EP2807167A1 - Dérivés d'isoquinuclidène réunis par fusion à de l'indole et du benzofurane et leurs procédés de préparation - Google Patents

Dérivés d'isoquinuclidène réunis par fusion à de l'indole et du benzofurane et leurs procédés de préparation

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Publication number
EP2807167A1
EP2807167A1 EP13741381.1A EP13741381A EP2807167A1 EP 2807167 A1 EP2807167 A1 EP 2807167A1 EP 13741381 A EP13741381 A EP 13741381A EP 2807167 A1 EP2807167 A1 EP 2807167A1
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EP
European Patent Office
Prior art keywords
group
compound
alkyl
formula
optionally substituted
Prior art date
Legal status (The legal status 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 status listed.)
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EP13741381.1A
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German (de)
English (en)
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EP2807167A4 (fr
Inventor
Robert M. Moriarty
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DemeRx Inc
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DemeRx Inc
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Priority claimed from PCT/US2012/022787 external-priority patent/WO2013112163A1/fr
Application filed by DemeRx Inc filed Critical DemeRx Inc
Publication of EP2807167A1 publication Critical patent/EP2807167A1/fr
Publication of EP2807167A4 publication Critical patent/EP2807167A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • indole and benzofuran fused isoquinuclidene derivatives and processes, preferably enantioselective processes, for preparing such derivatives including processes for preparing (-) and (+) noribogaine, in substantially
  • this invention provides (-) or (+) noribogaine or a salt, preferably a pharmaceutically acceptable salt, of each thereof, preferably in a substantially enantiomerically pure form, prepared according to the processes provided herein, and also provides pharmaceutical compositions comprising (-) noribogaine or a salt thereof thus prepared.
  • Noribogaine is a well known compound whose structure combines the features, for example, of tyrptamine, and isoquinuclidene.
  • the naturally occurring enantiomer of noribo aine can be depicted by the following formula:
  • the naturally occurring enantiomer of noribogaine is prepared by O-demethylation of naturally occurring ibogaine or prepared by
  • Voacangine and Ibogaine are obtained from plants where both the supply is limited and the quality of the supply is unpredictable.
  • indole and benzofuran fused isoquinuclidene derivatives and processes, preferably enantioselective processes, for preparing such derivatives including processes for preparing (-) or (+) noribogaine or a salt thereof, in substantially enantiomerically pure forms.
  • the processes provided herein employ the novel 1R,4R 7-oxo- 2-azabicyclo[2.2.2]oct-5-ene or a protected derivative thereof.
  • this invention provides (-) noribogaine or a salt, preferably a pharmaceutically acceptable salt, thereof, preferably in a substantially enantiomerically pure form, prepared according to the processes provided herein.
  • this invention provides a composition comprising the (-) noribogaine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • This invention also provides processes for preparing (+) noribogaine.
  • pharmaceutically acceptable refers to a safe and non-toxic composition, which is suitable for in vivo, preferably for human administration.
  • FIG. 1 illustrates a 1H-NMR spectrum in CDC1 3 of compound 3 :
  • FIG. 2 illustrates a 1H-NMR s ectrum in CDC1 3 of compound 1 :
  • FIG. 3 illustrates a 1H- MR spectrum in CDCI 3 of compound 2:
  • indole and benzofuran fused isoquinuclidene derivatives and processes, preferably enantioselective processes, for preparing such derivatives including processes for preparing (-) and (+) noribogaine or a salt of each thereof, in substantially enantiomerically pure forms.
  • alkenyl refers to hydrocarbyl groups having from 2 to 10 carbon atoms and at least one and up to 3 carbon carbon double bonds. Examples of alkenyl include vinyl, allyl, dimethyl allyl, and the like.
  • alkoxy refers to -O-alkyl
  • alkyl refers to hydrocarbyl groups having from 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1-4 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, n-decyl and the like.
  • alkynyl refers to hydrocarbyl groups having from 2 to 10 carbon atoms and at least one and up to 2 carbon carbon triple bonds. Examples of alkynyl include ethynyl, propargyl, dimethylpropargyl, and the like.
  • amino refers to -NR x R y wherein each R x and R y
  • 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-l,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-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at
  • base refers to a compound that can accept a proton or donate a lone electron pair.
  • bases include, alkali (OH ), carbonate, bicarbonate, alkoxides (alkyl-OQ), hydrides (alkali metal hydrides and CaH 2 ), amides (NH 2 ( ⁇ ), R ⁇ H ⁇ ), or (R b ) 2 N( ⁇ ), wherein R b is alkyl or 2 R b s together with the nitrogen form a 5-6 membered ring), and neutral nitrogen containing bases such as (R b ) 3 N, pyridine, 4-N,N- dialkylpyridine, and the like.
  • nucleophilic bases refer to preferably neutral nitrogen containing bases that can catalyze the addition of an acyl halide or a sulfonyl halide(such as R b COX or R b S0 2 X) to an -OH, -NH 2 , or an -NHR b group.
  • Preferred examples include, 4-N,N-dialkylpyridines.
  • a “Bronsted acid” refers to a compound that can donate a proton.
  • chlorinated solvent refers to chlorinated methane and ethane, which are preferably trichlorinated, and more preferably dichlorinated. Yet more preferably, the chlorinated solvent is dihloromethane.
  • compositions and methods are 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.
  • cycloalkyl refers to cyclic hydrocarbyl groups of from 3 to 10 carbon atoms having single or multiple condensed rings, which condensed rings may be aromatic or contain a heteroatom, provided that the point of attachment is at a cycloalkyl carbon atom.
  • Cycloalkyl includes, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Cycloalkyl rings are preferably saturated, though, cycloalkyl rings including 1-2 carbon carbon double bonds are also contemplated provided that the ring is not aromatic.
  • C x refers to a group having x carbon atoms, wherein x is an integer, for example, C 4 alkyl refers to an alkyl group having 4 carbon atoms.
  • ee refers to enantiomeric excess and is expressed as (e -e )%
  • e and e are the two enantiomers.
  • e and e are the two enantiomers.
  • the e 1 enantiomer is present in an ee of 90%.
  • the ee of an enantiomer in a mixture of enantiomers is determined following various methods well known to the skilled artisan, such as using chiral lanthanide based nuclear magnetic resonance shift reagents, forming derivatives with chiral compounds such as chiral hydroxyacids, amino acids, and the like.
  • Various physical measurements such as circular dichroism, optical rotation, etc. are also useful in determining the ee of a mixture of enantiomers.
  • deprotection condition refers to reaction conditions that transform a phenolic ether to the corresponding phenol and includes reacting with various Lewis acids such as BBr 3 , and when the alkyl group in the ether is a methyl group containing at least one phenyl or substituted phenyl group, reacting under hydrogenation conditions.
  • -C0 2 H “ester” refers to -C0 2 R E wherein R E is selected from the group consisting of C 6 -Cio aryl and Ci-C 6 alkyl optionally substituted with 1-3 C 6 -Cio aryl groups.
  • Fischer indole synthesis condition refers to reaction conditions for reacting phenylhydrazine with a ketone containing at least one a-methylene group and an acid to provide an indole derivative.
  • Bronsted acids such as HC1, H 2 S0 4 , polyphosphoric acid and p-toluenesulfonic acid are useful, as are Lewis acids such as boron trifluoride, zinc chloride, iron chloride, and aluminum chloride.
  • fluoroalkyl refers to an alkyl group substituted with up to 5, or preferably up to 3 fluoro groups.
  • halo refers to F, CI, Br, or I.
  • 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 -), provided that the ring has at least 5 ring atoms and up to 14, or preferably from 5-10, ring atoms.
  • 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.
  • heteroaryls include pyridyl, pyrrolyl, indolyl, thiophenyl, furyl, and the like.
  • heterocyclyl refers to a cycloalkyl 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 -), provided that the ring has at least 3 and up to 14, or preferably from 5-10 ring atoms.
  • heterocyclyl groups can have a single ring or multiple condensed rings wherein the condensed rings may not contain a heteroatom and/or may contain an aryl or a heteroaryl moiety, provided that the point of attachment is through an atom of the non-aromatic heterocyclyl group.
  • heterocyclyl include pyrrolidinyl, piperadinyl, piperazinyl, and the like.
  • Heterocyclyl rings are preferably saturated, though, heterocyclyl rings including 1-2 carbon carbon double bonds are also contemplated provided that the ring is not aromatic.
  • hydrogenation conditions refer to conditions including hydrogen gas at atmospheric or higher pressure and catalysts that catalyze the reaction of the hydrogen with a hydrogen reactive group, such as a benzyl group or a carbon carbon double/triple bond.
  • Catalysts useful for hydrogenation include palladium, platinum, and rhodium metals and their oxides or hydroxides, preferably supported on a material such as carbon or alumina.
  • 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 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 protecting group is selected to be compatible with the remainder of the molecule.
  • the protecting group is an "amine protecting group” which protects an -NH- or an -NH 2 - moiety, for example during the syntheses described here.
  • amine protecting groups include, for instance, benzyl, acetyl, oxyacetyl, carbonyloxybenzyl (Cbz), Fmoc, and the like.
  • the protecting group is a "hydroxy protecting group" which protects a hydroxyl functionality during the synthesis described here.
  • 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.
  • dialkylsilylethers such as dimethylsilyl ether
  • trialkylsilyl ethers such as
  • amine protecting groups are also useful as amine protecting groups. Additional examples of amine, hydroxy, and keto protecting groups are 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 hydroxyl, -NH-, -NH 2 -, and keto groups disclosed herein can be found in the art, and specifically in Greene and Wuts, supra, and the references cited therein.
  • a "Lewis acid” refers to a compound that can donate a lone electron pair.
  • non nucleophilic base refers to a base that is capable of abstracting an acidic hydrogen, e.g., from an -OH or -NH- moiety, but does not readily take part in a nucleophilic substitution reaction.
  • bases are metal hydrides such as alkali metal hydridies or Ca3 ⁇ 4.
  • oxidizing agent refers to a compound that can accept electrons, and e.g., convert a CH(OH) group to a keto group.
  • oxidizing agents are well known, and non limiting examples include hexavalent chromium reagents such as pyridinium chlorochromate, pyridinium dichromate, hypervalent iodine, and hypochlorite.
  • reducing agent refers to a compounds that can donate electrons or a hydride in a reaction.
  • Preferred examples include borohydrides such as NaBH 4 /CeCl 3 , and alanes such as diisobutyl aluminum hydride.
  • a salt refers to preferably a salt of a mineral acid, or an organic acid such as a carboxylic acid or a sulfonic acid, and/or to alkali, alkaline earth, and various ammonium (including tetraalkyl ammonium, pyridinum, imidazolium and the like) salts.
  • acid salts include salts of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, and citric acid.
  • ((S)-binol) refers to the (S)-enantiomer of 1 , 1 '-bi-2- naphthol
  • ((R)-binol) refers to the (R)-enantiomer of l,l'-bi-2-naphthol.
  • sil refers to Si(R z ) 3 wherein each R z independently is Ci-C 6 alkyl or C 6 -Cio aryl.
  • substantially enantiomerically enriched refers to an enantiomer in an enantiomeric mixture with at least 95% ee, preferably 98% ee, or more preferably 99% ee.
  • this invention provides compounds of Formulas (I) and (VI):
  • k is 1, 2, or 3;
  • each R 1 is independently selected from the group consisting of hydrogen, halo, amino, hydroxy, Ci-C 6 alkoxy, Ci-C 6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, cyano, nitro, - N 3 , and -C0 2 H or an ester thereof, wherein the alkyl, alkoxy, alkenyl, or the alkylnyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, -N 3 , phenyl optionally substituted with 1-3 substituents selected from the group consisting of Ci-C 6 alkyl and Ci-C 6 alkoxy, and - C0 2 H or an ester thereof;
  • R is hydrogen or C(R ) 2 is a keto group
  • R is selected from the group consisting of hydrogen, halo, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, or the alkylnyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, -N 3 , and -C0 2 H or an ester thereof;
  • each R is independently selected from the group consisting of Ci-C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -Cio aryl, C 3 -C 8 cycloalkyl, C2-C10 heteroaryl, C 3 -C 8 heterocyclyl, halo, amino, -N 3 , hydroxy, Ci-C 6 alkoxy, silyl, nitro, cyano, and C0 2 H or an ester thereof, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio aryl, C 2 -Cio heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocyclyl;
  • each R is independently selected from the group consisting of Ci-C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -Cio aryl, C 3 -C 8 cycloalkyl, C2-C10 heteroaryl, C 3 -C 8 heterocyclyl, halo, amino, -N 3 , hydroxy, Ci-C alkoxy, silyl, nitro, cyano, and C0 2 H or an ester thereof, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;
  • X in both occurrences is either oxygen or sulfur
  • n 1 , 2, 3, or 4;
  • n 1 or 2;
  • R 43 is selected from the group consisting of C 6 -Cio aryl and C 2 -Cio heteroaryl; R is selected from the group consisting of Ci-C 6 alkyl and C 6 -Cio aryl;
  • R is hydrogen, Ci-C 6 alkyl, C 2 -C6 alkenyl, and C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, or the alkynyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, Ci-C 6 alkoxy, amino, hydroxy, cyano, nitro, -NHCOCH 3 , and -C0 2 H or an ester thereof;
  • R 49 is hydrogen or Ci-C 6 alkyl
  • R 5 is selected from the group consisting of -O- and N-R 51 ;
  • R 51 is selected from the group consisting of hydrogen and Ci-C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, -N 3 , and -C0 2 H or an ester thereof;
  • C 14 content of a compound of Formula (I), that is tabernanthine, ibogamine, ibogaline, ibogamine, and noribogaine is less than 0.9 ppt, preferably less than
  • the compound of Formula (I) excludes a compound selected from Iboga alkaloids.
  • Iboga alkaloids are alkaloids, isolated from the plant Tabernanthe Iboga that contain a tryptamine and an isoquinuclidene moiety as present in ibogaine or noribogaine.
  • the excluded iboga alkaloid is
  • the compound of Formula (I) is of Formula (I A) or (IB):
  • R 1 , R 2 , R 4 , and R 5 are defined as in Formula (I) above.
  • the compound of Formula (I) is of Formula (IIIA) or (IIIB):
  • R 1 , R 3 , R 4 , and R 5 are defined as in Formula (I) above.
  • the compound of Formula (I) is of Formula (IV A) or (IVB):
  • R is selected from the group consisting of hydrogen and Ci-C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of halo, amino, hydroxy, cyano, nitro, -N 3 , -C0 2 H or an ester thereof, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of Ci-C 6 alkyl and Ci- C 6 alkoxy;
  • k 1 or 2;
  • R 1 , R 2 , R 3 , R 4 , and R 5 are defined as in Formula (I) above.
  • the compound of Formula (I) is of Formula (IVC), (IVD (VIA), or (VIB):
  • R 11 is selected from the group consisting of hydrogen and Ci-C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of halo, amino, hydroxy, cyano, nitro, -N 3 , and -C0 2 H or an ester thereof, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of Ci-C 6 alkyl and C ⁇ - C 6 alkoxy;
  • k 1 or 2;
  • R 2 , R 3 , R 4 , and R 5 are defined as in Formula (I) above.
  • the present invention provides compounds of formula (VA):
  • this invention provides a compound of Formula (VIC): as tabulated below.
  • Me, Et, Pr, Bu and Bn refer to methyl, ethyl, propyl, butyl, and benzyl, respectively.
  • this invention provides an isolated enantiomer of a compound of any one of Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (IVC), (IVD), (VA), (VI), (VIA), (VIB), or (VIC) in substantial enantiomeric excess.
  • this invention provides a compound of formula:
  • R 2 is hydrogen.
  • R 1 is methyl or benzyl.
  • the compound is provided as an isolated enantiomer in substantial enantiomeric excess.
  • this invention provides (+) noribogaine.
  • the (+) noribogaine has a 14 C content of less than 1 ppt, preferably less than 0.9 ppt, and more preferably less than 0.8 ppt.
  • 14 C has a half-life of about 5,730 years and is generated in the upper atmosphere as 14 C0 2 .
  • the amount of 14 C0 2 present is approximately 1 ppt (parts per trillion) and, through photosynthesis, accumulates in plants resulting in a 14 C content of plant material of approximately 1 ppt. Accordingly, plant derived compounds are expected to have approximately 1 ppt 14 C.
  • the synthetic compounds disclosed herein are derived from fossil fuels, which, due to 14 C decay, would have a 14 C content of less than 1 ppt 14 C.
  • synthetic indole and benzofuran fused isoquinuclidene derivative having a 14 C content of less than 1 ppt, preferably, less than 0.90 ppt, or more preferably less than 0.8 ppt.
  • k, R , R , R , and R are defined as in any aspect or embodiment herein.
  • Compound i is obtained, following the procedure described in U.S. application no. 13/ 358,446, which is incorporated herein in its entirety by reference.
  • Compound ii is available commercially or prepared easily from commercially available material following steps well known in the art.
  • this invention provides a process for preparing compound iii comprising contacting compound i with compound ii under conditions to provide compound iii. Accordingly, in step 1, compound i is coupled with compound ii, preferably in an inert solvent, in the presence of an amide or an ester coupling reagent.
  • the reaction is carried out at 0-50°C 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, 1 H-nuclear magnetic resonance (NMR) spectroscopy, and the likes.
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the products may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing compound iv comprising subjecting compound iii under conditions to provide compound iv. Accordingly, in step 2, compound iii is made to undergo an intramolecular Heck type cylization, preferably in an inert solvent, in the presence of 100-130 mole%, with respect to compound iii, of a Pd(II) salt, and an oxidant such as a silver (I).
  • a reducing agent such as a borohydride is used to reductively workup the reaction mixture to provide compound iv.
  • the reaction is carried out at 30-90°C 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, NMR spectroscopy, and the likes.
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the products may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing compound vi comprising contacting compound v with R 4 -M, wherein R 4 is Ci-C 6 alkyl, C2-C 6 alkenyl, or C3-C 6 alkynyl, optionally substituted with a protected form of amino or hydroxy, and M is lithium or magnesium halide, under conditions to provide compound vi.
  • step 3 compound v, which is compound iv wherein C(R 4 ) 2 is a keto group, and which is readily obtained from compound iv, where C(R 4 ) 2 is a cyclic ketal or thioketal by deprotection, is reacted with an R 4 anion equivalent, R 4 -M, wherein M is lithium, a magnesium halide, and the like.
  • the reaction is carried out, preferably with about a 10 fold excess of the R 4 -M in an inert solvent such as ether or tetrahydrofuran at a temperature of -5°C to 15°C 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, 1 H-nuclear magnetic resonance (NMR) spectroscopy, and the likes.
  • NMR 1 H-nuclear magnetic resonance
  • this invention provides a process for preparing compound vii comprising subjecting compound vi under conditions to provide compound vii.
  • step 4 compound vi is dehydrated, preferably using an acid such as a sulfonic acid to provide compound vii.
  • the dehydration is carried out in an inert solvent, preferably at a temperature where the solvent refluxes, 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, NMR spectroscopy, and the likes.
  • routine methods such as thin layer chromatography, NMR spectroscopy, and the likes.
  • solvents useful for this purpose is well known in the art and will be apparent to the skilled artisan upon reading this disclosure.
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the products may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing compound viii comprising subjecting compound vii under conditions to provide compound viii.
  • step 5 the amide carbonyl of compound vii is reduced to a -CH 2 - moiety by reacting with a borohydride, optionally activated with a Lewis acid, such as BF 3 etherate, or with an aluminum hydride.
  • the reaction is performed in an inert solvent, preferably, an ether or tetrahydrofuran at a temperature of 0-50°C or in a refluxing solvent.
  • the reaction is 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, NMR spectroscopy, and the likes.
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the products may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing compound ix comprising subjecting compound viii under conditions to provide compound ix. Accordingly, in step 6, compound viii is hydrogenated to provide compound viii. The hydrogenation is carried out using Pd or Pt or their oxides or hydroxides adsorbed on a solid support such as carbon, alumina, and the like, preferably in an amount less than 100 mole % with respect to compound viii, and hydrogen.
  • the hydrogenation is carried out in an inert solvent, such as an alcohol, ethyl acetate, or an ether, at 15-30°C 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, NMR spectroscopy, and the likes.
  • an inert solvent such as an alcohol, ethyl acetate, or an ether
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation.
  • C(R 4 ) 2 is ia cyclic ketal or thioketal.
  • R 5 is NH.
  • R 5 is O.
  • R 4 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, optionally substituted with 1-3 substituents, as provided herein, or their protected forms that will be apparent to the skilled artisan.
  • this invention provides processes, preferably, enantioselective processes, for preparing (-) noribogaine, in a substantially enantiomerically pure form, as schematically illustrated below, where the reagents indicated are merely illustrative and are not limiting, as discussed in further detail below.
  • this invention provides a process for preparing compound 2 comprising contacting compound 1 with 5-benzyloxyindoleacetic acid under conditions to provide compound 2.
  • Compound 1 is coupled with the benzyloxy substituted indole acetic acid to provide compound 2.
  • the coupling is performed preferably in an inert solvent, such as a chlorinated solvent such as dichloromethane, or in tetrahydrofuran, or acetonitrile, in the presence of a amide or ester coupling reagent.
  • the coupling is performed in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and a hindered base, such as diisopropylethyl amine (DIPEA).
  • EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DIPEA diisopropylethyl amine
  • the reaction is carried out at 0-50°C 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
  • FIG. 3 demonstrates the 1 H-NMR spectrum of compound 2.
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the product may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing compound 3 comprising subjecting compound 2 under conditions to provide compound 3.
  • step 2 compound 2 is deprotected by reacting with an aqueous acid.
  • Various mineral acids such as sulfuric acid or hydrochloric acid, and sulfonic acids, such as toluene sulfonic acid are useful as the acid.
  • the deprotected compound is subjected to an intramolecular Heck type cylization.
  • Various art known palladium reagents such as palladium chloride and complexes thereof (such as the bis acetonitrile complex) are useful as the cyclization reagent, used in 100-130 mole% with respect to compound 2, further in presence of an oxidant, such as a Ag(I) salt. Reductive workup, employing a borohydride was demonstrated to provide compound 3 (see, FIG. 1).
  • the reaction is carried out in an inert solvent, such as acetonitrile, alcohols, acetic acid, and mixtures thereof, at 30-90°C, preferably at 60-80°C 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, NMR spectroscopy, and the likes.
  • an inert solvent such as acetonitrile, alcohols, acetic acid, and mixtures thereof
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the product may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing compound 4 comprising contacting compound 3 with an ethyl anion equivalent under conditions to provide compound 4.
  • an ethyl anion equivalent is an anion that after this reaction is easily converted to an ethyl group.
  • compound 3 is reacted with an ethyl anion equivalent, such as, vinyl magnesium bromide (in a 10 fold mole/mole excess with respect to compound 3), in ether, tetrahydrofuran or a mixture thereof to provide after aqueous work up, compound 4.
  • the reaction is 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, NMR
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the product may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing compound 5 comprising subjecting compound 4 under conditions to provide compound 5.
  • compound 4 is dehydrated to provide compound 5.
  • the dehydration is performed preferably using an acid such as a sulfonic acid such as toluene sulfonic acid to provide compound vii.
  • the dehydration is carried out in an inert solvent, preferably at a temperature where the solvent refluxes, 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, NMR spectroscopy, and the likes.
  • Various solvents useful for this purpose is well known in the art and will be apparent to the skilled artisan upon reading this disclosure.
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the product may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing compound 6 comprising subjecting compound 5 under conditions to provide compound 6.
  • step 5 the amide carbonyl of compound 5 is reduced to provide compound 6, by reacting with a borohydride, optionally activated with a Lewis acid, such as BF 3 etherate, or with an aluminum hydride.
  • a preferred reagent is lithium aluminum hydride.
  • the reaction is performed in an inert solvent, preferably, an ether or tetrahydrofuran at a temperature of 0-50°C or in a refluxing solvent.
  • the reaction is 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, NMR spectroscopy, and the likes.
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation, or the product may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing (-) noribogaine or a salt thereof comprising subjecting compound 6 under conditions to provide (-) noribogaine or a salt thereof.
  • step 6 compound 6 is hydrogenated to provide (-) noribogaine or a salt thereof.
  • the hydrogenation is carried out using Pd, Pt, Rh or their oxides or hydroxides adsorbed on a solid support such as carbon, alumina, and the like, preferably in an amount less than 100 mole % with respect to compound 6, and hydrogen.
  • a preferred reagent is Pt0 2 .
  • the hydrogenation is carried out in an inert solvent, such as an alcohol, ethyl acetate, or an ether.
  • the hydrogenation is carried out at 15-30°C 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, NMR spectroscopy, and the likes.
  • the product can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, and precipitation.
  • the reactions are carried out, preferably in an inert solvent that will be apparent to the skilled artisan upon reading this disclosure, and at temperatures that will also be apparent to the skilled artisan upon reading this disclosure.
  • the reactions are performed 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, 1 H-nuclear magnetic resonance (NMR) spectroscopy, and the likes.
  • the products can be isolated and optionally purified using standard purification techniques, such as liquid chromatography, crystallization, precipitation, and distillation under reduced pressure, or the products may be used for a subsequent reaction without further purification.
  • this invention provides a process for preparing a compound of formula:
  • TBS silicon protecting group
  • Benzoquinone is combined with, e.g., at least an equimolar amount of the diene in an inert chlorinated solvent in presence of a catalytic amount, preferably 20%-35% molar amount, still more preferably, 25%-30% molar amount with respect to benzoquinone, of Ti((S)-binol)Cl 2 .
  • the concentration of the reactants and the catalyst in the reaction solvent are as follows: benzoquinone, 0.05-0.2 molar, preferably 0.09-0.13 molar, still more preferably 0.1 1 molar: diene, 0.05-0.2 molar, preferably 0.1-0.14 molar, still more preferably 0.12 molar; and the catalyst, 0.01- 0.1 molar, preferably 0.02-0.06 molar, still more preferably 0.03 molar.
  • the reaction is performed at room temperature for a period of time sufficient to effect a substantial completion of the reaction.
  • this invention provides a process for preparing a compound of formula:
  • Ti((S)-binol)Cl 2 or Ti((S)-binol)Cl 2 is preferably prepared in situ by reacting (R) or (S)-binol with Ti(- OCHMe 2 )2Cl 2 .
  • this invention provides a process for preparing a compound of formula:
  • the reducing agent is diisobutylaluminum hydride.
  • this invention provides a process for preparing a compound of formula:
  • R S S0 2 C1 wherein R s is alkyl, fluoroalkyl, aryl, or aryl substiotuted with an alkyl or a halogen group, a base, and optionally a nucleophilic catalyst such as 4- N,N-dialkylaminopyridine to provide a compound of formula:
  • R S S0 2 C1 wherein R s is alkyl, fluoroalkyl, aryl, or aryl substituted with an alkyl or a halogen group, a base, and optionally a 4-N,N-dialkylaminopyridine to provide a compound of formula:
  • Steps (i) to (x) can be performed substantially according to the methods described in White, supra.
  • the hydrogenation is performed preferably employing a catalyst such Rh/Al 2 0 3 and hydrogen, which catalyst does not produce substantial amounts of the hydrogenolyzed product.
  • the allylic hydroxy group(s) can be replaced by hydrogen atom(s).
  • a variety of oxidizing agents can be employed for step (ii) such as for example pyridinum dichromate, pyridinium chlorochromate, and the like. Those oxidizing agents are preferred that would not convert the tributylsilyloxy (OTB S) group to an -OH group.
  • step (iii) The selective ketalization of the less hindered ketone in step (iii) is performed using a mild acid catalyst such as pyridinium para tolune sulfonate (PPTS).
  • a salt of NH 2 OH is reacted with the ketone and a base to provide the oxime.
  • bases may be employed, including without limitation, acetates, preferably alkali metal acetates, alkali, and nitrogen containing bases such as pyridine, triethyl amine and the like.
  • step (vi) a variety of sulfonyl chlorides may be used, including without limitation para toluene sulfonyl chloride.
  • a variety of bases may be employed, including without limitation, alkali and nitrogen containing bases such as pyridine, triethyl amine and the like.
  • Preferred nucleophilic catalysts include 4-N,N-dimethylaminopyridine and 4-pyrrolidinopyridine.
  • fluoride sources may be used including tertiary alkyl ammonium fluorides, such a tetrabutylammonium fluoride.
  • a variety of bases may be employed, including without limitation, alkali and nitrogen containing bases such as pyridine, triethyl amine and the like.
  • Preferred nucleophilic catalysts include 4-N,N- dimethylaminopyridine and 4-pyrrolidinopyridine.
  • preferred non- nucleophilic bases used include, hydrides such as sodium, potassium and calcium hydrides.
  • a variety of acids can be used to convert the dimethyl ketal to the ketone.
  • chromatography Depending on the amount of impurity present, a product may be separated by column chromatography, crystallization, or such other techniques well known to the skilled artisan, or the reaction product may be used without further purification in the next step.
  • this invention provides a process for converting:
  • this invention provides a process for preparing a compound of formula:
  • R 1 is C 1 -C 4 alkyl optionally substituted with 1-3 phenyl or substituted phenyl groups, wherein the substituted phenyl is substituted with 1-3 C1-C4 alkyl or C1-C4 alkoxy groups, under Fischer indole synthesis conditions to provide the keto ibogaine derivative of formula:
  • R is methyl.
  • R is a methyl group substituted with 1-3, preferably 1-2, more preferably 1 phenyl group, which phenyl group is optionally substituted with 1-3 C1-C4 alkyl or C1-C4 alkoxy groups.
  • R is benzyl.
  • R is methyl, it is preferred to not use a boron based Lewis acid, such as BF 3 etherate, for this transformation.
  • the ketoamide compound is present at least 80%, preferably at least 90%, more preferably at least 95%, or still more preferably at least 98% as the (5aR,7R,9S,9aS)-9-ethyl-3,4,5a,6,7,8,9,9a-octahydro-l,7-methano-lH- benz [b] azepine-2,5 -dione enantiomer :
  • the ketoamide compound contains, at least 60%>, preferably at least 80%>, more preferably at least 90%, or still more preferably at least 96% ee of the
  • keto ibogaine derivative is present at least 80%, preferably at least 90%, more preferably at least 95%, or still more preferably at least 98% as the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer.
  • a substituted hydrazine containing an electron donating 4- alkoxy substituent effectively provides the tricyclic indole under Fischer indole synthesis conditions.
  • the ketoamide compound is combined with at least an equimolar amount of the substituted phenylhydrazme or a salt thereof, in the presence of an acid or a mixture of acids.
  • Suitable acids include carboxylic Bronsted acids such as acetic acid and Lewis acids such as BF and its solvates such as etherates.
  • the reaction is performed at 40°C- 60°C, and may optionally be warmed up to 70°C-90°C, for a period of time sufficient to effect a substantial completion of the reaction.
  • Suitable solvent include acetic acid, propionic acid and the like.
  • Suitable salts of the substituted phenylhydrazme include salts of mineral acids, such as HC1.
  • this invention provides a method of synthesis comprising contacting a ketoamide compound of formula:
  • R 1 is C 1 -C 4 alkyl optionally substituted with 1-3 phenyl or substituted phenyl groups, wherein the substituted phenyl is substituted with 1-3 C 1 -C 4 alkyl or C 1 -C 4 alkoxy groups, under Fischer indole synthesis conditions to provide a keto ibogaine derivative of formula:
  • the ketoamide compound is present at least 80%, preferably at least 90%, more preferably at least 95%, or still more preferably at least 98% as the (5aS,7S,9R,9aR)-9-ethyl-3,4,5a,6,7,8,9,9a-octahydro-l,7-methano-lH- benz [b] azepine-2,5 -dione enantiomer :
  • the keto ibogaine derivative is present at least 80%, preferably at least 90%), more preferably at least 95%, or still more preferably at least 98%> as the 2(S), 4(R), 5(R), 6(R) and 18(S) enantiomer.
  • the process further comprises subjecting the keto ibogaine derivative:
  • the keto ibogaine derivative is contacted with at least an equimolar, preferably 4-6 molar excess of a borohydride, preferably NaBH 4 and a Lewis acid, preferably, BF 3 etherate, in an inert solvent such as tetrahydrofuran.
  • a borohydride preferably NaBH 4
  • a Lewis acid preferably, BF 3 etherate
  • the reaction is performed initially at 0°C and then at room temperature for a a period of time sufficient to effect a substantial completion of the reaction.
  • the process further comprises subjecting the keto ibogaine derivative:
  • the process further comprises deprotecting the compound of formula:
  • the noribogaine obtained is present at least 80%, preferably at least 90%, more preferably at least 95%, or still more preferably at least 98% as the (-) or naturally occurring 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer of noribogaine.
  • R 1 is C1-C4 alkyl, and the deprotection is performed by using BBr 3 in an inert solvent under conditions well known to the skilled artisan.
  • R 1 is benzyl and the deprotection is performed by using
  • the process further comprises deprotecting the compound of formula:
  • the noribogaine obtained is present at least 80%, preferably at least 90%, more preferably at least 95%, or still more preferably at least 98%o as the (+) or nonnatural 2(S), 4(R), 5(R), 6(R) and 18(S) enantiomer of noribogaine.
  • this invention provides (-) noribogaine and (+)noribogaine, and intermediates thereto, preferably in substantially enantiomerically pure forms, prepared according to the processes provided herein.
  • the indole isoquinuclidene derivative (-) noribogaine has utility in the treatment of drug dependency and as an analgesic. See U.S. Patent Nos. 6,348,456 7,220,737, supra.
  • the indole and benzofuran fused isoquinuclidene derivatives provided and (+) noribogaine herein have utility to test their interaction with the opioid receptors to better understand the mechanism of (-) noribogaine 's analgesic action.
  • the novel compounds provided herein also have utility as intermediates to synthetic noribogaine or as compounds having activity in drug dependency or as analgesics.

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Abstract

La présente invention concerne des dérivés d'isoquinuclidène réunis par fusion à de l'indole et du benzofurane. Elle concerne églement des procédés, de préférence des procédés à énantiosélectivité, permettant de préparer de tels dérivés, comprenant des procédés de préparation de noribogaïne (-) et (+) ou un sel associé, dans des formes sensiblement pures d'un point de vue énantiomérique.
EP13741381.1A 2012-01-25 2013-01-24 Dérivés d'isoquinuclidène réunis par fusion à de l'indole et du benzofurane et leurs procédés de préparation Withdrawn EP2807167A4 (fr)

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US201261741798P 2012-01-25 2012-01-25
US201261590740P 2012-01-25 2012-01-25
US201261591258P 2012-01-26 2012-01-26
PCT/US2012/022787 WO2013112163A1 (fr) 2012-01-25 2012-01-26 Dérivés d'isoquinuclidène fusionnés à de l'indole et du benzofurane et procédés de préparation de ceux-ci
PCT/US2013/023017 WO2013112757A1 (fr) 2012-01-25 2013-01-24 Dérivés d'isoquinuclidène réunis par fusion à de l'indole et du benzofurane et leurs procédés de préparation

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