Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

• This invention is directed to phosphate esters of noribogaine.
• Noribogaine is a metabolite of ibogaine and is sometimes referred to as 12- hydroxyibogaine.
• Noribog can be depicted by the following formula:
• Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non-addictive alkaloid useful in treating drug dependency (U.S. Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737).
• This invention is directed in part to phosphate esters of noribogaine and a vicinal dihydro derivative of noribogaine and compositions thereof.
• the phosphate esters of this invention can be a mono-, di-, or a tri-phosphate or salts thereof. Accordingly, in certain aspects, the phosphate esters of the invention are represented by a compound of Formula I:
• ⁇ refers to a single or a double bond provided that when is a single bond, Formula I refers to the corresponding 9, 17 vicinal dihydro compound;
• R and R 1 are provided that at least one of R and R 1 is not hydrogen:
• one or more of the monophosphate, diphosphate and triphosphate groups of R and R 1 may be an ester, preferably a C ⁇ -C 6 ester, or a salt thereof.
• the compound of Formula II is oxidized back to noribogaine under relatively mild oxidation conditions, such as those existing in vivo and can act as a metered source of noribogaine, particularly, in vivo.
• the 9, 17 dihydro noribogaine and phosphate ester derivatives thereof include the 9a, 17 ⁇ ; 9a, 17a; 9 ⁇ , 17a; and 9 ⁇ , 17 ⁇ stereoisomers.
• this invention provides for a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or II above and at least a pharmaceutically acceptable excipient.
• this invention is directed to a method for treating pain in a patient, which method comprises administering to said patient with a therapeutically effective amount of a compound of Formula I or II above optionally in the presence of at least a pharmaceutically acceptable excipient.
• this invention is directed to a method for treating addiction in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of Formula I or II above optionally in the presence of at least a pharmaceutically acceptable excipient.
• compositions and methods shall mean that the compositions and methods include the recited elements, but not excluding others.
• compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition or method consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
• the invention is directed in part to a phosphate ester of noribogaine and dihydronoribogaie, esters thereof, or pharmaceutically acceptable salts of each thereof.
• noribogaine refers to the compound:
• noribogaine is prepared by demethylation of naturally occurring ibogaine:
• diphosphate refers to the group -P(0)(OH)-OP(0)(OH) 2 .
• triphosphate refers to the group -P(0)(OH)-
• esters As used herein, the term "ester” as it refers to esters of the mono-, di- or
• exemplary esters of the di- or triphosphate can be represented by the formulas -P(0)(OR 2 )-OP(0)(OR 2 ) 2 and -P(0)(OR 2 )-(OP(0)(OR 2 )) 2 OR 2 , where R 2 is as defined above.
• alkyl refers to alkyl groups having from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms and more preferably 1 to 3 carbon atoms.
• the alkyl group may contain linear or branched carbon chains. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like.
• C x alkyl refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C 3 refers to an alkyl group having 3 carbon atoms.
• aryl refers to an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2- benzoxazolinone, 2H- 1 ,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom.
• aryl refers to an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2- benzoxazolinone, 2H- 1 ,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment
• heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur within the ring, wherein the nitrogen and/or sulfur atom(s) of the heteroaryl are optionally oxidized (e.g., N-oxide, -S(O)- or -S(0) 2 -).
• heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
• condensed rings e.g., indolizinyl or benzothienyl
• heteroatom e.g., indolizinyl or benzothienyl
• hetcroaryls include pyridyl, pyrrolyl, indolyl, thiophenyl, and furyl.
• stress or “anxiety” refer to the consequence when a patient fails to respond appropriately to emotional or physical threats, which may be actual or imagined. Stress symptoms or conditions may be cognitive, emotional, physical or behavioral, including, but not limited to a state of alarm and adrenaline production, short- term resistance as a coping mechanism, exhaustion, irritability, muscular tension, inability to concentrate, poor judgment, a general negative outlook, excessive worrying, moodiness, irritability, agitation, inability to relax, feeling lonely, isolated or depressed, aches and pains, diarrhea or constipation, nausea, dizziness, chest pain, headache, rapid heartbeat, eating too much or not enough, sleeping too much or not enough, social withdrawal, procrastination or neglect of responsibilities, increased alcohol, nicotine or drug consumption, and nervous habits such as pacing about or nail-biting. Stress can develop into a disabling disorder of excessive and irrational fears, such as obsessive-compulsive disorder, panic
• the term "protecting group” or "Pg” refers to well known functional groups which, when bound to a functional group, render the resulting protected functional group inert to the reaction to be conducted on other portions of the compound and the corresponding reaction condition, and which can be reacted to regenerate the original functionality under deprotection conditions.
• the identity of the protecting group is not critical and is selected to be compatible with the remainder of the molecule.
• the protecting group is an "amino protecting group” which protects the amino functionality of noribogaine or derivatives thereof during the synthesis described here. Examples of amino protecting groups include, for instance, benzyl, acetyl, oxyacetyl, carbonyloxybenzyl (Cbz), and the like.
• the protecting group is a "hydroxy protecting group” which protects the hydroxyl functionality of noribogaine or a derivative thereof during the
• hydroxy 1 protecting groups include, for instance, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, dialkylsilylethers, such as dimethylsilyl ether, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, and t- butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl: and carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, and benzyl.
• dialkylsilylethers such as dimethylsilyl ether
• trialkylsilyl ethers such as
• the term "therapeutically acceptable amount” refers to the amount of a composition of this invention that is sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment.
• the therapeutically effective amount will vary depending upon the subject and condition being treated, the weight and age of the subject, the severity of the condition, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art.
• treatment means any treatment of a disease or condition in a patient, including:
• the term "addiction” refers to a persistent behavioral pattern marked by physical and/or psychological dependency to a substance, particularly drugs such as narcotics, stimulants, and sedatives, including but not limited to heroin, cocaine, alcohol, nicotine, caffeine, amphetamine, desoxyephedrine, methadone and combinations thereof.
• drugs such as narcotics, stimulants, and sedatives, including but not limited to heroin, cocaine, alcohol, nicotine, caffeine, amphetamine, desoxyephedrine, methadone and combinations thereof.
• the "treatment of addiction in a patient” refers to reducing the withdrawal symptoms associated with drug dependency as well as alleviating drug cravings in addicts. Such symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
• R is selected from the group consisting of hydrogen, a monophosphate, a diphosphate and a triphosphate
• R 1 is hydrogen, a monophosphate, a diphosphate or a triphosphate:
• R and R 1 are provided that at least one of R and R 1 is not hydrogen
• R and R 1 may be an ester, preferably a C 1 -C alkyl ester, or a salt of each thereof.
• R is a monophosphate. In some embodiments, R is a diphosphate. In some embodiments. R is a triphosphate. In some embodiments. R is hydrogen.
• R is a monophosphate and R 1 is hydrogen. In some embodiments, R is a diphosphate and R 1 is hydrogen. In some embodiments, R is a triphosphate and R 1 is hydrogen.
• R is hydrogen or a monophosphate and R 1 is
• R is hydrogen or a diphosphate and R 1 is monophosphate. In some embodiments, R is hydrogen or a triphosphate and R 1 is monophosphate.
• R is hydrogen or a monophosphate and R 1 is triphosphate. In some embodiments, R is hydrogen or a diphosphate and R 1 is triphosphate. In some embodiments, R is hydrogen or a triphosphate and R 1 is triphosphate.
• the compound of Formula I is a compound of Formula I-A:
• ' refers to a single or a double bond provided that when ⁇ is a single bond.
• Formula I-A refers to the corresponding vicinal dih dro compound
• R u ' is hydro
• R" is hydrogen or
• R 10 and R 1 1 are not hydrogen
• each m independently is 0, 1, or 2;
• each n independently is 0, 1 , or 2;
• each R is independently hydrogen, Ci-Cn alkyl, C3-C 10 cycloalkyl, C6-C 14 aryl, heteroaryl of 1 to 10 carbon atoms and 1 to 4 optionally oxidized heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
• ⁇ refers to a double bond. In some embodiments, refers to a single bond.
• R 10 is hydrogen.
• R N is:
• R 1 1 is hydrogen. In some embodiments, R 1 1 is:
• n is 0. In some embodiments, m is 1 . In some embodiments,
• n is 2. In some embodiments, n is 0. In some embodiments,! is 1. In some embodiments, n is 2.
• each R 2 is independently selected from hydrogen or ',, alkyl. In some embodiments, R 2 is hydrogen,
• this invention provides compounds of Formula I-A as tabulated below and pharmaceutically acceptable salts thereof.
• this invention provides a dihydronoribogaine derivative of Formula II:
• the 9,17 dihydro noribogaine and phosphate ester derivatives thereof include the 9a, 17a; 9a, 17 ⁇ ; 9 ⁇ , 17a; and 9 ⁇ , 17 ⁇ stereoisomers.
• the steroisomer is 9a, 17a stereoisomer.
• Noribogaine has properties that are well suited to the treatment of pain and of withdrawal symptoms associated with drug dependency or abuse.
• noribogaine binds to at least two classes of opioid receptors that have been associated with pain relief, the ⁇ and ⁇ receptors.
• the ⁇ -type receptors In the case of the ⁇ -type receptors,
• noribogaine acts as an opiate agonist.
• noribogaine elevates brain serotonin levels by blocking synaptic reuptake. It is believed that such levels (as well as ligand interactions at the ⁇ and ⁇ opiate receptors) play a role in the anxiety and drug cravings experienced by addicts during withdrawal.
• Noribogain is the first ⁇ opioid agonist which demonstrates analgesic properties without the propensity to cause addiction.
• a noribogaine phosphate of Formula I is a novel compound wherein the 12- hydroxyl group and/or the indole N-H of noribogaine is replaced with a biocompatible phosphate group.
• This group including esters and/or salts thereof, exhibit enhanced solubility over noribogaine.
• the phosphate group will hydrolyze in the gastrointestinal tract in a maimer which provides for a titrated release of noribogaine.
• the dihydronoribogaine of Formula II is contemplated to be oxidized, over time, for example under aerobic conditions existing in vivo, to noribogaine.
• a titrated release of noribogaine in accordance with this invention is important in controlling the amount of noribogaine absorbed by the body over a unit period of time.
• Another aspect of this invention is directed to a method for treating pain in a patient.
• the pain can be any type of pain including, but not limited to neuropathic or nociceptive pain, and various types thereof including somatic, visceral and phantom pain.
• the method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. See, for example, U.S. Patent No. 7,220,737 (incorporated herein in its entirety by reference). Treatment of Addiction
• Noribogaine has been known to be used to treat patients for alleviating the symptoms associated with withdrawal from drug dependency. Accordingly, this invention is also directed to a method for treating addiction in a patient, which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. See, for example, U.S. Patent No. 6,348,456 (incorporated herein in its entirety by reference),
• the treatment of addiction in a patient comprises alleviating the symptoms associated with withdrawal from drug dependency.
• symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
• noribogaine treatment decreases the drug gs normally d bv addicts after
• compositions disclosed herein comprising a compound of Formula I are especially useful in the treatment of addiction to narcotics such as heroin and methadone. However, it is also useful in treating patients addicted to cocaine, alcohol, amphetamines and combinations of these drugs.
• PTSD can develop into a disabling disorder of excessive and irrational fears, such as obsessive-compulsive disorder, panic disorder, acute stress disorder and post traumatic stress disorder (PTSD).
• PTSD is a severe stress disorder that can develop after exposure to an event which results in psychological trauma. Such events usually involve death of someone else, threat of death to oneself or to someone else, or trauma to the physical, sexual, or psychological integrity of one's own or someone else.
• PTSD may be an acute stress response or a long term stress response to such an event when it overwhelms one's ability to cope.
• Symptoms of PTSD include some or all of the following: recurrent re-experiencing of the trauma, for example, intrusive, upsetting memories of the event, flashbacks of the traumatic events (acting or feeling like the event is happening again), recurring nightmares (either of the event or of other frightening things); feelings of intense distress and/or intense physical reactions when reminded of the trauma; avoidance to the point of having a phobia of places, people, and experiences that remind the sufferer of the trauma and a general numbing of emotional responsiveness; inability to remember important aspects of the trauma; and physical signs of hyperarousal, including sleep problems, trouble concentrating, irritability, anger, poor concentration, blackouts or difficulty remembering things, increased tendency and reaction to being startled, and hypcrvigilancc to threat.
• Other symptoms include anhedonia, lack of interest in activities that used to be enjoyed, emotional deadness, distancing oneself from people, and/or a sense of a limited future (for example, not being able to think about the future or make future plans, not believing one will live much longer), guilt, shame, self-blame, depression and hopelessness, suicidal thoughts and feelings, feeling alienated and alone, headaches, stomach problems, chest pain and substance abuse.
• NMDA receptors belong to the glutamate receptor family. They are Hgand-gated ion channels permeable to Ca" and Na ions, and are involved in synaptic plasticity, neuronal development, and learning and memory. Long-term
• cAMP and cGMP are involved in a number of intracellular processes such as activation of kinases, signal transduction, gene transcription, and regulation of channel function.
• NMDA signaling pathways also has regulatory effect on the Arc translation, which plays an important role in the consolidation of memory. Bloomer, et al., J. Bio. Chem. 283(1): 582-592 (2008).
• An N- methyl D-aspartate pathway interrupter can be an antagonist or inhibitor of any the receptors, enzymes, ion channels, etc. that are involved in the regulation of synaptic plasticity, neuronal development, and learning and memory in which NMDA receptors play a role.
• the NMDA pathway interrupter is selected from the group consisting of amantadine, dextromethorphan, dextrorphan, ethanol, ketamine, ketobemidone, memantine, methadone, nitrous oxide, phencyclidine, dizocilpine (MK801) and tramadol.
• the NMDA pathway interrupter is cycloserine.
• any route of administration and dosage form may be compatible with the compound and methods discussed above.
• the appropriate dosing regimen and route of administration can be readily determined by the attending clinician.
• a therapeutically effective amount of each of the components of the composition of this invention may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
• the individual components of the composition can be administered separately at different times during the course of therapy or concurrently in divided or single composition forms.
• compositions suitable for oral, intravenous or intraarterial delivery will probably be used most frequently, other routes that may be used include peroral, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes.
• the composition can be administered transdcrmally in which drug is applied as part of a cream, gel, or patch (for examples of transdermal formulations, see U.S. Pat. Nos. 4,806,341 : 5,149,538; and 4,626,539).
• Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids,
• a compound of Formula I may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1 ,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like.
• Parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1 ,3-butanediol, ethanol, 1 ,2- propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
• the dosage required for treating pain may differ from the dosage required for treating addiction, however, the dosing regimen can be readily determined by the attending clinician based on the desired treatment. It is contemplated that for the treatment of pain, the dosage of a compound of Formula I administered to a patient may be from about 0.1 to about 100 mg per kg of body weight and, preferably, from about 0.1 to about 30 mg per kg of body weight. For the treatment of addiction, the dosage administered to a patient may be from about 0.1 to about 20 mg/ml.
• One aspect of this invention is directed to a kit of parts comprising a composition as disclosed herein and a means for administering the composition to a patient in need thereof.
• the means for administration to a patient can include, for example, any one or combination of a syringe, a needle, an IV bag comprising the composition, a vial comprising the composition, etc.
• the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants
• the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
• the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
• many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif, USA), Emka-Chemce or Sigma (St. Louis, Mo., USA). Others may be prepared by procedures, or obvious
• Phosphate sources for the following reactions are generally known reagents or can be prepared by known procedures.
• Scheme 1 shows reaction schemes to phosphorylate the 12 -hydroxyl group and optionally to diphosphorylate the 12-hydroxyl group and the indole nitrogen atom.
• Scheme 2 shows reaction schemes to selectively phosphorylate the indole nitrogen atom by blocking the 12-hydroxyl group with a conventional hydroxyl protecting group.
• a variety of protecting groups arc useful as the Pg. as will be apparent to the skilled artisan.
• the indole nitrogen of noribogaine can be protected, the mono-, di- or tri-phopsphrylation carried out on the hydroxy group of noribogaine, following which, the N-protecling group is deprotected.
• Methods for preparing the N-protected noribogaine will be apparent to the skilled artisan in view of this disclosure.
• X refers to a leaving group such a chloro. bromo, iodo, or a R s -S03-moiety, where R s ia C,-C 6 alkyl optionally subtitucd with 1 -3 fluoro atoms or R s is phenyl optionally substituted with 1 -3 halo or Cj-C6 alkyl groups.
• Compounds of this invention as represented by Formula 1 -1 can be prepared from noribogaine using an appropriate phosphate source, such as phosphoric acid or a
• phosphoramidite such as di-tert-b ty ⁇ ⁇ , ⁇ -diisopropylphosphoramidite.
• Compounds of Formula 1-2 can be prepared from compounds of Formula 1-1 using an appropriate phosphate source under known reaction conditions. The reactions are carried out for a period of time sufficient to provide a substantial amount of the product, which can be ascertained by using routine methods such as thin layer chromatography, 'H-nuclear magnetic resonance (NMR) spectroscopy, and the likes.
• Compounds of Formula 1-1 and 1-2 can be isolated and optionally purified using standard purification techniques, such as liquid chromatography.
• Scheme 2 follows much of the chemistry of Scheme 1 with the exception that a blocking (protecting group - Pg) is used to avoid phosphorylation of the 12 hydro xyl group.
• the dihydronoribogaine compounds of Formulas I, I-A, and II are synthesized by reducing the corresponding double bond of noribogaine.
• Various reducing agents well known to the skilled artisan are useful for this purpose.
• catalytic hydrogenation employing hydrogen and a catalyst such as Pd/C or Pt ' C is useful for providing the 9,17 cis, i.e. the ⁇ , ⁇ or the ⁇ . ⁇ dihydro compounds.
• Reagents such as borohydrtde or aluminum hydrides are useful for providing the ⁇ , ⁇ or the ⁇ , ⁇ dihydro compounds.
• a suppository of total weight 2.5 g is prepared by mixing the compound
• Witepsol® H-15 triglycerides of saturated vegetable fatty acid
• a phosphate ester of noribogaine is given via a microdialysis probe in the right frontal cortex, while a probe in the left cortex serves as a vehicle control site.
• Two dialysate samples are collected over a time period of 1 h before rats are injected with noribogaine. Following drug administration, further samples are collected over the next 2 h.
• the left microdialysis probe is perfused with the respective drug vehicle, e.g. Ringer solution.
• Noribogaine concentrations in dialysate and plasma samples is determined by HPLC with UV detection.
• a 75 kg male patient presents with post traumatic stress disorder.
• the patient is treated with one of the pharmaceutical compositions of Example 2 with 10-100 mg of a NMDA receptor pathway interrupter as determined by the attending clinician.

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• 2012
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