amount of noribogaine is sufficient to bogaine, noribogaine derivative, or pharmaceutically accept provide an average serum concentration of noribogaine from able salt or solvate thereof that is sufficient to maintain a about 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to serum concentration of 50 ng/mL to 180 ng/mL when admin about 120 ng/mL. In one embodiment, the amount of nori istered to a patient. bogaine is Sufficient to provide an average serum concentra 0278. In one embodiment, one dose comprises an initial tion of noribogaine from about 50 ng/mL to about 100 ng/mL, dose of noribogaine, noribogaine derivative, or pharmaceuti or about 60 ng/mL to about 100 ng/mL. In one embodiment, cally acceptable salt or Solvate thereof, said initial dose being the amount of noribogaine is Sufficient to provide an average Sufficient to achieve a therapeutic serum concentration when serum concentration of noribogaine from 50 ng/mL to 150 administered to a patient; and ng/mL, or 20 ng/mL to 150 ng/mL. In one embodiment, the 0279 at least one additional dose, said additional dose amount of compound is Sufficient to provide an average Sufficient to maintain atherapeutic serum concentration when serum concentration of noribogaine from 50 ng/mL to 100 administered to a patient, wherein the therapeutic serum con ng/mL, or 20 ng/mL to 100 ng/mL. In one embodiment, the centration is between 50 ng/mL and 180 ng/mL. In another amount of noribogaine is Sufficient to provide an average embodiment, the initial dose is from 75 mg to 120 mg. In serum concentration of noribogaine from 80 ng/mL to 100 another embodiment, the at least one additional dose is from ng/mL. The ranges include both extremes as well as any 5 mg to 25 mg. Subranges between. 0280. These dose ranges may beachieved by transdermal, 0285. In one embodiment, the amount of noribogaine is oral, or parenteral administration of noribogaine, noribogaine Sufficient to provide an average serum concentration of nori derivative, orpharmaceutically acceptable salt and/or Solvate bogaine from about 50 ng/mL to about 150 ng/mL, or about thereof in unit dose form. Such unit dose form may conve 20 ng/mL to about 150 ng/mL. In one embodiment, the niently be provided in transdermal patch, tablet, caplet, liquid amount of compound is Sufficient to provide an average or capsule form. In certain embodiments, the noribogaine is serum concentration of noribogaine from about 50 ng/mL to provided as noribogaine HCl, with dosages reported as the about 100 ng/mL, or about 20 ng/mL to about 100 ng/mL. In amount of free base noribogaine. In some embodiments, the one embodiment, the amount of noribogaine is sufficient to noribogaine HCl is provided in hard gelatin capsules contain provide an average serum concentration of noribogaine from ing only noribogaine HCl with no excipients. In some about 80 ng/mL to about 100 ng/mL. The ranges include both embodiments, noribogaine is provided in Saline for intrave extremes as well as any Subranges between. nous administration. 0286. In some embodiments, the initial unit dose of nori Formulations bogaine, noribogaine derivative, or pharmaceutically accept able salt or solvate thereof is from about 50 mg to about 120 0281. This invention further relates to pharmaceutically mg. In one embodiment, the unit dose is about 50 mg. In one acceptable formulations comprising a unit dose of nori embodiment, the unit dose is about 55 mg. In one embodi bogaine, noribogaine derivative, or pharmaceutically accept ment, the unit dose is 60 mg. In one embodiment, the unit dose able salt and/or solvate thereof, wherein the amount of nori is about 65 mg. In one embodiment, the unit dose is about 70 bogaine, noribogaine derivative, or pharmaceutically mg. In one embodiment, the unit dose is about 75 mg. In one acceptable salt and/or solvate thereof is sufficient to provide embodiment, the unit dose is about 80 mg. In one embodi an average serum concentration of 20 ng/mL to 180 ng/mL ment, the unit dose is about 85 mg. In one embodiment, the when administered to a patient. In a preferred embodiment, unit dose is about 90 mg. In one embodiment, the unit dose is the amount of noribogaine, noribogaine derivative, or phar about 95 mg. In one embodiment, the unit dose is about 100 US 2015/0258 104 A1 Sep. 17, 2015 22 mg. In one embodiment, the unit dose is 105 mg. In one three times a week, twice a week, or once a week. The dosage embodiment, the unit dose is about 110 mg. In one embodi and frequency of the administration depends on the route of ment, the unit dose is about 115 mg. In one embodiment, the administration, content of composition, age and body weight unit dose is about 120 mg. of the patient, condition of the patient, without limitation. 0287. In some embodiments, the at least one additional Determination of dosage and frequency Suitable for the dose of noribogaine, noribogaine derivative, or pharmaceuti present technology can be readily made a qualified clinician. cally acceptable salt or solvate thereof is from 5 mg to 75 mg. 0293. In some embodiments, the formulation designed for In one embodiment, the unit dose is 5 mg. In one embodi administration in accordance with the methods provide ment, the unit dose is 10 mg. In one embodiment, the unit dose herein can be suitable for a variety of delivery modes includ is 15 mg. In one embodiment, the unit dose is 20 mg. In one ing, without limitation, oral and transdermal delivery. Formu embodiment, the unit dose is 25 mg. In one embodiment, the lations Suitable for internal, pulmonary, rectal, nasal, vaginal, unit dose is 30 mg. In one embodiment, the unit dose is 35 mg. lingual, intravenous, intra-arterial, intramuscular, intraperito In one embodiment, the unit dose is 40 mg. In one embodi neal, intracutaneous and Subcutaneous routes may also be ment, the unit dose is 45 mg. In one embodiment, the unit dose used. Possible formulations include tablets, capsules, pills, is 50 mg. In one embodiment, the unit dose is 55 mg. In one powders, aerosols, Suppositories, parenterals, and oral liq embodiment, the unit dose is 60 mg. In one embodiment, the uids, including Suspensions, solutions and emulsions. Sus unit dose is 65 mg. In one embodiment, the unit dose is 70 mg. tained release dosage forms may also be used. All formula In one embodiment, the unit dose is 75 mg. tions may be prepared using methods that are standard in the 0288. In some embodiments, the formulation comprises a art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., delivery vehicle, as described above. In one embodiment, the A. Oslo editor, Easton Pa. 1980). delivery vehicle comprises 5 mg to 120 mg noribogaine, noribogaine derivative, orpharmaceutically acceptable salt or 0294. In a preferred embodiment, the formulation is designed for oral administration, which may conveniently be solvate thereof. provided in tablet, caplet, Sublingual, liquid or capsule form. 0289. In some embodiments, the formulation is a con trolled release formulation. The term “controlled release for In certain embodiments, the noribogaine is provided as nori mulation' includes Sustained release and time-release formu bogaine HCl, with dosages reported as the amount of free lations. Controlled release formulations are well-known in base noribogaine. In some embodiments, the noribogaine the art. These include excipients that allow for sustained, HCl is provided in hard gelatin capsules containing only periodic, pulse, or delayed release of the drug. Controlled noribogaine HCl with no excipients. release formulations include, without limitation, embedding 0295 Noribogaine or a noribogaine derivative can also be of the drug into a matrix: enteric coatings; micro-encapsula used in conjunction with any of the vehicles and excipients tion; gels and hydrogels; implants; transdermal patches; and commonly employed in pharmaceutical preparations, e.g., any other formulation that allows for controlled release of a talc, gum Arabic, lactose, starch, magnesium Stearate, cocoa drug. butter, aqueous or non-aqueous solvents, oils, paraffin deriva 0290. In some embodiments, the unit dose of noribogaine, tives, glycols, etc. Coloring and flavoring agents may also be noribogaine derivative, orpharmaceutically acceptable salt or added to preparations, particularly to those for oral adminis solvate thereof is from 20 mg to 120 mg. In one embodiment, tration. Solutions can be prepared using water or physiologi the unit dose is 20 mg. In one embodiment, the unit dose is 30 cally compatible organic solvents such as ethanol, 1,2-propy mg. In one embodiment, the unit dose is 40 mg. In one lene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, embodiment, the unit dose is 50 mg. In one embodiment, the triglycerides, partial esters of glycerine and the like. unit dose is 60 mg. In one embodiment, the unit dose is 70 mg. Parenteral compositions containing noribogaine may be pre In one embodiment, the unit dose is 80 mg. In one embodi pared using conventional techniques that may include sterile ment, the unit dose is 90 mg. In one embodiment, the unit dose isotonic saline, water, 1,3-butanediol, ethanol. 1,2-propylene is 100 mg. In one embodiment, the unit dose is 110 mg. In one glycol, polyglycols mixed with water, Ringer's Solution, etc. embodiment, the unit dose is 120 mg. 0296. The compositions utilized herein may be formu 0291. In some embodiments, the unit dose of noribogaine, lated for aerosol administration, particularly to the respira noribogaine derivative, orpharmaceutically acceptable salt or tory tract and including intrapulmonary or intranasal admin solvate thereof is from about 20 mg to about 120 mg. In one istration. The compound will generally have a small particle embodiment, the unit dose is about 20 mg. In one embodi size, for example of the order of 5 microns or less. Such a ment, the unit dose is about 30 mg. In one embodiment, the particle size may be obtained by means known in the art, for unit dose is about 40 mg. In one embodiment, the unit dose is example by micronization. The active ingredient may be pro about 50 mg. In one embodiment, the unit dose is about 60 vided in a pressurized pack with a suitable propellant Such as mg. In one embodiment, the unit dose is about 70 mg. In one a chlorofluorocarbon (CFC), (for example, dichlorodifluo embodiment, the unit dose is about 80 mg. In one embodi romethane, trichlorofluoromethane, or dichlorotetrafluoroet ment, the unit dose is about 90 mg. In one embodiment, the hane), carbon dioxide or other suitable gases. The aerosol unit dose is about 100 mg. In one embodiment, the unit dose may conveniently also contain a surfactant such as lecithin. is about 110 mg. In one embodiment, the unit dose is about The dose of drug may be controlled by a metered valve. 120 mg. Alternatively, the active ingredients may be provided in the 0292. In some embodiments, the formulation is designed form of a dry powder, for example a powder mix of the for periodic administration, such as once, twice, three time, compound in a suitable powder base Such as lactose, starch, four times or five time daily with noribogaine, noribogaine starch derivatives such as hydroxypropylmethylcellulose and derivative, or a pharmaceutically acceptable salt and/or sol polyvinylpyrrolidine. In some embodiments, the powder car vate thereof. In some embodiments, the administration is rier will form a gel in the nasal cavity. The powder composi once daily, or once every second day, once every third day, tion may be presented in unit dose form, for example in US 2015/0258 104 A1 Sep. 17, 2015 capsules or cartridges, gelatin or blisterpacks, from which the 0302 Blood was obtained for pharmacokinetic assess powder may be administered by means of an inhaler. ments pre-dose and then at 0.25, 0.5,0.75, 1.0, 1.25, 1.5, 2. 0297. The compositions utilized herein may be formu 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 14, 18, 24, 30, 36, 48, lated for Sublingual administration, for example as Sublingual 60, 72, 96, 120, 168 and 216 hours post-dose. Samples were tablets. Sublingual tablets are designed to dissolve very rap centrifuged and plasma stored at -70° C. until analyzed. idly. The formulations of these tablets contain, in addition to Block 24 hour urine collections were obtained following the drug, a limited number of soluble excipients, usually study drug administration for the 30 and 60 mg cohorts. lactose and powdered Sucrose, but sometimes dextrose and Aliquots were frozen at -20°C. until analyzed. mannitol. 0303 Pulse oximetry and capnography data were col 0298. It has been discovered that noribogaine has a bitter lected continuously using a GE Carescape B650 monitoring taste to at least Some patients. Accordingly, compositions for system from 2 hours prior to dosing and until six hours after oral use (including Sublingual, inhaled, and other oral formu dosing, and thereafter at 12, 24, 48 and 72 hours post-dosing. lations) may be formulated to utilize taste-masking technolo Additional oximetry data were collected at 120, 168 and 216 gies. A number of ways to mask the taste of bitter drugs are hours. Pupillary miosis was assessed by pupillometry. Dark known in the art, including addition of Sugars, flavors, Sweet adapted pupil diameter was measured in triplicate using a eners, or coatings; use of lipoproteins, Vesicles, and/or lipo Neuroptics PLR-200 pupillometer under standardized light Somes; granulation; microencapsulation; numbing of taste intensity (<5 lux) pre-dose, and at 2, 4, 6, 12, 24, 48,72, 96, buds; multiple emulsion; modification of Viscosity; prodrug 120, 168 and 216 hours post-dosing. or salt formation; inclusion or molecular complexes; ion 0304 Plasma noribogaine concentrations were deter exchange resins; and Solid dispersion. Any method of mask mined in the 3 mg and 10 mg dose groups using a validated, ing the bitterness of the compound of the invention may be sensitive LCMSMS method. Sample preparation involved used. double extraction of basified plasma samples with tert-butyl methyl ether, drying the samples under a stream of nitrogen EXAMPLES and reconstitution of sample with acetonitrile:B.P. water (5:95, V/v) containing 0.1% (v/v) formic acid. The com 0299 The following Examples are intended to further pounds were separated by a 150x2.0 mm Luna 5 um C18 illustrate certain embodiments of the disclosure and are not column and detected with a triple-quadrupole API 4000 or intended to limit its scope. 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Nori Example 1 bogaine-d was used as the internal standard. The precursor production transition values for noribogaine were m/z. 297. Pharmacokinetics and Pharmacodynamics of 6-> 122.3, and for the internal standard noribogaine-d m/z. Noribogaine in Humans 301.1 -> 122.2. Analyst(R) software was used for data acquisi tion and processing. The ratio of the peak area of noribogaine 0300. Thirty-six healthy, drug-free male volunteers, aged to the internal standard noribogaine-d was used for calibra between 18-55 years, were enrolled in and completed the tion and measurement of the unknown concentration of nori study. This was an ascending single-dose, placebo-con bogaine. The lower limit of quantification (LLOQ) was 0.025 trolled, randomized double blind, parallel group study. Mean ng/ml noribogaine. The calibration curve was between 0.025 (SD) age was 22.0 (3.3) years, mean (SD) height was 1.82 and 25.600 ng/ml noribogaine. Mobile phase A was acetoni (0.08) m, and mean (SD) weight was 78.0 (9.2) kg. Twenty trile:B.P. water (5:95, V/v) containing 0.1% (v/v) formic acid, six subjects were Caucasian, 3 were Asian, 1 Maori, 1 Pacific and mobile phase B was acetonitrile:B.P. water (95:5, V/v) Islander, and 5 Other. The protocol for this study was containing 0.1% (v/v) formic acid. Total run time was 6 approved by the Lower South Regional Ethics Committee minutes. Binary flow: Initial concentration was 8% mobile (LRS/12/06/015), and the study was registered with the Aus phase B; hold at 8% mobile phase B for 0.5 minutes and linear tralian New Zealand Clinical Trial Registry (AC rise to 90% mobile phase B over 1.5 minutes; hold at 90% TRN12612000821897). All subjects provided signed mobile phase B for 1 minute and then drop back to 8% mobile informed consent prior to enrollment, and were assessed as phase B over 0.01 minute. Equilibrate system for 3 minutes. suitable to participate based on review of medical history, Total run time was 6 minutes. Within- and between-day assay physical examination, safety laboratory tests, vital signs and precision was <9%, and within- and between-day assay accu ECG. racy was <9%. 0301 Within each dose level, 6 participants were random 0305 Plasma noribogaine concentrations were deter ized to receive noribogaine and 3 to receive placebo, based on mined in the 30 mg and 60 mg dose groups using a validated, a computer-generated random code. Dosing began with the sensitive LCMSMS method. Sample preparation involved lowest noribogaine dose, and Subsequent cohorts received the deproteinization of plasma samples with acetonitrile and next highest dose after the safety, tolerability, and blinded dilution of sample with 0.1% (v/v) formic acid. The com pharmacokinetics of the completed cohort were reviewed and pounds were separated by a 150x2.0 mm Luna 5 um C18 dose-escalation approved by an independent Data Safety column and detected with a triple-quadrupole API 4000 or Monitoring Board. Blinded study drug was administered as a 5000 mass spectrometer using electrospray ionization in capsule with 240 ml of water after an overnight fast of at least positive mode and multiple reaction monitoring. Nori 10 hours. Participants did not receive any food until at least 5 bogaine-d was used as the internal standard. The precursor hours post-dose. Participants were confined to the study site production transition values for noribogaine were m/z. 297. from 12 hours prior to drug administration, until 72 hours 6-> 122.3, and for the internal standard noribogaine-d m/z. post-dose, and there were Subsequent outpatient assessments 301.1 -> 122.2. Analyst(R) software was used for data acquisi until 216 hours post-dose. tion and processing. The ratio of the peak area of noribogaine US 2015/0258 104 A1 Sep. 17, 2015 24 to the internal standard noribogaine-d was used for calibra were used for calibration and measurement of the unknown tion and measurement of the unknown concentration of nori concentration of noribogaine and its glucuronide. Assay bogaine. The LLOQ was 0.50 ng/ml noribogaine. The cali LLOQ was 20.0 ng/ml for noribogaine and 2.0 ng/ml for bration curve was between 0.50 and 256.00 ng/ml noribogaine glucuronide. The calibration curve was between noribogaine. Mobile phase was the same as method A, and 20.0 and 5120.0 ng/ml noribogaine, and 2.0 and 512.0 ng/ml binary flow was also the same as method A. The within- and noribogaine glucuronide. Mobile phases were as described in between-day assay precision was <9%, and the within- and method A, and binary flow as in method C. The within- and between-day assay accuracy was <9%. between-day assay precision was <13%, and within- and 0306 Plasma noribogaine glucuronide concentrations between-day assay accuracy was <12%. were determined in the 30 mg and 60 mg dose groups using a 0308 Noribogaine and noribogaine glucuronide concen validated sensitive LCMSMS method. Sample preparation trations above the limit of quantification were used to calcu involved deproteinization of plasma samples with acetoni late pharmacokinetic parameters using model-independent trile, drying the samples under a stream of nitrogen and recon methods. The maximum plasma concentration (Cmax) and stitution of sample with acetonitrile: B.P. water (5:95, V/v) time to maximum plasma concentration (Tmax) were the containing 0.1% (v/v) formic acid. The compounds were observed values. Plasma concentration data in the post-dis separated by a 150x2.0 mm Luna 5 um C18 column and tribution phase of the plasma concentration-time plot were detected with a triple-quadrupole API 4000 or 5000 mass fitted using linear regression to the formula In C=In Co-t. Kel, spectrometer using electrospray ionization in positive mode where Co was the Zero-time intercept of the extrapolated and multiple reaction monitoring. Noribogaine-da was used terminal phase and Kel was the terminal elimination rate as the internal standard. The precursor-production transition constant. The half-life (t) was determined using the for values for noribogaine glucuronide were m/z, 472.8->297.3, mula t-0.693/Kel. The area under the concentration-time and for the internal standard noribogaine-dam/Z301.1 -> 122. curve (AUC) from time zero to the last determined concen 2. Analyst(R) Software was used for data acquisition and pro tration-time point (tf) in the post distribution phase was cal cessing. The ratio of the peak area of noribogaine glucuronide culated using the trapezoidal rule. The area under the curve to the internal standard noribogaine-d was used for calibra from the last concentration-time point in the post distribution tion and measurement of the unknown concentration of nori phase (Ctf) to time infinity was calculated from AUC.-Ctf/ bogaine glucuronide. The LLOQ was 0.050 ng/ml nori Kel. The concentration used for Ctif was the last determined bogaine glucuronide. The calibration curve was between value above the LLOQ at the time point. The total AUC. 0.050 and 6.400 ng/ml noribogaine glucuronide. Mobile was obtained by adding AUC, and AUC. Noribogaine phases was the same as method A. Binary flow: Initial con apparent clearance (CL/F) was determined using the formula centration was 6% mobile phase B; hold at 6% mobile phase CL/F=Dose/AUCox 1000, and apparent volume of distribu B for 0.5 minutes and linear rise to 90% mobile phase B over tion (Vd/F) was determined using the formula Vd/F=(CL/F)/ 2 minutes; hold at 90% mobile phase B for 1 minute and then Kel. Total urine noribogaine was the sum of both analytes. drop back to 6% mobile phase B over 0.01 minute. Equili 0309 Summary statistics (means, standard deviations, brate system for 3.5 minutes. Total run time was 7 minutes. and coefficients of variation) were determined for each dose The within- and between-day assay precision was <11%, and group for safety laboratory test data, ECG and pharmacoki the within- and between-day assay accuracy was <10%. netic parameters, and pharmacodynamic variables. Categori 0307 Urine noribogaine and noribogaine glucuronide cal variables were analysed using counts and percentages. concentrations were determined in the 30 mg and 60 mg dose Dose-proportionality of AUC and Cmax was assessed using groups using a validated sensitive LCMSMS method. Sample linear regression. The effect of dose on pharmacodynamic preparation involved deproteinization of urine samples with parameter values over time was assessed using two-factor acetonitrile and dilution of the sample with 0.1% (v/v) formic analysis of variance (ANOVA). Pairwise comparisons (with acid. The compounds were separated by a 150x2.0 mm Luna Tukey-Kramer adjustment) between each dose group to the 5 um C18 column and detected with a triple-quadrupole API placebo were conducted at each time point using the least 4000 or 5000 mass spectrometer using electrospray ioniza squares estimates obtained from the ANOVA, using SAS Proc tion in positive mode and multiple reaction monitoring. Nori Mixed (SAS ver 6.0). bogaine-d was used as the internal standard. The precursor production transition values for noribogaine were m/z. 297. Results 6-> 122.3, noribogaine glucuronide m/z, 472.8->297.3, and for the internal standard noribogaine-d m/z 301.1->122.2. 0310 Pharmacokinetics: Mean plasma concentration Analyst(R) Software was used for data acquisition and process time plots of noribogaine are shown in ing. The ratios of the peak area of noribogaine and nori 0311 FIG. 1, and mean pharmacokinetic parameters are bogaine glucuronide to the internal standard noribogaine-d shown in Table 1. TABLE 1 3 mg (n = 6) 10 mg (n = 6) 30 mg (n = 6) 60 mg (n = 6) Noribogaine (mean (SD)) (mean (SD)) (mean (SD)) (mean (SD) AUCo. 74.2 (13.1) 254.5 (78.9) 700.4 (223.3) 1962.2 (726.5) (ng hr/ml) AUCo. 216 72.2 (13.2) 251.4 (78.5) 677.6 (221.1) 1935.4 (725.4) (ng hr/ml) Cmax 5.2 (1.4) 14.5 (2.1) 55.9 (14.8) 116.0 (22.5) (ng ml) US 2015/0258 104 A1 Sep. 17, 2015

TABLE 1-continued 3 mg (n = 6) 10 mg (n = 6) 30 mg (n = 6) 60 mg (n = 6) Noribogaine (mean (SD)) (mean (SD)) (mean (SD)) (mean (SD) Tmax (hr) 1.9 (0.6) 2.9 (1.8) 1.8 (0.6) 2.4 (0.6) to (hr) 40.9 (8.7) 49.2 (11.5) 27.6 (7.0)) 29.1 (9.3) Vd/F(L) 2485.1 (801.5) 3085.8 (1197.0) 1850.8 (707.9) 1416.8 (670.1) CLF (L/h) 41.4 (7.0) 42.3 (12.0) 46.9 (16.4) 34.0 (11.4) Noribogaine glucoronide AUCo. 25.8 (9.3) 67.1 (21.9) (ng hr/ml) AUCo. 216 25.7 (9.1) 65.0 (21.5) (ng hr/ml) Cmax 1.8 (0.6) 4.1 (1.2) (ng/ml) Tmax (hr) 3.0 (0.6) 3.8 (1.2) to (hr) 20.6 (4.9) 23.1 (3.0)

0312 Noribogaine was rapidly absorbed, with peak con- lated dosage of noribogaine free base required to provide a centrations occurring 2-3 hours after oral dosing. Fluctua C. ranging from about 5.2 ng/ml to about 1980 ng/ml and tions in individual distribution-phase concentration-time pro an AUC/24 hr of about 3.1 ng/ml to about 1100 ng/ml was files may suggest the possibility of enterohepatic determined. recirculation (see highlighted individual 4-8 hour profiles in 0319 Pharmacodynamics: There was no evidence of FIG. 1, insert). Both Cmax and AUC increased linearly with pupillary constriction in Subjects dosed with noribogaine. No dose (Table 1, upper panel). Mean half-life estimates of 28-50 between-dose group differences in pupil diameter were hours were observed across dose groups for noribogaine. detected over time. After adjusting for baseline differences, Volume of distribution was extensive (1417-308.6 L across comparison of each dose group with placebo by ANOVA dose groups). showed no statistically significant differences (p-0.9). 0313 Mean plasma noribogaine glucuronide concentra 0320 Noribogaine treatment showed no analgesic effect tion-time plots for the 30 mg and 60 mg dose group are shown in the cold pressor test. Analgesic effect was assessed based in FIG.2, and mean pharmacokinetic parameters are shown in on duration of hand immersion in ice water and on visual Table 1, lower panel. Noribogaine glucuronide was detected analog scale (VAS) pain scores upon hand removal from the in all subjects by 0.75 hours, with peak concentrations occur water bath. For duration of hand immersion, after adjusting ring 3-4 hours after noribogaine dosing. Mean half-life of for baseline differences, comparison of each dose group with 21-23 hours was estimated for plasma noribogaine glucu placebo by ANOVA showed no statistically significant differ ronide. The proportion of noribogaine glucuronide Cmax and ences (p-0.9). Similarly, for VAS pain scores, after adjusting AUC relative to noribogaine was 3-4% for both dose groups. for baseline differences, comparison of each dose group with Total urine noribogaine elimination was 1.16 mg and 0.82 mg placebo by ANOVA showed no statistically significant differ for the 30 mg and 60 mg dose groups respectively, represent ences (p=0.17). ing 3.9% and 1.4% of the doses administered. 0314. The subject mean serum levels over time of nori Example 2 bogaine free base from a single dose of 3 mg noribogaine free base under fasting conditions were plotted. The mean C of Safety and Tolerability of Noribogaine in Healthy 5.2 ng/ml was observed 1.9 hours after administration, while Humans the mean AUC/24 hr of 3.1 ng/ml was obtained. 0321 Safety and tolerability of noribogaine were tested in 0315. The subject mean serum levels over time of nori the group of Volunteers from Example 1. Cold pressor testing bogaine free base from a single dose of 10 mg noribogaine was conducted in 1° C. water according to the method of free base under fasting conditions were plotted. The mean Mitchelletal. (J Pain 5:233-237, 2004) pre-dose, 6, 24, 48,72

C f of 14.5 ng/ml was observed 2.9 hours after administra and 216 hours post-dosing. Safety evaluations included clini tion, while the mean AUC/24 hr of 10.6 ng/ml was obtained. cal monitoring, recording of adverse events (AES), safety 0316 The subject mean serum levels over time of nori laboratory tests, vital signs, ECG telemetry from -2 h to 6 h bogaine free base from a single dose of 30 mg noribogaine after dosing, and 12-lead electrocardiograms (ECGs) up to free base under fasting conditions were plotted. The mean 216 hours post-dosing. C of 55.9 ng/ml was observed between 1.75 hours after administration, while the mean AUC/24 of 29.2 ng/ml was Results obtained. 0322. A total of thirteen adverse events were reported by 0317. The subject mean serum levels over time of nori seven participants (Table 2). Six adverse events were reported bogaine free base from a single dose of 60 mg noribogaine by three participants in the placebo group, five adverse events free base under fasting conditions were plotted. The mean were reported by two Subjects in the 3 mg dose group, and one C of 116 ng/ml was observed between 1.75 hours after adverse event was reported by single Subjects in the 10 mg administration, while the mean AUC/24 ng/ml of 61 was and 30 mg dose groups, respectively. The most common obtained. adverse events were headache (four reports) and epistaxis 0318. The subject mean serum levels over time of nori (two reports). All adverse events were of mild-moderate bogaine free base for all 4 cohorts were plotted. The extrapo intensity, and all resolved prior to study completion. There US 2015/0258 104 A1 Sep. 17, 2015 26 were no changes in vital signs or safety laboratory tests of directed to opioid-dependent participants in a randomized, note. In particular, there were no changes in oximetry or placebo-controlled, double-blind trial, the results show that a capnography, or changes in respiratory rate. There were no therapeutic window can be established for noribogaine. QTcF values >500 msec at any time. One subject dosed with 10 mg noribogaine had a single increase in QTcF of 60 msec 0324. The efficacy of noribogaine in humans was evalu at 24 hours post-dosing. ated in opioid-dependent participants in a randomized, pla cebo-controlled, double-blind trial. Patients had been receiv ing methadone treatment as the opioid substitution therapy, TABLE 2 but were transferred to morphine treatment prior to nori Dose bogaine administration. This was done to avoid negative nori (mg) Mild Moderate Severe bogaine-methadone interactions that are not observed Placebo Blepharitis Epistaxis between noribogaine and morphine. See U.S. application Ser. Bruising No. 14/214,157, filed Mar. 14, 2014 and Ser. No. 14/346,655, Dry Skin filed Mar. 21, 2014, which are incorporated herein by refer Eye pain, nonspecific ence in their entireties. Infection at cannula site 3 Back pain Headache 0325 Three cohorts of nine (9) subjects (6 administered Dizziness Epistaxis noribogaine and 3 administered placebo in each cohort) were Headache evaluated for tolerability, pharmacokinetics, and efficacy. 10 Headache Cohort 1 received a single dose of 60 mg noribogaine or 30 Headache placebo. Cohort 2 received a single dose of 120 mg nori 60 bogaine or placebo. Cohort 3 received a single dose of 180 mg noribogaine or placebo. Treatment was administered 2 hours after last morphine dose and the time to resumption of mor Example 3 phine (opioid substitution treatment, OST) was determined. Few adverse effects of noribogaine were observed in any of Safety, Tolerability, and Efficacy of Noribogaine in the participants, including no hallucinatory effects. Table 3 Opioid-Addicted Humans shows the reported adverse events for each treatment that were not attributable to withdrawal from opioids. Headaches 0323. This example is to illustrate that noribogaine can be were frequent in the placebo and 60 mg noribogaine treatment administered at a therapeutic dosing while maintaining an groups, but were attenuated in the 120 mg and 180 mg dose acceptable QT interval. While the therapy employed is groups. TABLE 3 Treatment Emergent Adverse Events Summary System Organ Class Placebo 60 mg 120 mg 180 mg Preferred Term (N = 9) (N = 6) (N = 6) (N = 6) Number of Subjects Reporting any AEs 19:7 (77.8%) 15:5 (83.3%) 28:6 (100.0%) 17:4 (66.7%) Ear and Labyrinth Disorders O O 2:2 (33.3%) O Tinnitus O O 2:2 (33.3%) O Eye Disorders 2:2 (22.2%) 3:3 (50.0%) 5:5 (83.3%) 5:4 (66.7%) Visual Impairment 2:2 (22.2%) 2:2 (33.3%) 5:5 (83.3%) 5:4 (66.7%) Dry Eye O 1:1 (16.7%) O O Gastrointestinal Disorders 3:2 (22.2%) 2:2 (33.3%) 7:2 (33.3%) 4:2 (33.3%) Nausea :1 (11.1%) O 3:2 (33.3%) 2:2 (33.3%) Dry Mouth O O 1:1 (16.7%) 1:1 (16.7%) Vomiting O O 2:1 (16.7%) 1:1 (16.7%) Diarrhoea :1 (11.1%) O 1:1 (16.7%) O Dyspepsia :1 (11.1%) 2:2 (33.3%) O O General Disorders and Administration Site Conditions 4:3 (33.3%) O 2:2 (33.3%) 1:1 (16.7%) Catheter Site Related Reaction O O O :1 (16.7%) Catheter Site Pain 3:2 (22.2%) O 2:2 (33.3%) O Malaise :1 (11.1%) O O O infections and Infestations :1 (11.1%) O 1:1 (16.7%) 2:2 (33.3%) Cellulitis O O 1:1 (16.7%) 1:1 (16.7%) Urinary Tract Infection O O O :1 (16.7%) Catheter Site Infection :1 (11.1%) O O O Musculoskeletal and Connective Tissue :1 (11.1%) 2:1 (16.7%) O 2:2 (33.3%) Disorders Back Pain :1 (11.1%) 2:1 (16.7%) O :1 (16.7%) Limb Discomfort O O O :1 (16.7%) Nervous System Disorders 7:5 (55.6%) 7:4 (66.7%) 5:4 (66.7%) 3:2 (33.3%) Headache 6:5 (55.6%) 7:4 (66.7%) 2:2 (33.3%) 3:2 (33.3%) Hyperaesthesia O O 1:1 (16.7%) O Pseudoparalysis O O 1:1 (16.7%) Tremor O O 1:1 (16.7%) Somnolence 1:1 (11.1%) O O Psychiatric Disorders 1:1 (11.1%) 1:1 (16.7%) O Depressed Mood O 1:1 (16.7%) O US 2015/0258 104 A1 Sep. 17, 2015 27

TABLE 3-continued Treatment Emergent Adverse Events Summary System Organ Class Placebo 60 mg 120 mg 180 mg Preferred Term (N = 9) (N = 6) (N = 6) (N = 6) Euphoric Mood 1:1 (11.1%) O O O Respiratory, Thoracic and Mediastinal O O 4:2 (33.3%) O Disorders Epistaxis O O 2:1 (16.7%) O Oropharyngeal Pain O O 1:1 (16.7%) O Rhinorrhoea O O 1:1 (16.7%) O Skin and Subcutaneous Tissue Disorders O O 2:1 (16.7%) O Skin Discomfort O O 1:1 (16.7%) O Skin Irritation O O 1:1 (16.7%) O

Note: Within each system organ class, Preferred Terms are presented by descending incidence of descending dosages groups and then the placebo group. Note: N = number of subjects in the safety population.

0326 FIG.3 indicates the average serum noribogaine con cebo. This demonstrates that increasing the dose of nori centration over time after administration of noribogaine for bogaine to 180 mg results in a shorter time to resumption of each cohort (60 mg. diamonds; 120 mg, squares; or 180 mg. OST than observed in patients receiving 120 mg noribogaine. triangles). Further results are detailed in U.S. Provisional Time to resumption of OST after treatment with 180 mg was Patent Application No. 62/023,100, filed Jul. 10, 2014, and still longer than untreated patients (7 hours, not shown) or titled METHODS FOR ACUTE AND LONG-TERM those administered 60 mg noribogaine. TREATMENT OF DRUGADDICTION,” which is incorpo rated herein by reference in its entirety. 0329 Patients were evaluated based on the Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Results Scale (SOWS), and Objective Opiate Withdrawal Scale 0327 Pharmacokinetic results for each cohort are given in (OOWS) scoring systems over the period of time between Table 4. Maximum serum concentration of noribogaine administration of noribogaine (or placebo) until resumption (Cmax) increased in a dose-dependent manner. Time to Cmax of OST. These scales are outlined in Guidelines for the Psy (Tmax) was similar in all three cohorts. Mean half-life of chosocially Assisted Pharmacological Treatment of Opioid serum noribogaine was similar to that observed in healthy Dependence, World Health Organization, Geneva (2009), patients. Annex 10, which is incorporated herein by reference in its TABLE 4 Pharmacokinetic results from the Patients in Phase IB Study Cohort 1 (60 mg) Cohort 2 (120 mg) Cohort 3 (180 mg) Data (meant SD) Data (meant SD) Data (meant SD) PK parameter range range range Cmax (ng/ml) 81.64 - 23.77 172.79 30.73 267.88 46.92 41.29-113.21 138.84-229.55) 204.85-338.21 Tmax (hours) 3.59 0.92 2.99 - 123 4.41 18O 2.50-5.00) 0.98-402 3.00-8.00 AUC of 2018.01 - 613.91 3226.38 - 1544.26 6523.28 2909.8O (ng hr/ml) 1094.46-2533.44 1559.37-5638.98 3716.69-10353.12) AUCo-y 2O60.31 60939 328O.SO 1581.43 6887.67 - 3488.91 (ng hr/ml) 1122.29-2551.63) (1595.84-5768.52) 3734.21-12280.91 Half-life (hrs) 29.32 7.28 30.459.14 23.945.54 18.26-37.33) 21.85-48.33) 19.32-34.90 VdAF 1440.7 - 854.O 2106.43 - 1644.54 1032.19 365.30 619.5-2772.5 824.24-5243.78 581.18-1608.98 CIF 32.14 - 12.38 44.68 - 21.40 31.47 1312 23.51-53.46) 20.80-75.20 14.66-48.20

0328 FIG. 4 indicates the time to resumption of morphine entirety. The scales measure the intensity of withdrawal (OST) for patients treated with placebo (circles), 60 mg nori symptoms, based on clinical, Subjective, and objective indi bogaine (squares), 120 mg noribogaine (triangles), and 180 cia. mg noribogaine (inverted triangles). Patients receiving a 0330 FIG. 5 shows the COWS scores at time of resump single 120 mg dose of noribogaine exhibited an average time tion of OST for each cohort. Box includes values representing to resumption of opioids of greater than 20 hours. Patients 25%-7.5% quartiles. Diamond-median; crossbar in receiving a single 180 mg dose of noribogaine exhibited an box=mean; whiskers=values within standard deviation of average time to resumption of opioids similar to that of pla mid-quartiles. No outliers present. The highly variable US 2015/0258 104 A1 Sep. 17, 2015 28

COWS scores across and within each cohort indicates that or solvate thereof, wherein the initial dose provides an patients were resuming opiates without relation to the inten average serum concentration of 50 ng/mL to 180 ng/mL, sity of withdrawal. This was also reflected in SOWS and and OOWS scores at the time of resumption of OST. b) administering at least one additional dose of nori 0331 FIG. 6A shows the mean change in total COWS bogaine, noribogaine derivative, or pharmaceutically scores over the first six hours following dosing and prior to acceptable salt or solvate thereof, such that the at least resumption of OST. FIG. 6B shows the mean AUC(0-6 hours) one additional dose maintains the average serum con of the COWS total score change from baseline. FIG. 7A centration of 50 ng/mL to 180 ng/mL for a period of shows the mean change in total OOWS scores over the first six time. hours following dosing and prior to resumption of OST FIG. 4. The method of claim 3, wherein the initial dose is from 7B shows the mean AUC(0-6 hours) of the OOWS total score 75 mg to 120 mg. change from baseline. FIG. 8A shows the mean change in 5. The method of claim 3, wherein the at least one addi total SOWS scores over the first six hours following dosing tional dose is from 5 mg to 25 mg. and prior to resumption of OST. FIG. 8B shows the mean 6. The method of claim 3, wherein the at least one addi AUC(0-6 hours) of the SOWS total score change from base tional dose is administered from 6 hours to 24 hours after the line. These data indicate that withdrawal symptoms get worse initial dose. over time after cessation of OST, and that patients adminis 7. The method of claim 3, wherein at least two additional tered placebo experience generally worse withdrawal Symp doses are administered, and further wherein the additional toms over that period. Patients who received 120 mg nori doses are administered from 6 hours to 24 hours after the bogaine generally experienced fewer withdrawal symptoms previous dose. than the other patients, regardless of the scale used. Patients 8. The method of claim 1, further comprising selecting an administered placebo generally experienced more with addicted patient who is prescreened to evaluate tolerance for drawal symptoms than patients who were administered nori prolongation of QT interval. bogaine. 9. The method of claim 1, wherein the aggregate dosage of 0332 Patients’ QT intervals were evaluated at regular time noribogaine, noribogaine derivative, or pharmaceutically points throughout the study. FIG. 9A shows the average acceptable salt or solvate thereof is from 70 mg to 150 mg per change in QT interval (AQTcl, i.e., QT interval prolongation) day. over the first 24 hours post noribogaine (or placebo) admin 10. A method for treating pain in a patient, comprising istration. FIG. 9B shows the estimated correlation between administering to the patient a dosage of noribogaine, nori noribogaine concentration and change in QT interval. There bogaine derivative, or pharmaceutically acceptable salt and/ is a dose-dependent increase in QT interval prolongation that or Solvate thereof that provides an average serum concentra is correlated with the serum concentration of noribogaine. tion of 50 ng/mL to 180 ng/mL, said concentration being 0333 Based on above data, it is believed that the therapeu sufficient to alleviate and/or inhibit said pain while maintain tic window for a single bolus dose of noribogaine is bound at ing a QT interval prolongation of less than about 20 ms during the lower end by 50 mg and at the upper end by less than 180 said treatment. mg. In particular, the therapeutic serum concentration in vivo 11. The method of claim 10, wherein the noribogaine, appears to be between about 50 ng/mL and about 180 ng/mL. noribogaine derivative, orpharmaceutically acceptable salt or Solvate thereof is administered as a single dose or multiple Example 4 doses. 12. The method of claim 11, comprising: Effect of Noribogaine on Treatment of Pain in a) administering an initial dose of noribogaine, nori Humans bogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an 0334. A female patient, age 57, with chronic back pain, is average serum concentration of 50 ng/mL to 180 ng/mL, treated with noribogaine hydrochloride at a dose of about 2 and mg/kg. Her pain level is determined by self-evaluation and b) administering at least one additional dose of nori clinical evaluation. bogaine, noribogaine derivative, or pharmaceutically What is claimed is: acceptable salt or solvate thereof, such that the at least 1. A method for treating pain in a patient, comprising one additional dose maintains the average serum con administering to the patient a dosage of noribogaine, nori centration of 50 ng/mL to 180 ng/mL for a period of bogaine derivative, or pharmaceutically acceptable salt and/ time. or Solvate thereof that provides an average serum concentra 13. The method of claim 12, wherein the initial dose is from tion of 50 ng/mL to 180 ng/mL, said concentration being 75 mg to 120 mg. sufficient to alleviate and/or inhibit said pain while maintain 14. The method of claim 12, wherein the at least one ing a QT interval of less than about 500 ms during said additional dose is from 5 mg to 25 mg. treatment. 15. The method of claim 12, wherein the at least one additional dose is administered from 6 hours to 24 hours after 2. The method of claim 1, wherein the noribogaine, nori the initial dose. bogaine derivative, or pharmaceutically acceptable salt and/ 16. The method of claim 12, wherein at least two additional or Solvate thereof is administered as a single dose or multiple doses are administered, and further wherein the additional doses. doses are administered from 6 hours to 24 hours after the 3. The method of claim 2, comprising: previous dose. a) administering an initial dose of noribogaine, nori 17. A method for alleviating pain symptoms in a human bogaine derivative, or pharmaceutically acceptable salt patient Susceptible to such symptoms, comprising adminis US 2015/0258 104 A1 Sep. 17, 2015 29 tering to the patient a dosage of noribogaine, noribogaine 27. The method of claim 1, wherein the noribogaine deriva derivative, orpharmaceutically acceptable salt and/or Solvate tive is represented by Formula II: thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL (AUC/24 h), said concentration being

Sufficient to attenuate said symptoms while maintaining a QT II interval of less than about 500 ms during said treatment. 18. The method of claim 17, wherein the pain symptoms are due to chronic pain. 19. The method of claim 17, wherein the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or Solvate thereof is administered as a single dose or multiple doses. 20. The method of claim 19, comprising: a) administering an initial dose of noribogaine, nori or a pharmaceutically acceptable salt and/or Solvate bogaine derivative, or pharmaceutically acceptable salt thereof, or solvate thereof, wherein the initial dose provides an wherein average serum concentration of 50 ng/mL to 180 ng/mL, r is a single or double bond; and R" is halo, OR, or C-C alkyloptionally substituted with b) administering at least one additional dose of nori 1 to 5 Ro: bogaine, noribogaine derivative, or pharmaceutically R’ is hydrogen or a hydrolysable group selected from the acceptable salt or solvate thereof, such that the at least group consisting of C(O) R. —C(O)OR and —C(O) one additional dose maintains the average serum con N(RR) where each R is selected from the group con centration of 50 ng/mL to 180 ng/mL for a period of sisting of C-C alkyl optionally substituted with 1 to 5 time. R', and each R7 is independently selected from the 21. The method of claim 20, wherein the initial dose is from group consisting of hydrogen, C-C alkyl optionally 75 mg to 120 mg. substituted with 1 to 5 R', C-C aryl optionally sub 22. The method of claim 20, wherein the at least one stituted with 1 to 5 R', C.-Co cycloalkyl optionally additional dose is from 5 mg to 25 mg. substituted with 1 to 5R', C.-Coheteroaryl having 1 to 23. The method of claim 20, wherein the at least one 4 heteroatoms and which is optionally substituted with 1 additional dose is administered from 6 hours to 24 hours after to 5 R', C.-Coheterocyclic having 1 to 4 heteroatoms the initial dose. and which is optionally substituted with 1 to 5 R', and 24. The method of claim 20, wherein at least two additional where each R', together with the nitrogen atom bound doses are administered, and further wherein the additional thereto form a C-C heterocyclic having 1 to 4 heteroa doses are administered from 6 hours to 24 hours after the toms and which is optionally substituted with 1 to 5 R' previous dose. or a C-Cheteroaryl having 1 to 4 heteroatoms and 25. The method of claim 1, wherein noribogaine or a phar which is optionally substituted with 1 to 5 R': maceutically acceptable salt and/or Solvate thereof is admin R is selected from the group consisting of hydrogen, istered. C-C alkyl optionally substituted with 1 to 5 R', aryl 26. The method of claim 1, wherein the noribogaine deriva optionally substituted with 1 to 5 R', C(O)R. tive is represented by Formula I: C(O)NR'R'' and C(O)CR: R" is selected from the group consisting of hydrogen, —(CH), OR, CR" (OH)R,-(CH2)CN, -(CH) COR. -(CH2)COR. -(CH),C(O)NR'R'', -(CH),C(O)NRNRR, -(CH),C(O)NRNRC (O)R’, and -(CH)NR'R'': CHCH m is 0, 1, or 2: L is a bond or C-C alkylene; R is selected from the group consisting of hydrogen, C-C alkyl substituted with 1 to 5 R', C-C alkenyl substituted with 1 to 5 R', X-R7. —CX' Y), X or a pharmaceutically acceptable salt and/or Solvate R7, SONR7R, O C(O)R’, C(O)CR, C(O) thereof, NR7R, NR7R, NHC(O)R’, and NR7C(O)R’; wherein R is hydrogen or a hydrolyzable group of the each R is independently selected from the group consist formula: ing of hydrogen, C1-C12 alkyl, C2-C2 alkenyl, C2-C2 alkynyl, C-C aryl, C-Cheteroaryl having 1 to 4 het eroatoms, and C-C heterocycle having 1 to 4 heteroa toms, and wherein the alkyl, alkenyl, alkynyl, aryl, het - C-X eroaryl, and heterocycle are optionally substituted with 1 to 5 R: wherein X is an unsubstituted C-C group or a C-C2 X' is selected from the group consisting of O and S; group Substituted by lower alkyl or lower alkoxy groups, Y is C-C alkylene or C-C arylene, or a combination wherein the noribogaine having the hydrolyzable group thereof; hydrolyzes in vivo to form 12-hydroxy ibogamine. n is 1, 2, or 3: US 2015/0258 104 A1 Sep. 17, 2015 30

R" and Rare each independently selected from the group lene-R' or OC(NR)NR'-arylene-R', and consisting of hydrogen, C-C alkyl optionally Substi wherein the alkylene and arylene are optionally substi tuted with 1 to 5 R', C-C heterocycle having 1 to 4 tuted with 1 to 2 R'': heteroatoms and which is optionally substituted with 1 R" is hydrogen, -S(O),OR. -S(O)R’, -C(O)R', to 5R', C.-Co cycloalkyl optionally substituted with 1 —C(O)NR'R''. —C(O)OR', C-C-alkyl option to 5 R', C.-Co aryl optionally substituted with 1 to 5 ally substituted with 1 to 5 R', C-C alkenyl option R" and C-Cheteroaryl having 1 to 4 heteroatoms ally substituted with 1 to 5 R', or aryl optionally sub optionally substituted with 1 to 5 R'; stituted with 1 to 5 R': R is selected from the group consisting of C-C alkyl R" is hydrogen, halo, —OR'7, —CN, C-C alkyl, optionally substituted with 1 to 5R', C.-Cheterocycle C-C alkoxy, aryl or aryloxy, where the alkyl, alkoxy, having 1 to 4 heteroatoms optionally substituted with 1 aryl, and aryloxy are optionally substituted with 1 to 5 to 5R', C.-Co cycloalkyl optionally substituted with 1 R16, to 5 R', Co-Co aryl optionally substituted with 1 to 5 each R" is independently selected from the group consist R'' and C-C heteroaryl having 1 to 4 heteroatoms ing of hydrogen, C1-C12 alkyl, C2-C2 alkenyl, C2-C2 optionally substituted with 1 to 5 R'; alkynyl, aryl, heteroaryl, and heterocycle, and wherein R" is selected from the group consisting of C-C alkyl, the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and hetero phenyl, halo, -OR'', CN, COR'', COR'', cycle are optionally substituted with 1 to 5 R'; C(O)NHR'', NR'R'', C(O)NR'R'', C(O) R" is selected from the group consisting of phenyl, halo, NHNHR'', C(O)NR''NHR'', - C(O) OR'7, CN, COR'7, COR'7, NR7R'7, NR''NR'R'', C(O)NHNRC(O)R'', C(O) NR7C(O)R'7, NR7SOR7, C(O)NR'7R'7, NHNHC(O) R', SONR'R'', C(O)NR''NRC C(O)NR''NR7R'7, SONR7R7 and C(O) (O)R'', and C(O)NR''NHC(O)R''; and NR7NR7C(O)R7; R'' is independently hydrogen or C-C2 alkyl; each R'' is independently hydrogen or C-C alkyl provided that: optionally substituted with from 1 to 3 halo: R" is hydrogen, C(O)R’, C(O)OR, C(O)N when L is a bond, then R is not hydrogen; (R0), or N(R)C(O)R’’: when - is a double bond, R' is an ester hydrolyzable R" is hydrogen, N(R'), C(O)N(R'), C(NR) group, R and Rare both hydrogen, then-L-R is not N(R0), C(NSOR2)N(R°), NRC(O)N(R) ethyl: NRC(S)N(R), NRC(NRN(R), NR when r is a double bond, R is -OH, halo or C-C, or tetrazole; and alkyl optionally substituted with 1 to 5 R', then R is each R' is independently selected from the group consist hydrogen; and ing of hydrogen, C-C alkyl and aryl; when "" is a double bond, R is OR, R is hydrogen, provided that: -L-R is ethyl, then R is not a hydrolyzable group when - is a double bond and RandR'' are hydrogen, Selected from the group consisting of an ester, amide, then R' is not hydroxy: carbonate and carbamate. when is a double bond, R'' is hydrogen, R'' is 28. The method of claim 1, wherein the noribogaine deriva -O-L-R, O-L"-R', -O-L-R, and L' is alky tive is represented by Formula III: lene, then-O-L-R,-O-L-R, O-L'-Rare not methoxy; when T is a double bond, R'' is hydrogen, R is O, L' is III —C(O)-alkylene. —C(O)-arylene. —C(O)O-arylene, —C(O)C)-alkylene. —C(O)NR'-alkylene, or - C(O) NR'-arylene, then none of R. R' or Rare hydro gen. 29. The method of claim 1, wherein the noribogaine deriva tive is represented by Formula IV:

or a pharmaceutically acceptable salt and/or Solvate IV thereof, wherein is a single or double bond; R’ is halo, -OH, -SH, -NH, -S(O)N(R'7), R LR19, R-L-R): R-L -R20 O —R-L"— CHR'R'', where R is O, S or NR7; L' is alkylene, arylene. —C(O)-alkylene. —C(O)-arylene, - C(O)O-arylene, C(O)O-alkylene, -C(O)NR'- alkylene, -C(O)NR'-arylene, C(NR)NR'-alky or a pharmaceutically acceptable salt and/or Solvate lene or -C(NR)NR'-arylene, wherein L' is config thereof, ured such that –O-L'-R' is —OC(O)-alkylene-R', wherein –OC(O)C-arylene-R', –OC(O)O-alkylene-R', R’ is selected from the group consisting of hydrogen, a –OC(O)-arylene-R', OC(O)NR'-alkylene-R', hydrolysable group selected from the group consisting OC(O)NR'-arylene-R, OC(NR)NR'-alky of C(O)R’, C(O)NR'R'' and C(O)OR, US 2015/0258 104 A1 Sep. 17, 2015 31

where R is selected from the group consisting of or a pharmaceutically acceptable salt and/or Solvate hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted thereof, alkenyl, alkynyland substituted alkynyl, RandR are wherein: independently selected from the group consisting of 1 is a single bond or a double bond, provided that when hydrogen, alkyl, Substituted alkyl, alkenyl, Substituted a1 is a single bond, alkenyl, alkynyl. Substituted alkynyl, aryl. Substituted Formula V refers to the corresponding dihydro compound; aryl, heteroaryl, substituted heteroaryl, heterocyclic and R7 is hydrogen or SOOR: substituted heterocyclic, R is selected from the group R’ is hydrogen or SOOR’’: consisting of alkyl, Substituted alkyl, alkenyl, Substi R’ is hydrogen or C-C alkyl: tuted alkenyl, alkynyl. Substituted alkynyl, aryl. Substi tuted aryl, heteroaryl, substituted heteroaryl, heterocy provided that at least one of R7 and R is not hydrogen. clic and substituted heterocyclic, provided that R is not 31. The method of claim 1, wherein the noribogaine deriva a saccharide or an oligosaccharide; tive is represented by Formula VI: L is selected from the group consisting of a covalent bond and a cleavable linker group; R’ is selected from the group consisting of hydrogen, VI alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substituted aryl, cycloalkyl, Substituted cycloalkyl, heteroaryl, Substi tuted heteroaryl, heterocyclic, and substituted heterocy clic, provided that R is not a saccharide or an oligosac charide; provided that when L is a covalent bond and R’ is hydro gen, then R is selected from the group consisting of or a pharmaceutically acceptable salt and/or Solvate C(O)NR'R'' and C(O)OR; and thereof, further provided that when R is hydrogen or—C(O)R’ wherein: and L is a covalent bond, then R’ is not hydrogen. 1 refers to a single or a double bond provided that when 30. The method of claim 1, wherein the noribogaine deriva 21 is a single bond, tive is represented by Formula V: Formula VI refers to the corresponding vicinal dihydro compound; R" is hydrogen, a monophosphate, a diphosphate or a triphosphate; and R" is hydrogen, a monophosphate, a diphosphate or a triphosphate: provided that both R" and R are not hydrogen; wherein one or more of the monophosphate, diphosphate and triphosphate groups of R' and R are optionally esterified with one or more C-C alkyl esters. k k k k k