WO2015142346A1 - Procédés et compositions de préparation et de purification de noribogaïne - Google Patents

Procédés et compositions de préparation et de purification de noribogaïne Download PDF

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Publication number
WO2015142346A1
WO2015142346A1 PCT/US2014/031364 US2014031364W WO2015142346A1 WO 2015142346 A1 WO2015142346 A1 WO 2015142346A1 US 2014031364 W US2014031364 W US 2014031364W WO 2015142346 A1 WO2015142346 A1 WO 2015142346A1
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WIPO (PCT)
Prior art keywords
noribogaine
ibogaine
solid support
bound
compound
Prior art date
Application number
PCT/US2014/031364
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English (en)
Inventor
Deborah C. Mash
Richard D. Gless, Jr.
Original Assignee
Demerx, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Demerx, Inc. filed Critical Demerx, Inc.
Priority to PCT/US2014/031364 priority Critical patent/WO2015142346A1/fr
Publication of WO2015142346A1 publication Critical patent/WO2015142346A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • This invention relates generally to methods and compositions for purifying the non- addictive alkaloid noribogaine.
  • Noribogaine is a well known derivative of ibogaine and is sometimes referred to as 12-hydroxyibogaine. It is a metabolite of ibogaine. US Patent No. 2,813,873 claims noribogaine albeit as "12-O-demethylibogame" while providing an incorrect structural formula for ibogaine.
  • the structure of noribogaine has now been thoroughly evaluated and is found to combine the features of tyrptamme, tetrahydrohavaine and indolazepines.
  • Noribogaine 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).
  • noribogaine is prepared by demethylation of naturally occurring ibogaine:
  • Ibogaine possesses hallucinogenic properties. It is a Schedule 1 -controlled substance as provided by the US Food and Drug Administration. Accordingly, methods for preparing nonbogaine from ibogaine require high levels of assurance that contamination with unacceptable levels of ibogaine is avoided. As above, a one-step method for preparation of noribogaine from ibogaine via demethylation does not provide the requisite assurance that ibogaine will consistently be removed as a potential contaminant.
  • This invention provides methods and compositions for the preparation of noribogaine wherein contamination by ibogaine is predictably reduced to acceptable levels, in particular, this invention employs the use of solid supports to effect separation of noribogaine from ibogaine such that any ibogaine contamination is significantly reduced if not essentially eliminated.
  • this invention is directed to a method for preparing and purifying noribogaine which method comprises:
  • this invention is directed to a method for preparing and purifying noribogaine which method comprises:
  • this invention is directed to a solid support having ibogaine or noribogaine covalentiy bound thereto through a cleavable linker,
  • the solid support of this invention comprises ibogaine covalentiy bound thereto through a cleavable linker.
  • the solid support of this invention comprises noribogaine covalentiy bound thereto through a cleavable linker.
  • This invention is directed to methods and compositions comprising noribogaine and, in particular, methods and compositions comprising highly pure noribogaine.
  • the following terras will first be defined.
  • compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose.
  • a composition consisting essentially of the elements as defined herein woul d 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.
  • compositions comprising noribogame and an excipient to facilitate transport across the blood brain barrier.
  • noribogame is prepared by demethylation of naturally occurring ibogaine:
  • Demethylation may be accomplished by conventional techniques such as by reaction with boron
  • diphenylphosphine (preferably an excess thereof), followed by conventional purification.
  • This invention is not limited to any particular chemical form of noribogaine and the compound may be present as either as a free base or as an acceptable addition salt,
  • solid support refers to a materia! having a rigid or semi-rigid surface which contain or can be derivatized to contain reactive functionality which covalently links noribogaine or ibogaine to the surface thereof through a cleavable linker.
  • materials are well known in the art and include, by way of example, silica, synthetic silicates, biogenic silicates, porous glass, hydrogels, silicate-containing minerals, synthetic polymers, polystyrene, polypropylene, polyacrylamide, polyethylene glycol, polyacrylamide and copolymers thereof including copolymers of polystyrene/polyethylene glycol and
  • ion exchange resin refers to an insoluble organic polymer containing charged groups that attract and hold oppositely charged ions present in a surrounding solution in exchange for counterions previously held.
  • Suitable ion exchange resins to be used herein contain cationic groups that attract and hold anions present in a surrounding solution, and are sometimes referred to as "anion exchange resins”.
  • the terra "cleavable linking arms” refers to linking arms, which are a. chemical group or a covalent bond which covalently attaches at one end to a solid support and at the other end to ibogaine or noribogaine. At least one of the covalent bonds of the linking arm which attaches ibogaine or noribogaine to the solid support can be readily broken by specific chemical or enzymatic reactions, thereby providing for ibogaine or noribogaine free of the solid support.
  • the chemical or enzymatic reactions employed to break the covalent bond of the linking arm are selected so as to be specific for bond breakage thereby preventing unintended reactions occurring elsewhere on the compound,
  • the cleavable linking group is selected relative to ibogaine/horibogame formed on the solid support so as to prevent premature cleavage of either ibogaine or noribogaine from the solid support as well as not to interfere with any of the procedures employed during synthesis on the support.
  • Suitable cleavable linking arms are well known in the art, and may include such groups as carbonate groups, carbamate groups, amide groups, and the like, in a preferred embodiment, the cleavable linker arm contains no more than 10 atoms. More preferably, the cleavable linker contains from 1 to 4 carbon atoms and from 2 to 4 heteroatoms selected from oxygen, nitrogen, sulfur, 8(0) and S(0) 2 .
  • an acceptable addition salt refers to pharmaceutically acceptable salts of a compound of Formula 1 which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkyla nmonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • protecting group refers to well known functional groups which, when bound to a functional group, render the resulting protected functional group inert to the reaction conditions to be conducted on other portions of the compound and which, at the appropriate time, can be reacted to regenerate the original functionality.
  • 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 ibogaine or noribogaine during the reactions describee! herein.
  • Examples of conventional amino protecting groups include, for instance, benzyl, acetyl, oxyacetyl, carboxybenzyl (Cbz), and the like.
  • the protecting group is a "hydroxy protecting group" which protects the hydroxyl functionality of noribogaine.
  • hydroxyl protecting groups include, for instance, benzyl p- methoxybenzyl, p-nitro benzyl, ally ⁇ , trityl , diaikylsilylethers, such as dimethylsityl ether, and trialky!siiy! ethers such as trimethylsilyl ether.
  • esters such as benzoyl, acetyl, phenylacetyi, formyi, mono-, di-, and trihaloacetyl such as chloroacetyL diehloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates such as methyl ethyl, 2,2,2-trichloroethyl, ailyl, benzyl, and p-nitrophenyl.
  • 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 or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functionai groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wins, Protecting Groups in Organic Synthesis, Fourth Edition, Wiley, N.Y., 2007, and references cited therein.
  • 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 stereoisoraer-enriched mixtures. Ail 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.
  • noribogaine can be prepared and/or purified from ibogaine by utilizing solid support as shown in the following Schemes, where PG represents an amine protecting group, LG represents a leaving group (e.g. a halo or alcohol), L represents a clcavable linking group (e.g. a carbonyl compound such as a carbonate or carbamate) and the shaded circle represents a solid support, in the following Schemes, the O-demethylation of the aryl methoxy group to provide the corresponding phenol can be accomplishing using any suitable method known in the art.
  • Suitable reagents include a Lewis acid (e.g.
  • BBr3 ⁇ 4, AICI3 a nucleophiie (e.g. R.S-, .3 ⁇ 4-, SCN-), NaCN at low pH (e.g. pH 12), lithium diphenylphosphine (preferably an excess thereof), and the like.
  • the O-demethylation should be performed without affecting the linkage to the solid support. Suitable reagents can be readily ascertained by one of skill in the art and can be found, for example, in T. W.
  • Noribogaine 5 can be prepared and purified from ibogaine 10 by any one of the routes shown in Scheme 1.
  • Noribogaine, compound 5 is differentiated from ibogaine by virtue of the fact that the methoxy group of ibogaine has been converted to a hydroxyl group in noribogaine.
  • the indole amine of ibogaine can be protected using an amine protecting group to provide compound 1. followed by either tandem O-demethylation and removal of the protecting group using L-selectride®, for example, or sequential O- demethylation and removal of the protecting group to provide noribogaine 5.
  • noribogaine can be directly prepared and purified from the O- demeihylation of ibogaine using methods known in the art and then purified by appending noribogaine to a solid support (compound 12 or 13), washing any contaminants, cleaving the linking group L, and recovering the noribogaine 5.
  • a solid support compound 12 or 13
  • one or more of the noribogaine or intermediates shown above can be purified using standard purification techniques known in the art (e.g. column chromatography, HPLC. and the like).
  • Compounds of formula 11 are commercially available or can be synthesized in one or two steps from commercially available starting materials (see. e.g. commercially available resins from Sigma-Aidrieh®),
  • purification techniques can be used to maximize the purity of the recovered noribogaine.
  • noribogaine can be contacted with a suitable ion exchange resin at a pH where the phenol group has deprotonated to a sufficient degree such that these compounds are suitable for purification. Typically for phenol deprotonation, a pH of 10 or greater is used.
  • a pH of 10 or greater is used for phenol deprotonation.
  • ibogaine does not have an ionizable pheno group, it will not bind to the ion exchange resin and can thus be eluted from column and separated from the resin-bound noribogaine.
  • Suitable ion exchange resins are commercial!; available and include Amberlite* Toyopearl*. Lewatit ® , Dowex ® , DiaionTM, and Amberlyst' (Sigma Aldrich, Inc.)
  • an aqueous solution having a pH of at least 10 and a compound of the formula:
  • the purification process typically comprises pretexting or washing the resin with a solvent system which has the same pH, and other components such buffers, stabilizers, etc., that will be used to dissolve the noribogaine or salt thereof ("wash solvent"). Washing preferably includes passing at least 1 void volume (the volume of solvent needed to fill the resin vessel) of the wash solvent through the resin under ambient conditions. Subsequently, noribogaine is added to the same solvent system used as the wash solvent at a concentration preferably less than the saturation concentration for noribogaine. Noribogaine may be present as the phenolic anion under these conditions and, accordingly, both will bind to the anion exchange resin while other compounds lacking an anionic charge (i.e. ibogaine) will pass through the resin. Etechnisch of the purified noribogaine can be then be accomplished using a cation-containing solution.
  • wash solvent preferably includes passing at least 1 void volume (the volume of solvent needed to fill the resin vessel) of the wash solvent through the resin under ambient conditions.
  • noribogaine
  • an anion exchange resin comprising an aqueous solvent system and a pH of at least 10 and either compound 2a or compound 4a bound thereto.
  • noribogaine can be prepared and purified from ibogaine in the manner described in Scheme 2 below:
  • a small portion of the solid support can be removed to provide a sample of noribogaine (after cleavage and deprotection).
  • the sample can then be analyzed for purity relative to any ibogaine present by conventional methods such as GC/MS, NMR, C 13 -NMR, etc.
  • contaminating ibogaine, noribogaine, compound 5 can be recovered from the solid support by cleavage of the cieavable linker and subsequent deprotection of the amino group. Both cleavage and deprotection are well known in the art.
  • exceptionally pure noribogaine, compound 5 can be obtained by repeating the process of forming the amino protected noribogame. compound 2, binding compound 2 to a solid support via the hydroxyl group of amino protected noribogame and washing any contaminating ibogaine frora the solid support, By repeating this process as often as necessary and preferably no more than 5 times, it is contemplated that noribogaine having less than 5 ppra ibogaine and preferably less than 100 ppt tbogaine can be prepared.
  • noribogaine can be prepared and purified from ibogaine in the manner described in Scheme 3 below:
  • ibogaine, compound 10 is bound via conventional techniques to a solid support, compound 11, through a cieavable linker arm which, for the sake of illustration only, is depicted as a carbamate bond in resulting compound 12.
  • Compound 12 is then contacted with boron tribromide in methylene chloride or lithium dtphenylphosphine using conditions well known in the art to provide for the noribogaine bound via the indole nitrogen to a solid support, compound 13.
  • Cleavage of the cieavable linker in compound 13 provides for noribogaine, compound 5,
  • compound 5 can be directly obtained from compound 12 using a reducing agent (e.g. L-Seleetride®).
  • compound 5 can be purified by conventional techniques including high performance liquid chromatography (HPLC) and the purity level of the resulting purified compound confirmed by GC/MS.
  • HPLC high performance liquid chromatography
  • compound 5 can be used in Scheme 2 as recited above by attaching a solid support to the hydroxyl functionality. In either case, very high levels of noribogaine purity can be obtained.
  • Example i illustrates one method for the synthesis and purification of noribogaine from ibogaine which method follows Scheme 4 below:
  • ibogaine is contacted with a stoichiometric excess of benzyl chloroforraate in an inert solvent such as methylene chloride.
  • the reaction mixture further contains at least a stoichiometric equivalent of diisopropylethylamine relative to ibogaine so as to scavenge the acid generated during the reaction.
  • the reaction is maintained at room temperature under an inert atmosphere until the reaction is substantially complete as evidenced by, for example, thin layer chromatograpy.
  • an O-demethylation reagent e.g.
  • boron tribromide, aluminum trichloride, or lithium diphenylphosphine), or preferably a stoichiometric excess thereof, is added to the reaction mixture which is then maintained under conditions (e.g. room temperature) wherein the methoxy group of ibogaine has been converted to the hydroxy! group of noribogame.

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  • Chemical & Material Sciences (AREA)
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Abstract

L'invention concerne des procédés et des compositions de purification de noribogaïne alcaloïde non addictive.
PCT/US2014/031364 2014-03-20 2014-03-20 Procédés et compositions de préparation et de purification de noribogaïne WO2015142346A1 (fr)

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PCT/US2014/031364 WO2015142346A1 (fr) 2014-03-20 2014-03-20 Procédés et compositions de préparation et de purification de noribogaïne

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311724A1 (en) * 1997-09-04 2010-12-09 Novoneuron, Inc. Noribogaine in the treatment of pain and drug addiction
WO2012012764A1 (fr) * 2010-07-23 2012-01-26 Demerx, Inc. Compositions de noribogaïne
US20120253037A1 (en) * 2011-03-28 2012-10-04 Demerx, Inc. Methods and compositions for preparing noribogaine from voacangine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311724A1 (en) * 1997-09-04 2010-12-09 Novoneuron, Inc. Noribogaine in the treatment of pain and drug addiction
WO2012012764A1 (fr) * 2010-07-23 2012-01-26 Demerx, Inc. Compositions de noribogaïne
US20120253037A1 (en) * 2011-03-28 2012-10-04 Demerx, Inc. Methods and compositions for preparing noribogaine from voacangine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GOUTAM KUMAR JANA ET AL.: "Total synthesis of ibogaine, epiibogaine and their analogues", TETRAHEDRON, vol. 68, 2012, pages 7155 - 7165, XP028426180 *

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