METHODS AND COMPOSITIONS FOR PREPARING AND PURIFYING

NORIBOGAINE

Field of the Invention

100011 This invention relates generally to methods and compositions for purifying the non- addictive alkaloid noribogaine.

State of the Art

[0002] 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;

[0003] 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).

[0004] Conventionally, noribogaine is prepared by demethylation of naturally occurring ibogaine:

which is isolated from Tabernanth ihoga, a shrub of West Africa. Deraethylation may be accomplished by conventional techniques such as by reaction with boron

tribromide/methyiene chloride at roo temperature followed by conventional purification.

[0005] 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.

[G0G6J Accordingly, there is an ongoing need to provide a method for preparing noribogaine from ibogaine wherein any ibogaine contamination of noribogaine can be effectively and repeatedly minimized.

Summary of the Inventi n

[0007] 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.

[0008] Accordingly, in one of its method aspects, this invention is directed to a method for preparing and purifying noribogaine which method comprises:

a) converting ibogaine to noribogaine wherein the indole nitrogen is optionally

protected

by an amino protecting group;

b) covalently attaching noribogaine to a soiid support via the hydroxy! group of noribogaine so as to form a suspension of solid supports having noribogaine bound thereto; c) removing residual ibogaine from said suspension;

d) cleaving and recovering noribogaine from the solid support; and

e) optionally repeating steps b), c) and d) up to 5 times;

f) purifying noribogaine as recovered per above. [0009] In another of its method aspects, this invention is directed to a method for preparing and purifying noribogaine which method comprises:

a) covalentiy attaching ibogaine to a solid support via the amino group of ibogaine so as to form a suspension of solid supports having ibogaine bound thereto;

b) converting ibogaine to noribogaine under conditions wherein the level of ibogaine bound to the solid support is less than 0.1 weight percent;

c) cleaving and recovering noribogaine from the solid support; and

d) purifying noribogaine as recovered per above,

[0010] In one of its composition aspects, this invention is directed to a solid support having ibogaine or noribogaine covalentiy bound thereto through a cleavable linker,

[0011] in one embodiment, the solid support of this invention comprises ibogaine covalentiy bound thereto through a cleavable linker. In another embodiment, the solid support of this invention comprises noribogaine covalentiy bound thereto through a cleavable linker.

Detailed Description of the Invention

{0012] This invention is directed to methods and compositions comprising noribogaine and, in particular, methods and compositions comprising highly pure noribogaine. However, prior to describing this invention in greater detail, the following terras will first be defined.

10013J It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary, it is also to be understood that the terminology used herein is for the purpose of describing particuiar embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. f0014] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutically acceptable excipient" includes a plurality of such excipients.

1. Definitions

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the fol lowing terms have the following meanings. [0016] As used herein, the term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others,

"Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein 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.

[0017] The term "about" when used before a numerical designation, e.g.. temperature, time, amount, and concentration, including range, indicates approximations which may vary by ( + ) or ( - ) 10 %, 5 % or 3 %.

[0018] As stated above, the invention is directed to compositions comprising noribogame and an excipient to facilitate transport across the blood brain barrier.

[0019] As used herein, the term "noribogame" refers to the compound:

and salts thereof. Conventionally, noribogame is prepared by demethylation of naturally occurring ibogaine:

which is isolated from Tabemanlh ibog , a shrub of West Africa. Demethylation may be accomplished by conventional techniques such as by reaction with boron

tribromide/roethylene chloride at room temperature, or reaction with lithium

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,

[0020| The term "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. Such 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

polyacrylamide poiyethylene glycol, and the like.

10021] As used herein, the term "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".

[0022] As used herein, 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 . {0023J As used herein, the term "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.

[0024] As used herein, 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 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. In one embodiment, 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. In another embodiment, the protecting group is a "hydroxy protecting group" which protects the hydroxyl functionality of noribogaine. Examples of 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. triethylsilyJ ether, and t-butyldimethylsilyi 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. Additional examples of hydroxy protecting groups may be found in standard reference works such as Greene and Wuts, Protective Groups in Organic Synthesis., 2d Ed., 1991 , John Wiley & Sons, and McOmie Protective Groups in Organic Chemistry, 1975, Plenum Press,

Preparation and Purification of Noribogaine

[0025] 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.

[0026] Additionally, as will be apparent to those skilled in the art, conventional 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.

[0027] Furthermore, 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.

[0028] it is contemplated that 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. BBr¾, AICI3 ), a nucleophiie (e.g. R.S-, .¾-, SCN-), NaCN at low pH (e.g. pH 12), lithium diphenylphosphine (preferably an excess thereof), and the like. In some embodiments, 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.

Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Fourth Edition, Wiley, N.Y.. 2007 (see, e.g., the reactivity charts at pages 1006-1008 and 1022-1032), and references cited therein.

SCHEME 1

[§029] 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. In one embodiment, 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. In addition, in one embodiment, 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. In the above syntheses, 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®),

[0030] In one preferred embodiment, purification techniques can be used to maximize the purity of the recovered noribogaine. In one embodiment, 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. As 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 ^® , Diaion™, and Amberlyst' (Sigma Aldrich, Inc.)

[003 Ij Accordingly, in one of its composition aspects, there is provided an aqueous solution having a pH of at least 10 and a compound of the formula:

[0032] 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. Ektion of the purified noribogaine can be then be accomplished using a cation-containing solution.

[0033] Accordingly, in another of its composition aspects, there is pro vided 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.

[0034J In one embodiment, noribogaine can be prepared and purified from ibogaine in the manner described in Scheme 2 below:

SCHEME 2 wherein Pg is hydrogen or an amino protecting group and the shaded circle represents a solid support.

J0035] Specifically, in Scheme 2, amino protected ibogaine, compound 1 , is contacted with boron tribromide in methylene chloride or lithium diphenylphosphine using conditions well known in the art to provide for the amino protected noribogaine, compound 2.

[0036] in Scheme 2, attachment of amino protected noribogaine, compound 2, to a solid support is accomplished by use of a chloroformate/sofid support, compound 3, under conventional conditions to provide for compound 4 wherein the carbonate group is shown for illustrative purposes only as the c!eavable linking group. Other cleavable linkers can likewise be used in Scheme 2. As amino protected ibogaine does not contain a functional group reactive with compound 3, only amino protected noribogaine, compound 2, will react with the solid support and provide for compound 4. Repeated washing of compound 4 will remove amino protected ibogaine contaminating the sample of amino protected noribogaine used in this reaction. Furthermore, at any time, 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.

[0037] Upon achieving the desired level of purity of noribogaine relative to any

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.

|0038J As desired, 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.

[0039 j In another embodiment, noribogaine can be prepared and purified from ibogaine in the manner described in Scheme 3 below:

SCHEME 3

[§§40] In Scheme 3, 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, In certain embodiments, compound 5 can be directly obtained from compound 12 using a reducing agent (e.g. L-Seleetride®). See US Patent 6,291,675. 10041] In one embodiment, 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. Alternatively, 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.

1 _. 00421 The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius.

EXAMPLES

10043J In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

Example 1 - Synthesis and Purification of Noribogaine from Ibegaine

10044] Example i illustrates one method for the synthesis and purification of noribogaine from ibogaine which method follows Scheme 4 below:

SCHEME 4

[0045] Specifically, in Scheme 4, 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. At which time, 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.

[Q046J The hydroxy! group generated above is then employed as a complementary functionality for attachment of a solid support. In particular, an excess of cMoroformate bound to a solid support is combined with N-CBZ-noribogaine under conventional conditions wherein a cleavable carbonate bond is formed. Chloroformate bound to a solid support can be prepared from a hydroxy-bearing polymer support (e.g. hydroxymethyl)poiystyrene or polymer-bound benzyl alcohol, both commercially available from Sigma- Akirich©) and carbonyl dichioride. As CBZ-ibogaine does not readily react under these O-demethylation conditions, it will remain in the solution phase of the reaction mixture and can be washed from the reaction mixture by conventional techniques including placing the solid support into a column and passing excess solvent through the column.

{0047] In one particular example, 5 kg of solid support containing CBZ-noribogaine is loaded onto a column. The stopper of the column is partially opened so that a flow rate through the column of 0,5 liters per hour is maintained. Methylene chloride is continuously fed to the top of the column and recovered at the base of the column. The recovered methylene chloride is stripped to provide residual CBZ-ibogaine. The process is continued until the effluent from the column no longer contains CBZ-ibogaine. At which time, a portion of the solid support is loaded into a hydrogenation vessel together with methanol and a catalytic amount of palladium on carbon, Hydrogenation is continued under elevated pressure for approximately 5 hours, The reaction is then stopped and the methanol recovered and stripped to provide for noribogaine. Additional purification of noribogaine can be achieved by HPLC as desired.