# Patent

## Title
Synthetic noribogaine

## Abstract

Synthetic noribogaine preferably free of ibogaine and, optionally, one or more of other naturally occurring Tabernanth iboga alkaloids, is provided.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation application of U.S. patent application Ser. No. 13/593,454 (filed Aug. 23, 2012), which claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional application No. 61/528,070, filed Aug. 26, 2011, all of which are incorporated by reference in their entirety into this application.


FIELD OF THE INVENTION
This invention relates to synthetic noribogaine free of ibogaine, methods of preparing such noribogaine, and pharmaceutically acceptable composition including such noribogaine.
STATE OF THE ART
Noribogaine is a well known compound and is a derivative of ibogaine and is sometimes referred to as 12-hydroxyibogamine. U.S. Pat. No. 2,813,873 claims noribogaine albeit as “12-O-demethylibogaine” while providing an incorrect structural formula for ibogaine. The structure of noribogaine has now been determined and found to combine the features of tyrptamine, tetrahydrohavaine and indolazepines. Noribogaine can be depicted by the following formula:




where the configuration at the 2, 4, 5, 6 and 18 atoms are 2(R), 4(S), 5(S), 6(S) and 18(R).

Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non-addictive alkaloid useful in treating drug dependency (U.S. Pat. No. 6,348,456) and as a potent analgesic (U.S. Pat. No. 7,220,737). Both of these patents are incorporated herein by reference in their entirety.
Noribogaine is prepared by O-demethylation of naturally occurring ibogaine:




which is isolated from Tabernanthe iboga, a shrub of West Africa. Demethylation may be accomplished by techniques such as by reaction with boron tribromide/methylene chloride at room temperature followed by purification. Alternatively, reaction with acetic acid and hydrogen bromide can be used. Regardless, noribogaine thus prepared will contain residual ibogaine resulting from incomplete O-demethylation.

Still further, noribogaine is prepared by decarboxylation and O-demethylation of naturally occurring voacangine:




Again, noribogaine thus prepared will contain residual ibogaine resulting from decarboxylation but incomplete O-demethylation. As both ibogaine and voacangine are obtained from plants, the natural supply of ibogaine and voacangine is limited and unpredictable.
Ibogaine is known to possess hallucinogenic properties and is a Schedule 1-controlled substance in the U.S.A. Accordingly, methods for preparing noribogaine, a non-hallucinogenic and non-controlled substance, from ibogaine require high levels of assurance that contamination with unacceptable amounts of ibogaine is avoided. However, noribogaine prepared by demethylation has not been reported as being substantially free of ibogaine (e.g., not more than 0.5 wt % relative to noribogaine). At best, U.S. Pat. No. 6,348,456 claims an essentially pure noribogaine compound but fails to disclose any methods for purification let alone what the phrase “essentially pure” encompassed or, for that matter, the level of ibogaine remaining in the composition. The synthesis of noribogaine from ibogaine was reported in U.S. Pat. No. 2,813,873. However, the '873 patent is also silent as to the purity of the noribogaine obtained in that synthetic process. Overall, it is accurate to state that the use of ibogaine or voacangine as a starting material for preparing noribogaine is complicated by the presence of residual ibogaine in the noribogaine thus prepared.
Accordingly, there is an ongoing need to provide synthetic noribogaine prepared in a manner in which ibogaine or voacangine is not an intermediate or side product, and which preferably provides noribogaine in an enantiomerically enriched (with more of the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer) form.
SUMMARY OF THE INVENTION
In one aspect, this invention provides synthetic noribogaine. Preferably, the synthetic noribogaine is free of ibogaine. More preferably, the synthetic noribogaine is also free of other naturally occurring Tabernanth iboga alkaloids. In one embodiment, at least 95% of the synthetic noribogaine is present as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer. In another embodiment, the synthetic noribogaine contains less than 1 ppt C14. Preferably, the synthetic noribogaine contains less than 0.95 ppt, and still more preferably, less than 0.8 ppt C14. In another aspect, this invention provides a pharmaceutical composition comprising the synthetic noribogaine provided herein and a pharmaceutically acceptable excipient. In another aspect, this invention provides methods for preparing the synthetic noribogaine free of ibogaine, and optionally free of other naturally occurring Tabernanth iboga alkaloids. In another aspect, this invention provides novel compounds useful in the synthesis of the synthetic noribogaine provided according to this invention.


DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to synthetic noribogaine and compositions comprising highly pure noribogaine, preferably, as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer. However, prior to describing this invention in greater detail, the following terms will first be defined.
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 particular embodiments only, and is not intended to be limiting, since the scope of this invention will be limited only by the appended claims.
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.
DEFINITIONS
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 following terms have the following meanings.
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 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.
As used herein, the term “noribogaine” refers to the alkaloid noribogaine including all enantiomers thereof, and also includes pharmaceutically acceptable salts of each thereof. Of particular interest is the enantiomer depicted by the formula:




where the configuration at the 2, 4, 5, 6 and 18 atoms are 2(R), 4(S), 5(S), 6(S) and 18(R).

As used herein, the term “noribogaine free of ibogaine” refers to noribogaine that contains less than 0.5 wt %, less than 0.1 wt %, less than 0.05 wt %, preferably, less than 0.02 wt % (or 200 ppm), more preferably, less than 100 ppm, or still more preferably less than 50 ppm ibogaine relative to the total amount of noribogaine. In one embodiment, the noribogaine contains no ibogaine detectable by known methods to detect ibogaine or such a compound. In a particularly preferred embodiment, the noribogaine is synthetic noribogaine which does not encompass ibogaine as an intermediate and, accordingly, is free of ibogaine.
As used herein, the term “other naturally occurring Tabernanth iboga alkaloids” refer to the following alkaloids: tabernanthine, ibogamine, ibogaline, iboluteine, iboquine, desmethoxyiboluteine, and hydroxyindolenine derivatives of ibogaine, ibogamine, voacangine, gabonine, kisanthine, and kimvuline. These alkaloids are, in addition to ibogaine, isolated from the Tabernanth iboga plant.
As used herein, the term “noribogaine free of one or more of other naturally occurring Tabernanth iboga alkaloids” refer to noribogaine that contains less than 1 wt %, less than 0.5 wt %, preferably, less than 0.1 wt %, or still more preferably, less than 0.02 wt % of one or more of the other naturally occurring Tabernanth iboga alkaloids, relative to the total amount of noribogaine. In a preferred embodiment, the noribogaine is synthetic noribogaine which does not encompass any of these alkaloids as an intermediate and, accordingly, is free of ibogaine.
As used herein, “alkyl” refers to groups having from 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. The term “Cx alkyl” refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C3 refers to an alkyl group having 3 carbon atoms.
As used herein, “alkoxy” refers to —O-alkyl.
As used herein, the term “reaction conditions” refers to details under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of a base or acid, or catalyst, etc.
As used herein, the term “pharmaceutically acceptable excipient” refers to a non toxic excipient useful for administration to a patient, such as, human.
As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutically acceptable, non toxic, salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, when the molecule contains an acidic functionality, counter ions such as sodium, potassium, calcium, magnesium, ammonium, tetraalkyl ammonium, and the like, and when the molecule contains a basic functionality, counter ions such as chloride, bromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
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 under deprotection conditions. 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 noribogaine intermediates during the noribogaine synthesis described herein. Examples of amino protecting groups include, for instance, benzyl, acetyl, oxyacetyl, carbonyloxybenzyl (Cbz), and the like. In another embodiment, the protecting group is a “hydroxy protecting group” which protects the hydroxyl functionality of noribogaine intermediates during the noribogaine synthesis described herein. Examples of hydroxyl 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. 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. Methods for protecting and deprotecting the phenolic hydroxyl group of the compounds disclosed herein can be found in the art, and specifically in Greene and Wuts, supra, and the references cited therein.
Synthetic Noribogaine and Intermediates Thereto
Synthetic noribogaine provided according to this invention is prepared as shown in the non limiting illustration below.




Compound 6 is converted to intermediate 17 as shown below:








See, also Kuehne et al., J. Org. Chem., 50:919 (1985), incorporated herein by reference. In the scheme above, the benzyl (Bn) protecting group can be replaced with other protecting groups well known to the skilled artisan. Intermediate 17 is converted to noribogaine following the methods shown below.








The decarboxylation is performed following various methods well known to the skilled artisan, such as using refluxing hydrazine. The decarboxylation is also contemplated to be performed by hydrolyzing the —COOMe group to an acid, and reacting the corresponding sodium or lithium salt with aqueous mineral acid.

With tryptamine (compound 1) used as a starting material, the hydroxy group is incorporated at the 5-position of the indole ring (the 12-position of noribogaine) via an iodo or bromo substituted indole intermediate (such as compounds 18 and 23). The iodo group is conveniently incorporated into the indole ring by reacting compound 17 or 22, e.g. and without limitation, with N-iodosuccinimide (NIS). The iodo group is also incorporated using a phenyl iodonium intermediate, and displacing the phenyl group as schematically shown below. The iodo or the bromo group is also incorporated by nitration, reducing the nitro group to an amino group, diazotizing the amino group, and reacting the diazonium compound with CuI or CuBr. Alternatively, the diazonium compound is converted to a hydroxy group simply by reacting with water. These transformations are illustrated below.







Compound 22 can be iodinated, brominated, or hydroxylated at the 12-position, in similar manner.

The iodo group is converted to —OR′ by reacting with the corresponding R1OH or R1O(−), e.g., in presence of a copper catalyst. For example, R1 is any hydroxy protecting group other than methyl. In one embodiment, —OR′ is benzyloxy ( ̃OBn) or a substituted benzyloxy group. As used herein, substituted benzyloxy refers to:




wherein R2 is C1-C6 alkyl or C1-C6 alkoxy. For example, and without limitation, CuI and a ligand such as tetramethyl phenanthroline (see, for example, “An Improved Cu-Based Catalyst System for the Reactions of Alcohols with Aryl Halides”, Altman et al., J. Org. Chem., 2008, 73, 284-286, incorporated herein by reference), or CuBr (U.S. Pat. No. 4,422,955, incorporated herein by reference) are useful for incorporating an —OR1 group, such as, benzyloxy or substituted benzyloxy group.

According to this invention, compound 17 is also converted to noribogaine via the route shown below. The alcohol, compound 30, provides a convenient route to the desired enantiomer, compound 30A (which yields substantially 2(R), 4(S), 5(S), 6(S) and 18(R) noribogaine), in a substantially pure form. For this purpose, compound 30 is esterified with a chiral carboxylic acid (such as R*COOH) and diastereomeric forms of compound 31 are separated. Various such chiral carboxylic acids are well known to the skilled artisan. The hydroxymethyl group is removed from compound 30 or 30A following a retro aldol reaction.




Thus in one embodiment, this invention provides a method comprising contacting a compound of formula 17 with an iodinating agent under reaction conditions to provide the compound of formula 18. In another embodiment, the method further comprises, contacting the compound of formula 18 with a benzyloxy ((−)OBn) or substituted benzyloxy anion in presence of copper catalyst under reaction conditions to provide a compound of formula 19. In another embodiment, the method further comprises decarboxylating the compound of formula 19 to provide the compound of formula 20.
In another embodiment, this invention provides a method comprising contacting a compound of formula 22 with an iodinating agent under reaction conditions to provide the compound of formula 23. In another embodiment, the method further comprises contacting the compound of formula 23 with a benzyloxy ((−)OBn) or substituted benzyloxy anion in presence of copper catalyst to provide a compound of formula 20. In another embodiment, the method further comprises removing the benzyl or substituted benzyl protecting group under conditions to provide noribogaine. Conditions suitable for removing a benzyl or a substituted benzyl protecting group include, without limitation, hydrogenolysis using hydrogen and a Pd, Pt, or Rh or their oxide based catalyst.
In another embodiment, this invention provides a method comprising contacting the compound of formula 23 with hydroxide and a copper catalyst under conditions to provide noribogaine.
It is also contemplated that synthetic noribogaine provided according to this invention is prepared starting from a halogenated tryptamine.







As shown above, R3 preferably is bromo or iodo. Compound 32 is prepared by reacting tryptamine with an iodinating or brominating agents as described herein and also those known to the skilled artisan. In certain instances, one of more nitrogen groups of the tryptamine may be protected during the iodination or bromination. A synthesis of noribogaine according to the above scheme is also contemplated where R3 is benzyloxy or substituted benzyloxy as defined herein. Conversion of 39 to 40 may result in deprotection of the 12-O benzyl or 12-O-substituted benzyl group; the deprotected compounds may be transformed to noribogaine as provided herein, or the deprotected compound may be selectively reprotected at the 12-OH group and transformed to noribogaine as provided herein. Compound 18 or 28 is converted to noribogaine as provided and illustrated herein.

As disclosed herein, introduction of the 12-OH group is possible, surprisingly, by using intermediates, which include the corresponding protected hydroxy group, or by using intermediates, which include hydroxy precursors such as halo, nitro, amino, and the like.
As will be apparent to the skilled artisan, the methods of making synthetic noribogaine as provided herein also require routine steps of separation and purification, which are performed by column chromatography, crystallization, and the like, as also well known to the skilled artisan. Enatiomerically enriched synthetic noribogaine, or an enatiomerically enriched intermediate thereto as utilized and provided herein is contemplated to be obtained, inter alia, by chiral chromatographic separation, and/or resolution via diastereomeric salt formation, and/or separation of diastereomeric derivatives. Chiral acids and bases suitable for resolving synthetic noribogaine or an intermediate thereto will be well known to the skilled artisan.
The synthetic ibogaine prepared herein is free of ibogaine, and optionally, one or more of the other naturally occurring Tabernanth iboga alkaloids, because, e.g., such alkaloids, particularly those that are methoxylated on the indole ring, including ibogaine are not intermediates and/or by-products in the preparation of noribogaine according to this invention. Ibogaine or the one or more of other naturally occurring Tabernanth iboga alkaloids are present in ibogaine, obtained from natural sources by partial synthesis, as an impurity.
The synthetic noribogaine of this invention is distinguished from plant derived noribogaine (e.g., and without limitation, noribogaine synthesized from naturally occurring ibogaine or voacangine) by its 14C content. 14C has a half-life of about 5,730 years and is generated in the upper atmosphere as 14CO2. The amount of 14CO2 present is approximately 1 ppt (parts per trillion) and, through photosynthesis, accumulates in plants resulting in a 14C content of plant material of approximately 1 ppt. Accordingly, plant derived noribogaine (e.g., and without limitation, noribogaine synthesized from naturally occurring ibogaine or voacangine) is expected to have approximately 1 ppt 14C. Conversely, the noribogaine and intermediates disclosed herein are derived from fossil fuels, which, due to 14C decay, would have a 14C content of less than 1 ppt 14C. Accordingly, provided herein is noribogaine having a 14C content of less than 1 ppt, preferably, less than 0.95 ppt, or more preferably less than 0.8 ppt. In one embodiment, provided herein is synthetic noribogaine having a 14C content of less than 0.6 ppt, or less than 0.5 ppt, or less than 0.4 ppt, or less than 0.3 ppt, or less than 0.2 ppt, or less than 0.1 ppt. In another embodiment, provided herein is synthetic noribogaine having a 14C content of 0.8 ppt to 0.95 ppt or 0.7 ppt to 0.95 ppt. The amount of 14C can be analyzed using methods well known in the art (i.e. radiocarbon analyses can be carried out according to the American Society for Testing Materials ASTM D6866 procedure (ASTM international, 100 Barr Harbon Drive, PO Box C700, West Conshohocken, Pa. 19428-2959)). Furthermore, provided is a method for distinguishing synthetic noribogaine from plant derived noribogaine based on the 14C content.
In another aspect, this invention provides the following compounds:











wherein,

X is chloro, bromo, or iodo;
R4 is H, NO2, NH2, —N2(+), —OR1, or R3;
R1 is a hydroxy protecting group other than methyl;
R3 is iodo, bromo, benzyloxy, substituted benzyloxy, allyloxy, or trialkylsilyloxy;
R5 is H, CO2R6, —CH2OH, or —CH2O2CR*;
provided that, when R5 is H, then R4 is not H; and
provided that when R4 is H, then R5 is —CH2O2CR*;
R* is an asymmetric carbon atom such that RCO2H is a chiral carboxylic acid;
R6 is H or C1-C6 alkyl; and
R7 is an amino protecting group;
or a salt, preferably a pharmaceutically acceptable salt, thereof.
In one embodiment, R4 is H. In another embodiment, R4 is NO2. In another embodiment, R4 is NH2. In another embodiment, R4 is —N2(+). In another embodiment, R4 is —OR1. In another embodiment, R1 is benzyl. In another embodiment, R1 is:




and R2 is C1-C6 alkyl or C1-C6 alkoxy. In another embodiment, R4 is R3. In another embodiment, R3 is iodo. In another embodiment, R3 is bromo. In another embodiment, R3 is benzyloxy. In another embodiment, R3 is substituted benzyloxy.

In another embodiment, R5 is H. In another embodiment, R5 is —CO2Me. In another embodiment, R5 is —CH2O2CR*. In another embodiment, R5 is —CH2OH.
In another embodiment, X is chloro. In another embodiment, X is bromo. In another embodiment, X is iodo.
In another embodiment, R7 is benzyl.
In another aspect, this invention provides synthetic noribogaine having 2(R), 4(S), 5(S), 6(S) and 18(R), configuration (the naturally occurring configuration); noribogaine having 2(S), 4(R), 5(R), 6(R) and 18(S) configuration; or a salt, preferably a pharmaceutically acceptable salt thereof.
In another aspect, this invention provides a compound of formula:




or a salt, preferably a pharmaceutically acceptable salt, thereof; or

an enantiomer or diastereomer of each thereof.

In one embodiment, the compound is a pure or substantially pure enantiomer having configurations at the 2, 4, 5, 6, and 18 position which are the same as that in naturally occurring voacangine. In another embodiment, the compound is a pure or substantially pure enantiomer having configurations at the 2, 4, 5, 6, and 18 positions, which are the mirror images of that in naturally occurring voacangine.
In another aspect, this invention provides a compound of formula:




or a salt, preferably a pharmaceutically acceptable salt, thereof; or

an enantiomer or diastereomer of each thereof.

In certain embodiments, the compounds provided by this invention are provided in substantially enatiomerically enriched or diastereomerically enriched form.
The various compounds provided herein are prepared according to methods disclosed here and/or those known to the skilled artisan.
UTILITY
2(R), 4(S), 5(S), 6(S) and 18(R) noribogaine has utility in treating drug dependency and as an analgesic. See U.S. Pat. No. 6,348,456 7,220,737, supra. The novel compounds provided herein have utility as intermediates to synthetic noribogaine or as compounds having activity in drug dependency or as analgesics.
It will be apparent to the skilled artisan that the products synthesized according to this invention are separated, as required, by techniques well known to the skilled artisan, such as, column chromatographic separation and crystallization.

## Claims

1. A pharmaceutically acceptable composition comprising:
a compound of Formula I:




or a salt thereof wherein,
R4 is —O-PG, OMs, or OTs;
PG is selected from the group consisting of:
a) —(C1-C6 alkyl)-X where X is selected from the group consisting of C6-C10 aryl, C2-C10 heteroaryl, and CO2H or an ester thereof; and
b)





—CH2CH═CH2, —CH2OCH3, —CHO, and —Si(R21)3 where each R21 is selected from the group consisting of C6-C10 aryl, and C2-C10 heteroaryl,
and a pharmaceutically acceptable excipient.

2. The pharmaceutically acceptable composition of claim 1 wherein,
R4 is selected from the group consisting of: OBn, OMs, OTs, and OCH2CH═CH2.

3. The pharmaceutically acceptable composition of claim 1, which is free of ibogaine.

4. A pharmaceutically acceptable composition comprising:
a compound of Formula I:




or a salt thereof wherein,
R4 is —O-(C1-C6 alkyl)-X, where X is selected from the group consisting of C6-C10 aryl, C2-C10 heteroaryl, and CO2H or an ester thereof; and

a pharmaceutically acceptable excipient.

5. The pharmaceutically acceptable composition of claim 4, wherein X is C6-C10 aryl.

6. The pharmaceutically acceptable composition of claim 4, wherein X is C2-C10 heteroaryl.

7. The pharmaceutically acceptable composition of claim 4, wherein X is CO2H or an ester thereof.

8. The pharmaceutically acceptable composition of claim 4, which is free of ibogaine.

9. A pharmaceutically acceptable composition comprising:
a compound of Formula I:




or a salt thereof wherein,
R4 is —O-PG,
PG is selected from the group consisting of:





—CH2CH═CH2, —CH2OCH3, and —CHO;
and a pharmaceutically acceptable excipient.

10. The pharmaceutically acceptable composition of claim 9, which is free of ibogaine.