EP3164402A1 - Promédicaments de noribogaïne n-substitué - Google Patents

Promédicaments de noribogaïne n-substitué

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Publication number
EP3164402A1
EP3164402A1 EP14890017.8A EP14890017A EP3164402A1 EP 3164402 A1 EP3164402 A1 EP 3164402A1 EP 14890017 A EP14890017 A EP 14890017A EP 3164402 A1 EP3164402 A1 EP 3164402A1
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European Patent Office
Prior art keywords
substituted
compound
group
alkyl
heterocyclic
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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EP14890017.8A
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German (de)
English (en)
Inventor
Deborah C. Mash
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DemeRx Inc
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DemeRx Inc
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Publication of EP3164402A1 publication Critical patent/EP3164402A1/fr
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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
    • C07D487/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • This invention relates generally to prodrugs of noribogaine or noribogaine derivatives.
  • This invention also relates to pharmaceutical compositions comprising the prodrugs of noribogaine or noribogaine derivatives as well as methods of treating pain, addiction and or stress using such compounds and/or pharmaceutical compositions.
  • Noribogaine is a metabolite of ibogaine and is sometimes referred to as 12- hydroxyibogamine.
  • US Patent No. 2,813,873 claims noribogaine albeit as "12-0- demethylibogaine" while providing an incorrect structural formula for ibogaine.
  • the structure of noribogaine has no w been thoroughly evaluated and is found to combine the features of tryptamine, tetrahydrohavairie and indoiazepines.
  • Noribogaine can be depicted the following formula:
  • Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non-addictive alkaloid useful in treating drug dependency (U.S. Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737).
  • Noribogaine is typically administered orally or intravenously and becomes systemically available to the treated patient. While noribogaine allostericaily binds tightly to the ⁇ and ⁇ receptors, the systemic circulation of noribogaine increases the likelihood of undesirable side effects while the availability of noribogaine is limited by the efficiency of its passage across the blood brain barrier.
  • the invention relates, in part, to a class of noribogaine prodrugs which, after administration, release noribogaine in vivo.
  • the prodrug moiety is selected to be readily cleavable either by a cleavable linking ami or by cleavage of the prodrug entity that binds to noribogaine such that noribogaine is generated in vivo.
  • the prodrug moiety Is selected to facilitate binding to the ⁇ and or ⁇ receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the ⁇ and/or receptors.
  • This invention also relates, in part, to a class of prodrugs of noribogaine derivatives.
  • this invention is directed to compounds which are represented by Formula I or II below:
  • L is selected from the group consisting of a covending bond and a cleavable linker group
  • R is selected from the group consisting of hydrogen, a hydrolysabie group selected from the group consisting of ⁇ C(0)R 2 , -C(0)NR 3 R 4 and -C(0)OR 5 , where R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl and substituted alkynyl,
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyi. substituted alkenyi, alkynyl, substituted alkynyl, aryl. substituted ary!, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic,
  • R 3 is selected from the group consisting of alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic provided that R is not a saccharide or an oligosaccharide: ' is selected from the group consisting of hydrogen, aiky!, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyuyl, aryl, substituted aryl, eycloalkyl, substituted cycioalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic provided that R 1 is not a saccharide or an oligosaccharide;
  • R l ' is hydrogen or -OR
  • R n is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, (CH 2 ) m OC(0)aikyL (CH 2 ) m OH, (CH 2 )n,Oalkyl, CH2-X-CH 3 or
  • R 1 is hydrogen, then either R is selected from the group consisting of ⁇ C(0)NR 3 R and -C(0)OR 5 or R a is not alky!;
  • R H is selected from the group consisting of hydrogen, C1-C3 alkyl, substituted C1 -C3 alkyl, C1-C3 alkoxy and substituted alkoxy,
  • R' 1 is H.
  • R 1 1 is C 1 -C3 alkyl, such as ethyl, In one embodiment.
  • R is C3 ⁇ 4C3 ⁇ 4OH, in one embodiment,
  • R ! 1 is CH 2 CH 2 OCH 3 .
  • R 1 1 is CH2CH2OCH2PI1.
  • Ph represents a phenyl group.
  • R u is CH 2 CH 2 OC(0)aIkyL such as CH 2 CH 2 OC(0)(CH2)ioCH3.
  • R u is CH 2 CH 2 0(CH 2 ) p O(CH2) «0(CH 2 ) r CH 3 .
  • R 11 is C 1 -C3 alkyl optionally substituted with YH, YR 12 , YC(0)R 12 , C(0)YR i2 s C(0)NH 2 , C(0) HR 12 , C(0)NR 12 R 13 , N3 ⁇ 4.
  • R ! 5 is C1-C3 alkoxy optionally substituted with. YH, YR ! ? .
  • R is hydrogen and L is a cleavable group.
  • R is hydrogen
  • L is a -C(G)-, -C(0)0 ⁇ , or -C(0)NH-
  • R ! is substituted alkyl.
  • R ! is alkyl substituted with -NR 6 R 7 where R 6 and R' are independently selected from the group consisting of hydrogen, alkyl, alkenyl substituted aikenyl, aikynyl, substituted aikynyl, aryl, substituted aryl, cycloalkyl, substituted cycloaikyl, heteroaryJ, substituted heleroaryl, heterocyclic, and substituted heterocyclic.
  • R is selected from the group consisting of - € G)NR " 'R 4 and -CiC ⁇ OR 5 and R 1 is hydrogen,
  • a compound of Formula II which is selected from those as set ibrth in Table I below or a pharmaceutically acceptable salt and/or solvate thereof:
  • the compound of Formula I is a compound wherein R i0 is H, L and R ! are as defined in Table 1 above, and R' ' is C1-C3 alkyl optionally substituted with YH, YR' ⁇ YC(0)R 12 , C(0)YR !2 , C(0)N3 ⁇ 4, C(0)NHR ,2 9 C(0)NR L2 R 13 , NH 2 , NHPJ 2 , NR I2 R 13 , NHC(Q)R !2 , or NR L 2 C(0)R 13 , where Y is O or S, R 12 and R 13 are independently C,-C 3 alkyl, or a pliarmaceuticaiiy acceptable salt and/or solvate thereof.
  • the compound of Formula I is a compound wherein R I 0 is -OR, R, L and R 1 are as defined in Table ⁇ above, and R 1 1 is Cj-C 3 alkyl optionally substituted with YH, YR 12 , YC(0)R !2 , C(0)YR I 2 , C(0)NH 2 , C(0)NHR 12 , C(0)NR ,2 R 13 , H 2 , NHR 12 ,
  • NR ,2 R 13 NHC(0)R n or NR ! 2 C(0)R ! 3 5
  • Y is O or S
  • R ! 2 and R 13 are independently C C 3 alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
  • this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipieni and a therapeutically effective amount of a compound of Formula I or ⁇ or Table I above.
  • this invention is directed to a method for treating addiction in a patient which method comprises administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula I or II or Table I above.
  • this invention is directed to a method for treating pain, addition and/or stress in a patient which method comprises administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula I or II or Table ⁇ above.
  • 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.
  • the invention is directed to compositions comprising the prodrugs described herein and an excipierit to facilitate transport across the blood brain barrier.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), w-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH ), .sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), /-butyl ((CH 3 ) 3 C-), n-pentyl
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-OC-) unsaturation.
  • Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably i to 2 substituents, selected from the group consisting of aikoxy, substituted aikoxy, acyl. aeylamino, acyioxy, amino, substituted amino, aminocarbonyl,
  • heterocyciyloxy heterocvclylthio, substituted heterocyciylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyi, thiol, alkylthio, and substituted aikylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of aikoxy, substituted aikoxy, acyl, aeylamino, acyioxy, amino, substituted amino, aminocarbonyl,
  • arninothiocarbonyl aminocarboriylamino, aminothiocarbonylamino, aminocarbonyioxy, aminosul fonyl, aminosuifonyloxy, aminosulfbnylamino, arnidino, aryi, substituted ar l.
  • aryloxy substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyi ester, (carboxyl ester)amtno, (carboxyi ester)oxy, cyano, cycioalkyl, substituted cycioalkyl, cycloaikyloxy, substituted cycloaikyloxy, cycloalkylthio, substituted cycloalkylthio, cycloaikenvl, substituted cycloaikenvl, cvcloaikenyloxy, substituted cvcloaikenyloxy, cycioaikenylthio, substituted cycioaikenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryi, substituted heteroaryi.
  • heteroaryloxy substituted heteroaryloxy, heteroarylthio, substituted heieroarytthio, heterocyclic, substituted heterocyclic, heteroeyclyloxy, substituted heteroeyclyloxy, heterocyclyithio, substituted heterocyelylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkyithio, arid substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to an acetylenic carbon atom.
  • '"Aikoxy refers to the group -O-a!kyl wherein alkyS is defined herein, Aikoxy includes, by way of example, methoxy, ethoxy, H-propoxy, isopropoxy, «-butoxy, -butoxy, sec-butoxy, and w-pentoxy,
  • Substituted aikoxy refers to the group -0-(substituted afkyl) wherein substituted aikyi is defined herein.
  • Acyl refers to the groups H-C(O)-, alkyl-C(0 , substituted aikyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(0)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyi ⁇ C(0)-, substituted cycloalkyl-C(O)-, eyeloalkenyi-C(O)-, substituted cyeloalkenyl-C(O)-, aryl-C(O)-, substituted ary!-C(O)-, heteroary!-C(O)-, substituted heteroaryl-C(0)-, heterocyctic-C(O)-, and substituted heteroeyciic-C(O)-.
  • aikyi, substituted alkyl, aikenyl, substituted aikenyl, alkynyi, substituted alkynyl, cycloalkyi. substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryi, substituted aryi, heteroaryi, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein, Acyl includes the "acetyl" group CHjCtQ)-.
  • Acylamino refers to the groups -NR 17 C(0)alkyl, -NR 17 C(0)substituted alkyl, -NR l7 C(0)cycloalkyl, -NR i7 C(0)substiiuted cycloalkyi, -NR l7 C(0)cycloalkenyi s
  • R 17 is hydrogen or aikyi and wherein alkyl, substituted a!kyi, aikenyl, substituted aikenyl, alkynyl, substituted alkynyi, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryi, substituted aryi, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein,
  • Acyloxy refers to the groups a!kyl-C(0)0 ⁇ , substituted a!kyl ⁇ €( €))0-, alkenyl-C(0)0-, substituted a!kcnyj-UOKK aikynyi-C(0)0 ⁇ , substituted alkynyi - €(0)0 ⁇ , aryl-C(0)0-, substituted aryl-C(0)0- s cycloalkyl-C(O)C ) -, substituted eycioaikyhC(0)0-, cycloalkenyI-C(0)0-, substituted cycloalkenyl-C(0)0-, heteroaryi ⁇ C(O)0 ⁇ , substituted heteroaryl-C(0)0-, heterocycHc-C(0)0-, and substituted heterocyciic-C(0)0- wherein alky!, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyi, cycl
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -NR'*R 19 where R' 8 and R i 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -S0 2 -alky], ⁇ S0 2 -subsiituied alkyl, -SCb-alkenyl, -SG 2 -substituted alkenyl, -S02-cycloalkyl, -S0 2 -substituted cylcoaikyl, -SOycycloalkenyl, -S0 2 -substituted c
  • R !S and R ,v are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 1 * and R !S are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyi, substituted alkynyl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • R' 8 is hydrogen and R' 9 is alkyl
  • the substituted amino group is sometimes referred to herein as alkyl amino.
  • R S and R 19 are alkyl, the substituted amino group is sometimes referred to herein as dialkylaniino.
  • a monosubstituted amino it is meant that either R 1$ or R h ⁇ is hydrogen but not both.
  • R 1 S nor R 19 it is meant that neither R 1 S nor R 19 are hydrogen.
  • Aminocarbonyl refers to the group -C(O)NR 20 R z l where R i0 and R 2 ' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyi, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 20 and R 21 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substi tuted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cyclo
  • Aminothiocarbonyl refers to the group -C(S)NR 20 R 2 (where i ° and R 21 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyl.
  • alkenyl substituted alkenyl , alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, heteroaryl.
  • substituted heteroaryl, heterocyclic, and substituted heterocyclic where R 0 and R 2 i are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminocarbonylamino refers to the group -NR ! 'C(O)NR 20 R 21 where R' 7 is hydrogen or alkyi and R 20 and R *1 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted
  • cycloaikenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic where R 2 and R 2 ' are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • AiiJtnothiocarbonylamino refers to the group -NR 1 'C(S)NR 20 R 2! where R 17 is hydrogen or alkyi and R 20 and R 2! are independenily selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted
  • cycloaikenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic where R 20 and R 2 ' are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Arninocarbonyloxy refers to the group -O-C(Q)NR 2 R 2i where R 20 and 2i axe independently selected from the group consisting of hydrogen, alkyl, substituted alky!, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl.
  • cycloalkyl substituted cycloalkyl, cycloaikenyl, substituted cyc!oaikenyl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and where R 20 and R ai are optionally- joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl substituted alkenyl, alkynyl, substituted alkynyl cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryi, substituted aryl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein.
  • Aminosulfonyl refers to the group -SO 2 NR 20 R 25 where R 20 and R 2i are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and where R 20 and R 2 ' are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cyclo
  • Aminosulfonyloxy refers to the group -OSG 2 NR 2(3 R 21 where R 20 and R 2 i are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted aikynyl, aryl substituted aryl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and where R 20 and R 2i are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloaikenyl, substituted
  • Aminosulfonylamino refers to the group - R 1 '-3C3 ⁇ 4NR 20 R i where R 17 is hydrogen or alkyl and R 20 and R 21 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aikynyl, substituted alkynyl, aryl, substituted aryl, cycloaikyi, substituted cycloaikyi cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R i0 and R S are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloaikyi, substituted cyclo
  • Aryl refers to a monovalent aromatic carbocyciie group of from 6 to 1 carbon atoms having a single ring ⁇ e.g. , phenyl) or multiple condensed rings ⁇ e.g., naphthyl or ant ryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolmone, 2H-1 ,4-henzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom, Preferred aryl groups include phenyl and naphthyl.
  • Substituted aryl refers to aryl groups which are substituted with I to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alky!, alkenyl, substituted alkenyl.
  • alkynyl substituted alkynyl, alkoxy, substituted alkoxy, acyi, acyiamino, acyloxy, amino, substituted amino, amlnocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylantino, aminocarbonyloxy, amtnosu!fonyl, aminosulfonyloxy, arninosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, aryithio, substituted arylihio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloaikyi, substituted cycloaikyi, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substitute
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryioxy refers to the group -Q-(substituted ary!) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryi, where aryi is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryi), where substituted aryi is as defined herein.
  • Carboxy or “carboxyl” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the groups -C(0)0-alkyl
  • alkyl or hydrogen is alkyl or hydrogen, and wherein alkyl, substituted aikyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyeioalkyl, substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)oxy refers to the group -0-C(0)0-aIkyl, substituted
  • cycloaikenyl -0-C(0)0-heteroaryl, -0-C(0)0-substituted heteroaryl, -0-C(0)0-heterocyclic ( and -0-C(0)0-substituted heterocyclic wherein alkyi, substituted alkyi alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, cycloalkyl substituted cycloalkyl, cycloaikenyl, substituted cycloaikenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Cyano refers to the group -CN.
  • Cycloalkyl refers to cyclic alkyi groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring.
  • suitable cycloalkyl groups include, for instance, adaciantyi, cyclopropyl, cyelohutyL cyelopentyl, and cyclooctyl.
  • Other examples of cycloalkyl groups include bicyele[2,2,2,]oetanyl, norbornyl, and spirobicyclo groups such as spiro[4.5]dec-8-yl:
  • Substituted cycloalkyl and “substituted cycloaikenyl” refers to a cycloalkyl or cycloaikenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting ofoso, thione, alkyi, substituted alkyi, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy.
  • cycloalkylthio cyeloalkenyi, substituted cyeloalkenyi cycloaikenyioxy, substituted cycloaikenyioxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryi, substituted heteroarvl. heteroaryioxy, substituted heteroaryloxy, heteroarylthio.
  • substituted heteroarylthio heterocyclic, substituted heterocyclic, heterocyclyioxy, substituted heterocyelyioxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol alky!thio, and substituted alkylthio, wherein said substituents are defined herein.
  • Substituted cycloalkyloxy refers to -0 ⁇ (substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycioalky!.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyi).
  • Substituted cycloaikenyioxy refers to -0-(substituted cyeloalkenyi).
  • Cycloalkenylthio refers to -S-cycloalkenyl.
  • Substituted cycloalkenylthio refers to -S-(subsiituted cyeloalkenyi ⁇ .
  • Substituted guanidino refers to -NR 2i C(" R 2jl )N(R- J ) 2 where each R 2i is independently selected from the group consisting of hydrogen, alkyl substituted aiky!, aryl, substituted aryl heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and two R 23 groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R 2j is not hydrogen, and wherein said substituents are as defined herein,
  • Halo or "halogen” refers to fluoro, chloro, bromo and iodo and preferabl is fluoro or chloro.
  • Haloaikyl refers to alkyl groups substituted with 1 to 5, 1 to 3, or I to 2 halo groups, wherein alkyl and halo are as defined herein.
  • Haloalkoxy refers to aikoxy groups substituted with 1 to 5, 1 to 3, or I to 2 halo groups, wherein aikoxy and halo are as defined herein,
  • Haloalky!thio refers to alkylthio groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein,
  • Heieroaryl refers to an aromatic group of from 1 to 10 carbon atoms and I to 4 heteroaioms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heieroaryl groups can have a single ring (e.g. , pyridinyl or furyl) or multiple condensed rings (e.g.
  • indolizinyl or benzothienyi wherein the condensed rings may or may not be aromatic and/or contain a heteroatora provided that the point of attachment is through an atom of the aromatic heieroaryl group, in one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heieroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), suifmyl, and/or su!fonyl moieties.
  • Preferred heteroaryls include pyridinyl pyrroiyl, mdolyi, thiophenyl, and furanyl.
  • Substituted heieroaryl refers to heieroaryl groups that are substituted with from 1 to 5. preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryi.
  • Heteroaryloxy refers to -O-heteroaryl
  • Substituted heteroaryloxy refers to the group -0-(substituted heteroaryi),
  • Heieroarylthio refers to the group -S-heteroaryl.
  • Substituted heieroarylthio refers to the group -S-(substituted heteroaryi).
  • Heterocycle or “heterocyclic' '' or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from I to 10 ring carbon atoms and from 1 to 4 ring heteroaioms selected from the group consisting of nitrogen, sulfur, or oxygen, Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, ary , or heteroaryi provided that the point of attachment is through the
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, suifmyl, and/or sutforryl moieties.
  • OOSSj “Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyP refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably I to 3 of the same substituems as defined for substituted cyeloalkyl
  • Heteroeyclylosy refers to the group -O-heterocycyl.
  • Substituted heteroeycl loxy refers to the group -G ⁇ (substituted heterocycyl).
  • Heterocyelylthio refers to the group -S-heterocycyl.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl),
  • heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazoie, pyridine, pyrazine, pyrimidine, pyridazme, indolizine, isoindo!e, indole, dihydroindole, indazoie, purine, quinolizine, isoquinoline, quinoline, phthalaz e, naphihylpyridine, qumoxaltne, quinazoline, cinnoiine, pteridine.
  • carhazole carboline, phenanthridine, acridine, p enanthroline, isoibiazole, phenazine, isoxazole, phenoxazme, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, p haiirnide, i ,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetehydrobenzoj3 ⁇ 4]thiophene, thiazole, thiazoJidine, thiophene, benzofbjthiophene, morpholinyl, thiomorpholinyl (also referred to as
  • Ne refers to the group -N0 2 .
  • Oxo refers to the atom (-0) or (-0 " ).
  • Substituted suifonyl refers to the group -S0 2 -aikyI, -SOa-substitoted aikyl, -SOralkenyl, -SOj-substituted aikenyl, -SOj-cycloalkyl, -SOa-substituted cylcoaikyi, -SOa-eyeloalkenyl, -SC3 ⁇ 4-substiiuted cylcoalkenyl, -SOj-aryL -SOs-substituted aryS,
  • heterocyclic wherein alkyl, substituted alkyl, aikenyl, substituted aikenyl, aikynyl, substituted aikynyl, cyeloalkyl, substituted cyeloalkyl, cycloalkenyl, substituted cyeloalkenyi, aryl, substituted aryl, heteroaryl substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Substituted sulfonyl includes groups such as methyl - SO - phenyl-S0 2 - s a d 4-methylphenyl-SQ2-.
  • alkyisulfonyl refers to -SCh-alkyl.
  • '3 ⁇ 4aioalkylsttlfonyl refers to -SCh-haloalkyl where haloalkyl is defined herein.
  • (substituted suifonybamino) * refers to -NHisubstituted sulfonyi), and the term
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, . alkynyl, substituted aikynyl, cycioalkyi, substituted cycioalkyi,, cycioaikenyl, substituted cycioaikenyl, aryl, substituted aryl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein,
  • Thioacyt refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, aikeny!- (S ⁇ -. substituted alkenyl-C(S)-, aikynyl-C(S)- s substituted alkynyi-C(S)-, cycIoaikyl ⁇ C(S) ⁇ ⁇ substituted cycloalkyi-C(S)-, cydoaikeny!-C(S)-, substituted
  • Alkylthio refers to the group -S-aikyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-fsubstituted alkyl) wherein substituted alkyl is as defined herein.
  • Steps or “stereoisomers'” refer to compounds thai differ in the ebirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • noribogaine refers to the compound:
  • noribogaine is prepared by demethylation of naturally occurring ibogaine:
  • the term "pharmaceutically acceptable salt” refers to salts derived from organic or inorganic acids.
  • examples of such acids include, without limitation, hydrochloric acid, hydrobromie acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, cmbonic acid, enanthie acid, and the like.
  • solvate refers to a solid form of a compound that crystallizes with solvent molecules trapped inside and includes, but is not limited to, complexes of a compound of the invention with less than one, one or more solvent molecules. or from about 0, 1 to about 100, or about 1 to about 10, or about 0.5, 1, 2, 3 or 4 solvent molecules,
  • a "pharmaceutically acceptable solvate" of a compound of the invention refers to a solvate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • solvents that cars be used to create solvates include, but are certainly not limited to, water, methanol, ethanol, isopropanol, butanol, C1 -C6 alcohols in general (and optionally substituted), tefrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water, and solvent mixtures thereof.
  • Other biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention.
  • various organic and inorganic adds and bases can be added or used alone as the solvent to create a desired solvate. Such acids and bases are known in the art.
  • the solvate is referred to as hydrate, such as hemihydrate (two compound molecules are complexed with one water molecule), monohydrate (one compound molecule is complexed with one water molecule) or dehydrate (one compound molecule is complexed with two water molecules).
  • the term "therapeutically effective amount' ' ' refers to the amount of a composition of this invention that is sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment.
  • the therapeutically effective amount will vary depending upon the subject and condition being treated, the weight and age of the subject, the severity of the condition, the particular composition or exeipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art,
  • treatment means any treatment of a disease or condition in a patient, including:
  • the term "pain” refers to all types of pain, including neuropathic and nociceptive pain. It is also contemplated that the compositions disclosed herein can be used to treat other types of pain such as phantom pain which is the sensation of pain from a limb or organ that has been lost or from which a person no longer receives physical signals, and is an experience almost universally reported, by amputees and quadriplegics.
  • the term "addiction” refers to a persistent behavioral pattern marked by physical and/or psychological dependency to a substance, particularly drugs such as narcotics, stimulants, and sedatives, including but not limited to heroin, cocaine, alcohol, nicotine, caffeine, amphetamine, desoxyephedrine, methadone and combinations thereof.
  • the "treatment of addiction in a patient” refers to reducing the withdrawal symptoms associated with drag dependency as well as alleviating drug cravings in addicts. Such symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
  • blood-brain barrier refers to the barrier between the peripheral circulation and the brain and spinal cord which is formed by tight junctions within the brain capillary endothelial plasma membranes, creating an extremely tight barrier that restricts the transport of molecules into the brain.
  • the blood-brain barrier within the brain, the blood-spinal cord barrier within the spinal cord, and the blood-retinal barrier within the retina are contiguous capillary barriers within the central nervous system (CNS), and are collectively referred to herein as the blood-brain barrier or BBB.
  • the term "cleavable linking group” refers to a linking group that can be attached to noribogaine or a derivative at any possible position.
  • the linker is biocompatible (i.e. does not produce undesired side effects or have an intolerable toxicity), is readily cleaved in the body (preferably in the brain), and does not inhibit or alter the desired physiological effect of noribogaine or derivative.
  • the linking group is preferably sufficiently stable in the circulatory system (serum or blood), but is cleaved to release the noribogaine or derivative upon entry into the brain.
  • Suitable biocompatible, cleavable linking groups comprise from 1 to 20 atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus, and are, in general, susceptible to cleavage conditions or agents in the brain (i.e. H, redox potential or the presence of degradative molecules such as enzymes).
  • the biocompatible, cleavable linking group can be an ester-based cleavable linking group (- C(0)0- or -OC(O)-), an amide-based cleavable linking group (-C(0) R 9 - or -NR 9 C(0)-), or a phosphate-based cleavable linking group (-P(O)(OR 9 )-0-, -0-P(S)(OR 9 )-0-, -0-P(S)(SR)- 0-, -S-P(0)(OR 9 )-0-, -O-PCOXOR ⁇ -S-, -S-P ⁇ 0)(OR 9 )-S- s -0 ⁇ P(5)(OR 9 )-S-, -S-P(S)(GR 9 )- C.k.
  • R 9 can be hydrogen or alkyi.
  • saccharide or ''monosaccharide refers to a saccharide or derivative thereof, having at least 6 carbon atoms (which may be linear, branched or cyclic) with aii oxygen, nitrogen or sulfur atom bonded to each carbon atom.
  • oligosaccharides includes oligosaccharides containing from about 2-9 monosaccharide units.
  • Specific monosaccharides include C5 and above (preferably Cs-Cg) saccharides such as etbritol, zylitol, galactose, lactose, xylose, dulcitoi, myo-insoitol, fructose, mannitoi, sorbitol, glucose, arabmose, arabinose, celloboise, maltose, raffmose, rhamnose, nielibiose, ribose, adonitol, arabitol, arabitol, fxteose, lyxose, lyxose, glucosamine, mannosamine, and gaiactosamine; di- and trisaccharides include saccharides having two or three
  • the term "patient” refers io mammals and includes humans and non-human mammals.
  • this invention is directed to compounds which are represented by Formula I below:
  • L is selected from the group consisting of a covalent bond and a cleavab!e linker group
  • R 1 is selected from the group consisting of hydrogen, alkyl, substituted alkyi, alkenyi, substituted alkenyi, alkynyl, substituted alkynyl, ary!, substituted aryi cyeloaikyl, substituted cyeloaikyl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic provided thai R ! is not a saccharide or an oligosaccharide;
  • R i0 is hydrogen or -OR
  • R 1 ' is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, (CH 2 )mOC(0)alkyl, (CH 2 ) m OH, (CH 2 ) m Oalkyl, CH 2 -X-alkyl or
  • R is selected from the group consisting of hydrogen, a hydrolysaMe group selected from the group consisting of -C(0)R 2 , -C(0)NR J R 4 and -C(0)OR 5 , where R 2 is selected from the group consisting of hydrogen, alkyi, substituted alkyi, aikenyl, substituted aikenyl, alkynyl and substituted alkynyl,
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyi, substituted alkyi, aikenyl, substituted aikenyl, alkynyl, substituted alkynyl, aryl, substituted aryh heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and
  • R" is selected from the group consisting of alkyi, substituted alkyi, aikenyl, substituted aikenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic provided that R is not a saccharide or an oligosaccharide;
  • R is selected from the group consisting of -C(0)NR 3 R and -C(0)OR s ;
  • R 1 is not hydrogen
  • R 1 1 is selected from the group consisting of hydrogen, C 1 -C3 alkyi, substituted Ci-Cs alkyi, C1 -C3 alkoxy and substituted C-. -C3 alkoxy.
  • R f f is H.
  • R" is C 1 -C3 alkyi, such as ethyl.
  • R H is C%CH 2 OH.
  • R" is CH2CH2OCH3.
  • R" is ⁇ 3 ⁇ 4 ⁇ 3 ⁇ 40 € ⁇ 2 ⁇ 1 ⁇ , in one embodiment, R' 1 is CH 2 CH 2 OC(0)alky], such as CH 2 CH 2 OC(0)(CH2)ioCH3.
  • R i l is CH2-X-CH3.
  • R n is CH 2 CH20(C3 ⁇ 4) p O(CH 2 ) q O(CH 2 ) f CH 3 .
  • R ! 1 is C 1 -C3 alkyi optionally substituted with YH, YR 12 , YC(0)R i2 , C(0)YR 12 , C(0)N13 ⁇ 4, C(C))NHR !2 , C(0)NR , 2 R , NH 2 , NHR 12 , NR 12 R U , NHC(0)R i2 , or NR 12 C(0)R 13 , where Y is 0 or S, R 12 and R 13 are independently C r C 3 alky! ,
  • R 1 1 is C1-C3 alkoxy optionally substituted with YH, YR' 2 , YC(0)R 12 , C(0)YR !2 , C(0)NH 2 , C(0)NHR ! 2 s C(0)NR 12 R 13 , NH 2 , NHR 12 , NR 12 R 13 ,
  • NHC(0)R 12 or R ,2 C(0)R 13 , where Y is O or S, R 12 and R 13 are independently C C 3 alkyi.
  • L is a suitable biocompatible, eleavable linking group described herein. [0126] In one embodiment, L is -C(0) ⁇ . In another embodiment, L is - €(0)0-, In still another embodiment, I, is -C(0)NR-, where R is hydrogen or alkyl
  • L is selected from the group consisting of -P(0)(OR 9 )-0-, -O- P(S)(OR 9 )-0-, -0-P(S)(SR 9 ).0- 5 -S-P(0) ⁇ OR 9 )-0., -0.p(0)(OR 9 )-S ⁇ 5 -S-P(0)(OR 9 )-S- ; -0-P(S)(OR 9 )-8-, ⁇ 5-P(S)(OE 9 ) ⁇ 0 ⁇ , -0-P ⁇ 0)(R*)-0- s ⁇ 0- ⁇ S K R -S-P(0)(R 9 )-0-, -S-P(S)(R 9 )-0- s -S-P ⁇ 0)(R 9 )-S- s and -0-P(S)(R 9 )-S-, where R 9 Is hydrogen or alkyl.
  • R is hydrogen.
  • L is a cova!ent bond or - ( .. ' (( ) ⁇ -. and R s is substituted alkyl.
  • R f is alkyl substituted with -NR 6 R'' where R 6 and R ' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyny], aryl, substituted aryl, eyeioalkyl, substituted cycioaikyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic,
  • R is selected from the group consisting of ⁇ C(0)NR 3 R 4 and -C(0)OR 5 and R ! is hydrogen.
  • the compound of Formula I is a compound wherein R 1 is H, L and R 1 are as defined in Table II below, and R I ! is Cp3 ⁇ 4 alkyl optionally substituted with YH, YR 12 , YC(0)R 12 , C(0)YR !2 , C(0) 13 ⁇ 4, C(0)NHR 12 , C(0)NR% 13 , NH 2 , NHR 12 , NR 12 R°, NHC(0)R 12 , or NR ,2 C(0)R 13 , where Y is O or S, R 12 and R 13 are independently C,- C3 ⁇ 4 alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compound of Formula ⁇ is a compound wherein R i( ' is H, L and R* are as defined in Table II below, and R 11 is selected from H, CH2CH2OH,
  • the compound of Formula 1 is a compound wherein R s0 is -OR, R, L and R 1 are as defined in Table II below, and R 11 is C r (3 ⁇ 4 alkyl optionally substituted with YH, YR 12 , YC(0)R n , C(0)YR 12 , C(0)NH 2 , C(0)NHR 12 , C(0) R I2 R t3 , H3 ⁇ 4 NHR 12 , NR I2 R 13 , NHC(0)R 12 , or NR ,2 C(0)R 13 , where Y is O or 8, R 12 and R are independently C r C3 a!kyl, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compound of Formula I is a compound wherein R s0 is -OR, R. L and R 1 are as defined in Table II below, and R l ! is selected from H. CH 2 CH 2 OH,
  • the compound of Formula I is a compound wherein R'° is -OR, R, L and R 1 are as defined in Table II below, and R ! 1 is selected from H, CH2CH2OH,
  • the compound of Formula I is a compound wherein R.” J is -OR, R, L and R 3 are as defined in Table II below, and R ! 1 is H, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compound of Formula I is a compound wherein R'° is -OR, R » L and R 3 ⁇ 4 are as defined in Table II below, and R 1 ' is CH2CH2OH, or a pharmaceuticaliy acceptable salt and/or solvate thereof.
  • the compound of Formula I is a compound wherein R ! 0 is -OR, R, L and R 1 are as defined in Table II below, and R' 1 is CH 2 CH 2 OCH3, or a pharmaceuticaliy acceptable salt and/or solvate thereof.
  • the compound of Formula 1 is a compound wherein R 10 is -OR, R, L and R 1 are as defined in Table II below, and R" is CH2OCH3, or a pharmaceutically acceptable salt and/or solvate thereof,
  • the compound of Formula I is a compound wherein R 10 is -OR, R. L and R 1 are as defined in Table 11. below, and R n is ( ⁇ i 2 0 fTX'i Ph.. or a
  • the compound of Formula I is a compound wherein R i0 is -OK, R, L and R 1 are as defined in Table II below, and R ! ! is CH2CH20C(0)alk l, such as C i2 alkyi, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compound of Formula I is a compound wherein R Uj is -OR, R, L and R 1 are as defined in Table ⁇ below, aid R ! ! is
  • the compound of Formula ⁇ is a compound wherein R i 0 is -OR, R, L and R 1 are as defined in Tabie II below, and R 1 1 is methyl or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compound of Formula I is a compound wherein R'° is -OR, R, L and R 1 are as defined in Table II below, and R f 1 is C ⁇ alkyi, or a pharmaceutically acceptable salt and/or solvate thereof.
  • R is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of -C(0)R ⁇ -C(0)NR 3 R 4 and -C(0)OR ⁇ where R 2 is selected from the group consisting of hydrogen, alkyL substituted aikyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R J and R 4 are independently selected from the group consisting of hydrogen, aikyl, substituted aikyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R 5 is selected from the group consisting of aikyl, substituted alkyf, alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
  • L is selected from the group consisting of a covending bond and a eleavab!e linker group
  • R ! is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyi, substituted alkenyi, a!kynyh substituted alkynyi, aryl, substituted aryi, cycioalkyl, substituted cycloalkyi, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that R ! is not a saccharide or an oligosaccharide;
  • R is selected from the group consisting of -C(0)NR. 3 R 4 and -C(0)OR 5 ;
  • R is hydrogen or -C(0)R z and L, is a covending bond, then R ! is not hydrogen,
  • R is hydrogen and L is a cleavable group
  • L is a suitable biocompatible, cleavable linking group.
  • Suitable biocompatible, cleavable linking groups comprise a covending bond and a linking group having from 1 to 20 atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus, and are, in general, susceptible to cleavage conditions or agents in the brain (i.e. H, redox potential or the presence of degradative molecules such as enzymes, e.g., proteases, lipases, etc.).
  • the cleavage conditions or agents should be more prevalent or found at higher levels or activities in the brain than in serum or b!ood.
  • degradative agents include: redox agents which are selected for particular substrates or which have no substrate specificity, including, e.g., oxidative or reductive enzymes or reductive agents such as esterases; enzymes that can hydrolyze or degrade an acid cleavabie linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases.
  • redox agents which are selected for particular substrates or which have no substrate specificity, including, e.g., oxidative or reductive enzymes or reductive agents such as esterases; enzymes that can hydrolyze or degrade an acid cleavabie linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases.
  • the suitability of a candidate cleavable linking group can be evaluated by testing the ability of a cleaving agent (or condition) to cleave the linking group, it will also be desirable to also test the linking group for the ability to resist cleavage in the serum, blood or when in contact with other non-target tissue.
  • a cleaving agent or condition
  • the linking group for the ability to resist cleavage in the serum, blood or when in contact with other non-target tissue.
  • the linking group is an ester-based linking group. In another embodiment, the linking group is an amide-based linking group. In yet another embodiment, the linking group is a phosphate-based linking group. In another embodiment of the compounds of this invention, L is a cova!ent bond.
  • L is -C(0) « , In another embodiment, L is - €(0)0-. In still • another embodiment, h is -C(0)NR-, where R is hydrogen or alkyL
  • L is seiected from the group consisting of -P(0)(OR 9 ) ⁇ 0-, -O- P(5) ⁇ OR 9 )-Q-, -G-P(S) ⁇ 8R 9 )- ⁇ , -S-P(0) ⁇ OR 9 )-C)-, ⁇ 0-P(G)(GR 9 )-g-, ⁇ 8 ⁇ P(0)(OR 9 )-S ⁇ , .0-P(S)iC)R 9 ) ⁇ S ⁇ ; -S-P($)(OR' 0-.
  • R is hydrogen
  • L is a covalent bond or -C(0)- s
  • R 1 is substituted alkyl.
  • R 1 is alkyl substituted with -NR 6 R ; where R 6 and R' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, substituted aikenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, hetefoatyl, substituted heteroaiyi, heterocyclic, and substituted heterocyclic,
  • R is selected from the group consisting of -C(0)NR 3 R 4 and -C(0)OR 3 and R 1 is hydrogen.
  • the compound of Formula II is a compound as set forth in Table I below or a pharmaceutically acceptable salt and or solvate thereof- Table I
  • Compounds of this invention are contemplated to be useful in treating pain and/or addiction as an active ingredient or a prodrug, in some embodiments, the compounds of this invention are prodrugs whose and/or -i>R J groups are cleaved in vtvo to produce nori oga ne or a noribogaine derivative.
  • the compound is at least 2, 5 or 10 times more stable in serum plasma than in the central nervous system, such as the brain, in a more preferred embodiment, the prodrugs have improved BBB penetration property as compared with noribogaine or the noribogaine derivative, for example, the compounds of this invention have at least 20 %, 50 % or 100 % more BBB penetration ability than noribogaine or the noribogaine derivative,
  • the present invention is directed to a method for treating a pain in a patient which method comprises administering to said patient a compound of this invention or a pharmaceutically acceptable salt and/or solvate thereof or a
  • the pain can be any type of pain including, but not limited to neuropathic or nociceptive pain, and various types thereof including somatic, visceral and phantom pain.
  • the use of noribogaine for treatment of pain is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,738, filed on March 13, 2014 and titled "USE OF NORIBOGAINE FOR THE TREATMENT OF PAIN", which is incorporated herein by reference is its entirety.
  • the present invention is directed to a method for reducing tolerance to opioid analgesics in a patient undergoing treatment for pain.
  • the use of noribogaine for reducing tolerance to opioid analgesics is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,74!, filed on March 13, 2014 and tided "METHODS AND COMPOSITIONS FOR REDUCING TOLERANCE TO OPIOID
  • the present invention is directed to a method for treating addiction in a patient which method comprises administering to said patient a compound of this invention or a pharmaceutically acceptable salt and or solvate thereof or a composition comprising a compound of this invention and a pharmaceutically acceptable excipient.
  • the treatment of addiction in a patient comprises alleviating ⁇ the symptoms associated-with withdrawal from drug dependency.
  • -Such -symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
  • treatment with a compound of this invention decreases the drug cravings normally experienced by addicts after cessation of the self-administration of the abused substance.
  • the compositions disclosed herein are especially useful in the treatment of addiction to opioids such as heroin and methadone.
  • the invention is also directed to a method for treating drag addiction (involving drag dependency or drug abuse) during withdrawal therapy by administering a compound of this invention to a patient at a dosage sufficient to reduce or eliminate one or more symptoms associated with withdrawal.
  • Symptoms of acute withdrawal include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chilis and headache.
  • treatment with a compound of this invention is contemplated to decrease the drug cravings normally experienced by addicts after cessation of the self-administration of the abused substance, for example, opioids such as heroin and methadone,
  • opioids such as heroin and methadone
  • compounds of this invention are contemplated to be also useful in treating patients addicted to other substances, cocaine, alcohol, amphetamines, tobacco, caffeine, opioid-like drugs, cannabinoids, benzodiazepines, and any other illicit, prescription, or generally available addictive substance, as well as combinations of these drugs.
  • Compounds of this invention may be administered to patients suffering from drug dependence or abuse in conjunction with an opioid antagonist such as naloxone, naltrexone or nalorphine, for example, at a concentration of between 0, 15 mg and 0.5 mg for each mg of the compound of this invention administered.
  • the invention is also directed to a method for preventing relapse to drag use after drug use has been stopped (e.g., after treatment to ameliorate drag abuse), by administering a compound of this invention to a patient at a dosage sufficient to reduce or eliminate one or more symptoms associated with post-acute withdrawal, including cravings.
  • the compound may be administered at a lower (e.g., "maintenance") dose compared to that used for treatment of addiction and acute withdrawal symptoms.
  • the present invention is directed to a method for treating depressive disorders in a patient in need of the treatment, which method comprises administering to said patient a compound of this invention or a pharmaceutically acceptable salt and/or solvate thereof or a composition comprising a compound of this invention and a pharmaceutically acceptable excipient.
  • Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1 94b).
  • Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes,
  • a major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearl every day for at least 2 weeks): it can include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
  • Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
  • noribogaine for treatment of depression is described, for example, in U.S. Provisional Patent Application Serial No. 61/952,733, filed on March 13, 2014 and titled “METHODS AND COMPOSITIONS FOR TREATING DEPRESSION", which is incorporated herein by reference in its entirety.
  • the present invention is directed to a method for treating stress, such as post-traumatic stress disorder, in a patient in need of the treatment, which method comprises administering to said patient a compound of this invention or a pharmaceutically acceptable salt and/or sol vate thereof or a composition comprising a compound of this invention and a pharmaceutically acceptable excipient.
  • stress such as post-traumatic stress disorder
  • Stress or anxiety refers to the consequence when a patient fails to respond appropriately to emotional or physical threats, which may be actual or imagined. Stress symptoms or conditions may be cognitive, emotional, physical or behavioral, including, but not limited to a state of alarm and adrenaline production, short-term resistance as a coping mechanism, exhaustion, irritability, muscular tension, inability to concentrate, poor judgment, a genera!
  • PTSD is a severe stress disorder that can develop after exposure to an event which results in psychological trauma. Such events usually involve death of someone else, threat of death to oneself or to someone else, or trauma to the physical, sexual, or psychological integrity of one's own or someone else. PTSD may be an acute stress response or a long term stress response to such an event when it overwhelms one's ability to cope.
  • Symptoms of PTSD include some or all of the following; recurrent re-experiencing of the trauma, for example, intrusive, upsetting memories of the event, flashbacks of the traumatic events (acting or feeling like the event is happening again), recurring nightmares (either of the event or of other frightening things); feelings of intense distress and/or intense physical reactions when reminded of the trauma; avoidance to the point of having a phobia of places, people, and experiences that remind the sufferer of the trauma and a general numbing of emotional responsiveness; inability to remember important aspects of the trauma; and physical signs of hyperarousal, including sleep problems, trouble concentrating, irritability, anger, poor concentration, blackouts or difficulty remembering things, increased tendency and reaction to being startled, and hypervigilanee to threat.
  • Other symptoms include anbedonia, lack of interest in activities that used to be enjoyed, emotional deadness, distancing oneself from people, and/or a sense of a limited future (for example, not being able to think about the future or make future plans, not believing one will live much longer), guilt, shame, self-blame, depression and hopelessness, suicidal thoughts and feelings, feeling alienated and alone, headaches, stomach problems, chest pain and substance abuse.
  • co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time.
  • co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound of this invention and the other agent or that the two agents be administered at precisely the same time.
  • co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
  • a compound of this invention can be used as an adjunct to conventional drug withdrawal therapy, specifically providing for the administration of a compound of this invention with one or more opioid antagonists,
  • this invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of this invention or mixtures of one or more of such compounds.
  • compositions suitable for oral, intravenous or intraarterial delivery will probably be used most frequently, oilier routes that may be used include peroral, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes.
  • the composition can be administered transdermal!' in which drug is applied as part of a cream, gel, or patch (for examples of transdermal formulations, see U.S. Pat, Nos.4,806,341; 5,149,538; and 4,626,539).
  • dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used, for example, in a transdermal patch form. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed. 5 A. Oslo editor, Easton Pa. 1 80). Intranasal administration is an effective method for delivering a therapeutic agent directly to the respiratory tract, where the therapeutic agent may be quickly absorbed,
  • compositions are comprised of in general, a compound of this invention or a mixture thereof in combination with at least one pharmaceutically acceptable exeipient.
  • excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention.
  • excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous exeipient that is generally available to one of skill in the art.
  • Pharmaceutical compositions in accordance with the invention are prepared by conventional means using methods known in the art.
  • Solid pharmaceutical excipients include starch, cellulose, tale, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's
  • compositions disclosed herein may be used in conjunction, with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, guro arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration.
  • vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, guro arable, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc.
  • Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration.
  • Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1 ,2-propylene glycol, poiyglycols, dimethyisulfoxi.de, fatty alcohols, triglycerides, partial esters of glycerine and the like.
  • Parenteral compositions containing the compounds described herein may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3- butanediol, ethanol, 1,2 -propylene glycol, poiyglycols mixed with water, Ringer's solution, etc.
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art, Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01 to 99.99 wt % of a compound of this invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1 to 80 wt %.
  • a compound of this invention should generally be present in such compositions at a concentration of between about 0.1 and 20 rng/rnl.
  • naloxone or naltrexone When either naloxone or naltrexone is combined with a compound of this invention, they should be present at 0,05 to 0.5 mg for each mg of the compound of this invention.
  • the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the compound can be formulated as liquid solution, suspensions, aerosol propellents or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDi) and dry powder inhalers (DPI).
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
  • MDI's typically are formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
  • the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose, A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation,
  • U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparfieles (average particle size of 400 Mi) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably hig bioavailability.
  • a narrow therapeutic dose of a compound of the invention is administered to a patient such that the patient's QT interval is not prolonged to unacceptable levels.
  • patients are administered therapeutic doses of the compound in a clinical setting with cardiac monitoring, in some embodiments, the patient will, be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with the compound.
  • the patient's QT interval is not prolonged by more than about 50 ms, preferably, not more than about 30 ms, and more preferably, not more than about 20 ms.
  • the patient's QT interval does not exceed about 500 ms, preferably, does not exceed about 450 ms, and more preferably does not exceed about 420 ms.
  • the dosage of a compound of this invention that is administered to the patient is sufficient to provide an average serum concentration of about 50 Bg/mL to about 850 ng mL (area under the curve/24 hours, AUC/24 h), or any subrange or subvalue there between,
  • the dose of noribogame, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng mL (AUC/24 h),
  • the compound of this invention is administered in an effective amount It is contemplated that the dosage required for treating pain or addiction, or a combination thereof may differ according to the condition(s) being treated, however, the dosing regimen can be readily determined by the attending clinician based on the desired treatment, it is contemplated that generally, the aggregate dosage of a compound of this invention administered to a patient may be from about 1 to about 8 mg per kg of body weight per day (rag/kg/day), or from about 1 to about 4 mg kg day, preferably, from about 1 to about 3 mg kg day.
  • the dosage range would preferably be about 70 to 210 mg per day,
  • a lower dosage of a compound of this invention is administered, for example from about 50 ng to less than 10 pg per kg of body weight per day.
  • a maintenance dosage of a compound of this invention is administered, for example approximately 80% or less of the
  • therapeutically effective dose may be effective for prevention of relapse of drug use in an addicted patient treated to ameliorate their substance abuse.
  • a patient is pre-screened with a compound of the invention to determine whether the patient is a candidate for treatment with the compound, for example whether the patient's QT interval will be prolonged to an unacceptable level by treatment with the compound.
  • the patient is treated with a sub-therapeutic dosage of the compound, for example about 50% to about 90% of the therapeutically effective dosage of compound, and the patient's response to the compound is monitored.
  • the patient's QT interval is monitored before and during treatment with the compound.
  • the present invention is directed to a pharmaceutical composition, preferably in unit dose form, comprising a compound of this invention.
  • a pharmaceutical composition preferably in unit dose form, comprising a compound of this invention.
  • one or more unit doses provide an amount of a compound of this invention effective to treat a disease or condition as described above, including pain, depression, stress, and/or addiction,
  • composition administered will depend on a number of factors, including but not limited to the desired final concentration of the compound, the
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual, compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions are administered in one dosing of a single formulation and in other embodiments, compositions are administered in multiple dosing of a single formulation within a specified time period, in some embodiments, the time period is between about 3 hours to about 6 hours. In other embodiments, the time period is between about 6 hours and 12 hours, in additional embodiments, the time period is between about 12 hours and 24 hours. In yet further embodiments, the time period is between about 24 hours and 48 hours,
  • the administration of separate formulations can be simultaneous or staged throughout a specified time period, such thai all ingredients are administered within the specified time period,
  • 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 reaetants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reaetants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • 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 stereoisorner-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the staiting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif,, USA), Emka-Chemce or Sigma (St. Louis, Mo., USA).
  • noribogaine can react with LO-R where LG is a leaving group such as hydroxy, alkoxy, halo, etc, to give compound 1-1, which may further react with LG-L-R' to form compound 1-2.
  • the phenol is protected by reaction with a suitable protecting group, PG-LG, where LG is a Leaving group such as defined above, such that the indole nitrogen is derivatized with L-R 1 .
  • suitable protecting groups are well known in the art (see T. W. Greene. P. G. M. Wuts, Protective
  • compounds of this invention wherein L-R is not hydrogen may be prepared by reacting ibogaine with LG-L-R 5 to give compound 2-1.
  • Compound 2-1 can be demethvlated by methods known in the art, such as reaction with boron tribromide/methyleiie chloride at room temperature to give compound 1-4. which may further react with LG-R to give compound J -2.
  • Scheme 2
  • Compound 3-2 can be de-car oxylated by methods described herein or known in the art. such as using refluxing hydrazine, or hydrolyzing the -COOCH3 group to an acid, and reacting the corresponding sodium or lithium salt with aqueous mineral acid to give compound 3-3.
  • An exemplifying decarboxylation procedure for preparing an intermediate 7- 3 is illustrated in Scheme 7 below, which includes a procedure for preparing an
  • Intermediate 7-3 when the starting material 7-1 is a racemic mixture or when racemization occurs during redeutton.
  • Intermediate 7-3 can react with LG-L-R 1 to give compounds of ibis invention.
  • Compound 4-1 is halogenated to compound 4-2.
  • X is iodo
  • the iodo group can be conveniently incorporated into the indole ring by reacting compound 4-1 , e.g. and without limitation, with N-iodosuce nimide (NTS).
  • NTS N-iodosuce nimide
  • the iodo group can be also incorporated using a phenyl iodonium intermediate by reaction with PhI(OH)OTs, followed by removal of the phenyl group through reaction with OH " .
  • the iodo or the bromo group can be incorporated by nitration to form a nitro intermediate, foilowed by reducing the nitro group to an amino group, diazotizing the amino group to form a diazonium group, and reacting the diazonium compound with Cul or CuBr.
  • Exemplifying halogenation procedures are illustrated in Scheme 6 below?.
  • Compound 4-2 is then converted to compound 4-3 b reacting with ROH or RO " , e.g., in presence of a copper catalyst such as Cwl and a ligand, such as tetramethyi phenanthroline (see, for example.
  • 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 functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 4* Edition, Wiley-Interscience, New York, 2006, and references cited therein.
  • the stalling materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich® Chemical Co.
  • Compound 1 may be prepared by reacting noribogaine with at least two equivalents of (CH3) 2 NCH ? .CH 2 C(0)C1 in the presence of a base in a suitable solvent.
  • reaction is conducted in a polar solvent.
  • compound 1 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used without purification and/or isolation.
  • Compound 2 may prepared by reacting noribogaine with at least one equivalent of (CH 3 ) 2 NC3 ⁇ 4CH 2 CC0)C1 in the presence of a base in a suitable solvent to give an intermediate product.
  • the reaction is conducted in a polar' solvent
  • the intermediate product can be demethylated by reaction with boron iribromide/methyiene chloride at room temperature to give compound 2,
  • compound 2 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used without purification and/or isolation.
  • Compound 3 may prepared by reacting noribogaine with one equivalent of
  • reaction mixture was then cooled to -78 °C, and sodium ⁇ , ⁇ -dimethylethanolamine solution (1.4 mL, 1.4 mmo!, 1 M in THF) was added.
  • the reaction mixture was allowed to wans to rt and stirred for 30 min. Water (5 mL) was added, and the reaction mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were concentrated under reduced pressure, and the crude product was purified by Flash Chromatography (ethyl
  • the following example illustrates how to treat an opioid addicted patient having an immediate craving for the opioid.
  • a 65 kg cocaine addicted male patient presenting with an immediate craving for a cocaine "fix” is administered a bolus comprising 0.1 % weight volume of a compound of this invention in sterile buffered saline.
  • the aqueous composition is administered in an i,v, format and the serum concentrations of the compound of Formula II and noribogaine which is produced by in vivo cleavage of the compound of this invention are monitored.
  • a sufficient amount of the compound is administered until a therapeutic serum concentration of the compound and or noribogaine is achieved.
  • the patient is then monitored until the craving is diminished or relieved.
  • the following example illustrates how to treat severe pain in a patient.
  • a 80 kg male patient presenting severe trauma due to several gunshots to the chest and legs is administered a bolus comprising 1 gm of a compound of Formula II in 10 niL of sterile buffered saline.
  • the aqueous composition is injected into the patient to provide immediate analgesia for the pain.
  • a transdermal patch is then placed on the patient's back.
  • the patch contains a sufficient amount of the compound in a sustained release fonn wherein the amount of noribogaine released is sufficient to maintain serum concentration of the compound or noribogaine which is produced by in vivo cleavage of the compound of this invention in the patient for a period of 48 hours.
  • a suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H-15 ⁇ triglycerides of saturated vegetable fatty acid;

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Abstract

La présente invention concerne d'une manière générale des promédicaments de noribogaïne. L'invention porte également sur des compositions pharmaceutiques comprenant lesdits promédicaments de noribogaïne, ainsi que sur une méthode de traitement de la douleur, de la toxicomanie et/ou du stress au moyen de ces composés et/ou compositions pharmaceutiques.
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CA2942638A1 (fr) 2013-03-15 2014-09-18 Demerx, Inc. Procede pour le traitement avec la noribogaine de l'addiction de patients sous methadone
US9561232B2 (en) 2014-02-18 2017-02-07 Demerx, Inc. Low dose noribogaine for treating nicotine addiction and preventing relapse of nicotine use
US9561233B2 (en) * 2014-03-13 2017-02-07 Demerx, Inc. Use of ibogaine for the treatment of pain
US9592239B2 (en) * 2014-09-12 2017-03-14 Demerx, Inc. Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake
WO2016086194A1 (fr) 2014-11-26 2016-06-02 Demerx, Inc. Procédés et compositions pour potentialiser l'action d'analgésiques opioïdes en utilisant des alcaloïdes de l'iboga
WO2017184531A1 (fr) * 2016-04-18 2017-10-26 Demerx, Inc. Traitement de troubles liés au mouvement au moyen de la noribogaïne

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US7220737B1 (en) * 1997-09-04 2007-05-22 Novoneuron, Inc Noribogaine in the treatment of pain and drug addiction
US20030153552A1 (en) * 2002-02-14 2003-08-14 Mash Deborah C. Method of treating chemical dependency in mammals and a composition therefor
US8362007B1 (en) * 2010-05-11 2013-01-29 Demerx, Inc. Substituted noribogaine
US8741891B1 (en) * 2010-06-22 2014-06-03 Demerx, Inc. N-substituted noribogaine prodrugs
US8637648B1 (en) * 2010-06-22 2014-01-28 Demerx, Inc. Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier
CA2855994A1 (fr) * 2011-12-09 2013-06-13 Demerx, Inc. Esters phosphoriques de noribogaine
US20150051192A1 (en) * 2012-03-27 2015-02-19 Albany Medical College Blocking of cue-induced drug reinstatement

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