WO2015163844A1 - N-substituted noribogaine prodrugs - Google Patents

N-substituted noribogaine prodrugs Download PDF

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Publication number
WO2015163844A1
WO2015163844A1 PCT/US2014/034826 US2014034826W WO2015163844A1 WO 2015163844 A1 WO2015163844 A1 WO 2015163844A1 US 2014034826 W US2014034826 W US 2014034826W WO 2015163844 A1 WO2015163844 A1 WO 2015163844A1
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substituted
compound
group
alkyl
heterocyclic
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PCT/US2014/034826
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French (fr)
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Deborah C. Mash
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Demerx, Inc.
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Priority to EP14890017.8A priority Critical patent/EP3164402A1/en
Priority to CA2983727A priority patent/CA2983727A1/en
Priority to PCT/US2014/034826 priority patent/WO2015163844A1/en
Publication of WO2015163844A1 publication Critical patent/WO2015163844A1/en

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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;

Abstract

This invention relates generally to prodrugs of noribogaine. This invention also relates to pharmaceutical compositions comprising the prodrugs of noribogaine as well as method of treating pain, addiction and/or stress using such compounds and/or pharmaceutical compositions.

Description

^-SUBSTITUTED NORIBOGAINE PRODRUGS
Field of the Itsveafien
[ttftOl } 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.
State of the Art
[0002] 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:
Figure imgf000002_0001
[0003] Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non-addictive alkaloid useful in treating drug dependency (U.S. Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737).
[0004] Certain noribogaine derivatives and their uses are described in, for example, U.S. Patent No. 8,362,007 which is incorporated herein by reference in its entirety.
[0005] Noribogaine is typically administered orally or intravenously and becomes systemically available to the treated patient. While noribogaine allostericaily binds tightly to the μ and κ 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.
[0906] Accordingly, there is a need to reduce the systemic circulation of noribogaine while maintaining or increasing its concentration in the brain particularly at the μ and κ receptors. Summary of the lavention
f 00071 I'his 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. In one preferred embodiment, the prodrug moiety Is selected to facilitate binding to the μ and or κ receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the μ and/or receptors. This invention also relates, in part, to a class of prodrugs of noribogaine derivatives.
[§008] Accordingly, in one embodiment, this invention is directed to compounds which are represented by Formula I or II below:
Figure imgf000003_0001
If
wherein L is selected from the group consisting of a covaient 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)R2, -C(0)NR3R4 and -C(0)OR5, where R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyi, substituted alkenyi, alkynyl and substituted alkynyl,
R3 and R4 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,
R3 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 R1 is not a saccharide or an oligosaccharide;
Rl ' is hydrogen or -OR;
Rn is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, (CH2)mOC(0)aikyL (CH2)mOH, (CH2)n,Oalkyl, CH2-X-CH3 or
(CH2)mO(CH2)pO(CH2)q( CH2)rCH3, where each of m, p and q is 1 , 2 or 3; and r is 0, 1 or 2, X is O or NH;
or a pharmaceutically acceptable salt and/or solvate thereof,
provided that when L is a covalent bond and R1 is hydrogen, then either R is selected from the group consisting of ~C(0)NR3R and -C(0)OR5 or Ra is not alky!; and
further provided that when R is hydrogen or -C(0)R2 and L is a covalent bond, ihen R is not hydrogen.
[0009] In one embodiment, RH is selected from the group consisting of hydrogen, C1-C3 alkyl, substituted C1 -C3 alkyl, C1-C3 alkoxy and substituted
Figure imgf000004_0001
alkoxy,
[0010] In one embodiment. R' 1 is H. In one embodiment, R1 1 is C1-C3 alkyl, such as ethyl, In one embodiment. R is C¾C¾OH, in one embodiment, R! 1 is CH2CH2OCH3. in one embodiment, R1 1 is CH2CH2OCH2PI1. Ph represents a phenyl group. In one embodiment, Ru is CH2CH2OC(0)aIkyL such as CH2CH2OC(0)(CH2)ioCH3. In one embodiment, Ru is CH2CH20(CH2)pO(CH2)«0(CH2)rCH3.
[00111 In one embodiment, R11 is C1-C3 alkyl optionally substituted with YH, YR12, YC(0)R12, C(0)YRi2 s C(0)NH2, C(0) HR12, C(0)NR12R13, N¾. NHR12, NR!2RU, NHC(0)Ri2, or NRi2C(0)R13, where Y is O or S, R12 and RB are independently C,-C3 alkyl.
[00121 in one embodiment, R! 5 is C1-C3 alkoxy optionally substituted with. YH, YR! ?.
YC(0)R12, C(0)YRi2, C(0)NH2, C(0)NHR12, C(0)NR12Ri3, NH2> NHR12, NR!2R13, NHC(0)R12, or NR!2C(0}R , where Y is O or S, R12 and R13 are independently C-,-C3 alkyl
[0013] in one embodiment, R is hydrogen and L is a cleavable group.
[00 4] In one embodiment, R is hydrogen, L is a -C(G)-, -C(0)0~, or -C(0)NH-, and R! is substituted alkyl. Preferably R! is alkyl substituted with -NR6R7 where R6 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.
I001SJ In one embodiment, R is selected from the group consisting of -€ G)NR"'R4 and -CiC^OR5 and R1 is hydrogen,
{0016] In one embodiment, provided is 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:
Table
Figure imgf000005_0001
Figure imgf000006_0001
{0017] In one embodiment, the compound of Formula I is a compound wherein Ri0 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)R12, C(0)YR!2, C(0)N¾, C(0)NHR,2 9 C(0)NRL2R13, NH2, NHPJ2, NRI2R13, NHC(Q)R!2, or NRL 2C(0)R13, where Y is O or S, R12 and R13 are independently C,-C3 alkyl, or a pliarmaceuticaiiy acceptable salt and/or solvate thereof.
|00i8] in one embodiment, the compound of Formula I is a compound wherein R I 0 is -OR, R, L and R1 are as defined in Table Ϊ above, and R1 1 is Cj-C3 alkyl optionally substituted with YH, YR12, YC(0)R!2, C(0)YRI 2, C(0)NH2, C(0)NHR12, C(0)NR,2R13, H2, NHR12,
NR,2R13, NHC(0)Rn or NR ! 2C(0)R! 3 5 where Y is O or S, R! 2 and R13 are independently C C3 alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
10019] In one of its composition aspects, 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 Π or Table I above. [0020} In one of ts method aspects, 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.
[§02 J } In another of its method aspects, 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 Ϊ above.
Detailed Description
|0022] This invention is directed to noribogaine prodrugs, pharmaceutical compositions of such prodrugs and methods for their use. However, prior to describing this invention in greater detail, the following terms will first he defined.
{0023] It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will he limited only by the appended claims.
[00241 It must be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutically acceptable excipient" includes a plurality of such excipients.
1, Definitions
{00251 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings,
|Ό§26| As used herein, the term ''comprising5' or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others,
"Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of" shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
{§§27] The term "about" when used before a numerical designation, e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by ( + ) or ( - ) 10 %, 5 % or 1 %.
{0028] in some embodiments, the invention is directed to compositions comprising the prodrugs described herein and an excipierit to facilitate transport across the blood brain barrier.
|00291 "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 (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH ), .sec-butyl ((CH3)(CH3CH2)CH-), /-butyl ((CH3)3C-), n-pentyl
(CH3CH2CH2CH2CH2-)5 and neopentyl «CH3)3CCH2-).
[0030] "Alkenyl" refers to straight or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (>C= <) isnsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and tram isomers or mixtures of these isomers.
[0031] "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. Examples of such alkynyl groups include acetylenyl (-C=CH), and propargyl (-€H2C=CH).
1 32 j "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,
aminothioearbonyl, aminoearbonylamino, aminothiocarbonylarnino, aminocarbonyloxy, aminosulfonyl, aminosul fonyloxy , aminosulfonyiamino, amidino, aryi, substituted aryl, aiyloxy, substituted aryloxy, arylthio, substituted aryithio, carboxyl, carboxyl ester, (carboxyl ester )amino, (carboxyl ester)oxy, cyano, eycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cyeloalkenyloxy, substituted cycloalkenyloxy, cycloaikenyltfaio, substituted cycioaikenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryi, substituted heteroaryi, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyciyloxy, substituted heterocyciyloxy, heterocyciylthio, substituted heterocvclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyi, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein,
[0033] "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,
arninothiocarbonyl, aminocarbonylamino, amiiiothiocarbonyiamino, aminocarbonyioxy, aminosulfonyl, aminosuifonyloxy, aminosulfbnylamino, amiditio, aryi, substituted aryi, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyi ester)amino, (carboxyl 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 heteroarylthio, heterocyclic, substituted heterocyclic, heterocyciyloxy, substituted
heterocyciyloxy, heterocvclylthio, substituted heterocyciylthio, nitro, SO3H, 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.
[0034] "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, SO3H, 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.
1 035] '"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,
(0036] "Substituted aikoxy" refers to the group -0-(substituted afkyl) wherein substituted aikyi is defined herein.
[0037] "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)-. wherein 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)-.
[0038] "Acylamino" refers to the groups -NR17C(0)alkyl, -NR17C(0)substituted alkyl, -NRl7C(0)cycloalkyl, -NRi7C(0)substiiuted cycloalkyi, -NRl7C(0)cycloalkenyis
-NRi 7C(Q)substituted cycloalkenyl, -NR,7C(0)alkenyl, -NR17C(0)substituted aikenyl, -NRi7C(0)alkynyl, -NR! 7C(0)subsiituted alkynyi, -NRl7C(0)aryl, -NR17C(0)substituted aryi, -NRl7C(0)heteroaryi, -NR17C(0)substituted heteroaryl, -NR! 'C(0)heterocyclic, and -NR17C(0)substituted heterocyclic wherein R17 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,
[0039] "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, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroary!, heterocyclic, and substituted heterocyclic are as defined herein.
[0040] "Amino" refers to the group -NH2.
[0041] "Substituted amino" refers to the group -NR'*R19 where R'8 and Ri 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, -S02-alky], ~S02-subsiituied alkyl, -SCb-alkenyl, -SG2-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cylcoaikyl, -SOycycloalkenyl, -S02-substituted cylcoalkenyi,-S02-aryl, -SCVsubstituted aryl,
-S02-heteroary], -SCVsubstituted heteroaryl, -S02-heterocyclic, and -S02-$ubstituted heterocyclic and wherein R!S and R,v are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R1* and R!S are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyi, substituted alkynyl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R'8 is hydrogen and R'9 is alkyl, the substituted amino group is sometimes referred to herein as alkyl amino. When R S and R19 are alkyl, the substituted amino group is sometimes referred to herein as dialkylaniino. When referring to a monosubstituted amino, it is meant that either R1$ or Rh} is hydrogen but not both. When referring to a di substituted amino, it is meant that neither R1 S nor R19 are hydrogen.
[0042} "Aminocarbonyl" refers to the group -C(O)NR20Rz l where Ri0 and R2' 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 R20 and R21 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 cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
{0043) "Aminothiocarbonyl" refers to the group -C(S)NR20R2 ( where i ° and R21 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 and where R 0 and R2 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.
{0044] "Aminocarbonylamino" refers to the group -NR! 'C(O)NR20R21 where R' 7 is hydrogen or alkyi and R20 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 and where R2 and R2' 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.
[0045J "AiiJtnothiocarbonylamino" refers to the group -NR1 'C(S)NR20R2! where R17 is hydrogen or alkyi and R20 and R2! 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 and where R20 and R2' 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.
Π {00 61 "Arninocarbonyloxy" refers to the group -O-C(Q)NR2 R2i where R20 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 R20 and Rai 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.
f§047j "Aminosulfonyl" refers to the group -SO2NR20R25 where R20 and R2i 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 R20 and R2' 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, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein.
[00481 "Aminosulfonyloxy" refers to the group -OSG2NR2(3R21 where R20 and R2 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 R20 and R2i 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, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein.
[0O49J "Aminosulfonylamino" refers to the group - R1 '-3C¾NR20R i where R17 is hydrogen or alkyl and R20 and R21 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 Ri0 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 cycloaikyi cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
PSOJ i'Aniidinow refers to the group -€(=MR22)NR20R21 where R26, R2, s and R22 are independently selected from the group consisting of hydrogen, alky L substitated alky], alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, aryl, substituted aryl, cycloaikyi, substituted cycloaikyi, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 0 nd R21 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 cycloaikyi, cycloalkenyl, substituted cycloalkenyl, aryl. substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
10051] "Aryl" or "Ar" 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.
{0052] "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, substituted cycloalkenyl, cycloalkenyioxy, substituted cycloalkenyioxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl. substituted beteroaryl, heteroaiyloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyioxy, substituted heterocyclyioxy, heterocyclylthto, substituted heteroeyei lthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted aikyithio, wherein said substituents are defined herein,
|β053] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
|0054] "Substituted aryioxy" refers to the group -Q-(substituted ary!) where substituted aryl is as defined herein.
fOOSSj "Arylthio" refers to the group -S-aryi, where aryi is as defined herein.
|0056J "Substituted arylthio" refers to the group -S-(substituted aryi), where substituted aryi is as defined herein.
[0057] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=0)~.
[0058] "Carboxy" or "carboxyl" refers to -COOH or salts thereof.
|0059| "Carboxyl ester" or "carboxy ester" refers to the groups -C(0)0-alkyl,
-C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C{0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(())0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted cyeioalkyl, -C(0)0-cyc3oalkenyl, -C(0)0-substituted eycloaikenyl -C(Q)0-heteroaryl, -C(0)0-substituted beteroaryl, -C(0)0-heterocyclic, and
-C(0)0-substituted heterocyclic wherein alkyl, substituted aikyl, alkenyl, substituted aikenyi, alkynyl, substituted alkynyl, cyeioalkyl, substituted cyeioalkyl, eycloaikenyl, substituted eycloaikenyl, aryl, substituted aryi, heteroaryl, substituted beteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
1006 )1 "(Carboxyl es er )annno'? refers to the group -NR! '-C(0)0-aikyl, -NR, 7-C(0)0- substituted alkyl, -NRi?-C(0)0-alkeny!, -NR!7-C(0)0-substituted alkenyl,
-NR.17-C(0)0-alkynyl, -NR17-C(0)0-substitated alkynyl, -NR,7-C(0)0-aryi,
-NR! 7-C(0)0-substituted aryl, -NR17-C(0)0-cycloalkyl, -N 17-C(0)0-substituted
cyeioalkyl, -NR! '-C(0)0-cycloalkenyl, -NRi 7-C(0)0-substituted cycloalkenyl,
-NR! 7-C(0)0-heteroaryi, -NR,7-C(0)0-substituted heteroaryl, -NR!7-C(0)0-heterocyclic, and -NR17-C(0)0-substituted heterocyclic wherein R! ' 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.
{0061] "(Carboxyl ester)oxy" refers to the group -0-C(0)0-aIkyl, substituted
-O-QOjO-alkyl, -0~C(Q)G-aikenyL -0-C(0)0-substituted alkenyl -0-C(0)0-alkynyl, -0-C{0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl,
-0-C{0)0-cyc{oalkyl, -0-C(0)0-substituted cycloalkyl, -0-C(0)0-cycloaikenyls
-0-C(0)0-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.
100621 "Cyano" refers to the group -CN.
|Θ063| "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. Examples of 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:
Figure imgf000016_0001
[0064] "Cycloaikenyl" refers to non-aromatic cyclic alky! groups of from 3 to 10 carbon atoms having single or multiple cyclic rings and having at least one >C=C< ring unsaturation and preferably from 1 to 2 sites of >C=C< ring unsaturation.
[0065] "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. acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, arninothtocarbonyl, aminocarbonyiamino, am otfaiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, am osulfonylamino, amidino, aryl, substituted aryl aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)a.mino, (carboxyl ester)oxy, cyano, cycloalkyi, substituted cycloalkyi, cycloalkyloxy, substituted eycloalkyloxys eycloaikyithio, substituted
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.
|!)066| "Cycloalkyloxy" refers to -O-cycIoalkyl.
10067] "Substituted cycloalkyloxy" refers to -0~(substituted cycloalkyl).
(0068] "Cycloalkylthio" refers to -S-cycioalky!.
[0069] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyi).
| 070| "Cycloaikenyioxy" refers to -G-cycioaikenyi.
[0071] "Substituted cycloaikenyioxy" refers to -0-(substituted cyeloalkenyi).
(0072] "Cycloalkenylthio" refers to -S-cycloalkenyl.
{0073] "Substituted cycloalkenylthio" refers to -S-(subsiituted cyeloalkenyi}.
[0074] "Guanidino" refers to the group -NHC(=NH)NH2.
[0075J "Substituted guanidino" refers to -NR2iC(" R2jl)N(R-J)2 where each R2i is independently selected from the group consisting of hydrogen, alkyl substituted aiky!, aryl, substituted aryl heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and two R23 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 R2j is not hydrogen, and wherein said substituents are as defined herein,
[0076] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferabl is fluoro or chloro.
[0077] "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. {0078} "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,
{0079 J "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,
[0080} "Hydroxy" or "hydroxy!" refers to the group -OH.
{0081 J "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.
[0082] "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.
j 00831 "Heteroaryloxy" refers to -O-heteroaryl
|0§84] "Substituted heteroaryloxy" refers to the group -0-(substituted heteroaryi),
{0085] "Heieroarylthio" refers to the group -S-heteroaryl.
{0086] "Substituted heieroarylthio" refers to the group -S-(substituted heteroaryi).
{0087] "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
non-aromatic heterocyclic ring. In one embodiment, 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
10089] "Heteroeyclylosy" refers to the group -O-heterocycyl.
|0090] "Substituted heteroeycl loxy" refers to the group -G~(substituted heterocycyl).
[00 Tj "Heterocyelylthio"" refers to the group -S-heterocycyl.
[0092] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocycyl),
1 093 j Examples of 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-tetehydrobenzoj¾]thiophene, thiazole, thiazoJidine, thiophene, benzofbjthiophene, morpholinyl, thiomorpholinyl (also referred to as
tMamoipholinyl), 1,1-dioxothiomorpholmyi, piperidmyl, pyrrolidine, and tetrahydrofuranyl.
{0094] "Nitre" refers to the group -N02.
| 095] "Oxo" refers to the atom (-0) or (-0").
[0096J "Spiro ring systems" refers to bicyclic ring systems that have a single ring carbon atom common to both rings,
[00971 "Sulfonyl" refers to the divalent group -8(0)2-.
{0098] "Substituted suifonyl" refers to the group -S02-aikyI, -SOa-substitoted aikyl, -SOralkenyl, -SOj-substituted aikenyl, -SOj-cycloalkyl, -SOa-substituted cylcoaikyi, -SOa-eyeloalkenyl, -SC¾-substiiuted cylcoalkenyl, -SOj-aryL -SOs-substituted aryS,
-SC -heteroaryl, -SOa-subsiituted heteroaryl, -S02-heteroeyciie, -S02-substituted
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-S02-s a d 4-methylphenyl-SQ2-. The term "aikyisulfonyl" refers to -SCh-alkyl. The term '¾aioalkylsttlfonyl" refers to -SCh-haloalkyl where haloalkyl is defined herein. The term "(substituted suifonybamino"* refers to -NHisubstituted sulfonyi), and the term
"(substituted sulfonyi)aminocailx>Byi" refers to -C(0)NH(substituted sulfonyi), wherein substituted sulfonyi is as defined herein,
[00931 ¾S«ifoEyloxy" refers to the group -OSOz-a!ky!, ~OSO2-subst.ttt.ted alkyl,
-OS(¾-aBcKiyls -OSOi-substiftited alkenyl, -OSOj-cycIoalkyl, -GSOj-substituted cylcoalkyl, -OSO;> -cycioaikenyl, -OSOa-su stiiuted eylcoalkenyk-OSOi-aryl, -OSOi-substituted ar l, -OSO;-heteroaryl. -OS02-substituied heteroaryi, -OSOa-heteroeyclic, -OSO -substituted heterocyclic, wherein .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,
fOIiOj "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
cycloalkenyl-C(S)-, aryl~C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryi-C(S)-, heterocyclic-C(S)-, and substituted heierocycIic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycioalkyi, substituted cycioalkyi, cycioaikenyl, substituted cycioaikenyl, aryl, substituted aryl, heteroary i, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein,
fO10.ll "Thiol" refers to the group «SH.
|01§2] ••f bioc rbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=8)~, {01031 "Thione" refers to the atom (=S),
{0104} "Alkylthio" refers to the group -S-aikyl wherein alkyl is as defined herein.
[0105] "Substituted alkylthio" refers to the group -S-fsubstituted alkyl) wherein substituted alkyl is as defined herein.
{01. 61 "Compound" or "compounds" as used herein is meant to include the stereoiosmers and tautomers of the indicated formulas.
[0107] "Stereoisomer" or "stereoisomers'" refer to compounds thai differ in the ebirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. {0108] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine^namine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
{§1091 As used herein, the term "noribogaine" refers to the compound:
Figure imgf000021_0001
as well as its pharmaceutically acceptable salts and/or solvates thereof. Conventionally, noribogaine is prepared by demethylation of naturally occurring ibogaine:
Figure imgf000021_0002
which is isolated from Tabernanth iboga, a shrub of West Africa. Demethy!ation may be accomplished by conventional techniques such as by reaction with boron
tribromide/methylene chloride at room temperature followed by conventional purificaiion. Methods for the synthesis and purification of noribogaine are disclosed in US Patent
Application No. 61/333,476, entitled Methods and Compositions fox Preparing and Purifying Noribogaine, filed on May 11, 2010, which is hereby incorporated by reference in its entirety. This invention is not limited to any particular chemical form of noribogaine and the drug may be given to patients either as a free base or as a pharmaceutically acceptable addition salt or a pharmaceutically acceptable solvate of noribogaine or the salt,
[011.03 As used herein, 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.
{0! 111 As used herein, the term 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. A few examples of solvents that cars be used to create solvates, such as pharmaceutically acceptable 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. Additionally, 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. When the solvent is water, 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).
[0112] As used herein, 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,
{0113] As used herein, the term "treatment" or "treating" means any treatment of a disease or condition in a patient, including:
* preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop, for example, in a subject at risk of suffering from such a disease or condition, thereby substantially averting onset of the disease or condition;
* inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or
* relieving the disease or condition thai is, causing the regression of clinical symptoms.
J0114J As used herein, 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.
f 115J As used herein, 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. As used herein, 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.
[0116] As used herein, the terms "blood-brain barrier" or "BBB" refer 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.
[0117] As used herein, the term "cleavable linking group" refers to a linking group that can be attached to noribogaine or a derivative at any possible position. Preferably, 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. Specifically, 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) R9- or -NR9C(0)-), or a phosphate-based cleavable linking group (-P(O)(OR9)-0-, -0-P(S)(OR9)-0-, -0-P(S)(SR)- 0-, -S-P(0)(OR9)-0-, -O-PCOXOR^-S-, -S-P<0)(OR9)-S-s -0~P(5)(OR9)-S-, -S-P(S)(GR9)- C.k. ~0-P(0}(R9)-0-, -0-P(S)(R9)-0-, -S-P(O (R;V( -S-P(S)(R )-0-, -S-P(0)(R9)-S-, or -O- P(S)(R9)-S-) where R9 can be hydrogen or alkyi.
[01I8J As used herein, the term "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. The term
"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, lyxose, glucosamine, mannosamine, and gaiactosamine; di- and trisaccharides include saccharides having two or three
monosaccharide units.
|0119J As used herein, the term "patient" refers io mammals and includes humans and non-human mammals.
2, Compounds
[01203 Accordingly, in one embodiment, this invention is directed to compounds which are represented by Formula I below:
Figure imgf000024_0001
wherein L is selected from the group consisting of a covalent bond and a cleavab!e linker group;
R1 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;
Ri0 is hydrogen or -OR;
R1 ' is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, (CH2)mOC(0)alkyl, (CH2)mOH, (CH2)mOalkyl, CH2-X-alkyl or
(CH2)mO(CH2)pO(CH2)qO(CH2)rCH3, where each of m, p and q is 1 , 2 or 3; and r is 0, I or 2, X is O or NH; R is selected from the group consisting of hydrogen, a hydrolysaMe group selected from the group consisting of -C(0)R2, -C(0)NRJR4 and -C(0)OR5, where R2 is selected from the group consisting of hydrogen, alkyi, substituted alkyi, aikenyl, substituted aikenyl, alkynyl and substituted alkynyl,
R3 and R4 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;
or a pharmaceutically acceptable salt and/or solvate thereof,
provided that when L is a eovalem bond and Rl is hydrogen, then R is selected from the group consisting of -C(0)NR3R and -C(0)ORs; and
further provided that when R is hydrogen or -C(0)R2 and L is a covaient bond, then R1 is not hydrogen.
[0121] In one embodiment, R1 1 is selected from the group consisting of hydrogen, C1-C3 alkyi, substituted Ci-Cs alkyi, C1 -C3 alkoxy and substituted C-. -C3 alkoxy.
[0122] In one embodiment, Rf f is H. In one embodiment, R" is C1 -C3 alkyi, such as ethyl. In one embodiment, RH is C%CH2OH. In one embodiment, R" is CH2CH2OCH3. In one embodiment, R" is α¾ί¾0€Η2Ρ1ι, in one embodiment, R' 1 is CH2CH2OC(0)alky], such as CH2CH2OC(0)(CH2)ioCH3. In one embodiment, Ri l is CH2-X-CH3. In one embodiment, Rn is CH2CH20(C¾)pO(CH2)qO(CH2)fCH3.
[01231 In one embodiment, R! 1 is C1-C3 alkyi optionally substituted with YH, YR12, YC(0)Ri2, C(0)YR12, C(0)N1¾, C(C))NHR!2, C(0)NR, 2R , NH2, NHR12, NR12RU, NHC(0)Ri2, or NR12C(0)R13, where Y is 0 or S, R12 and R13 are independently CrC3 alky! ,
[01241 in one embodiment, R1 1 is C1-C3 alkoxy optionally substituted with YH, YR'2, YC(0)R12, C(0)YR!2, C(0)NH2, C(0)NHR! 2 s C(0)NR12R13, NH2, NHR12, NR12R13,
NHC(0)R12, or R,2C(0)R13, where Y is O or S, R12 and R13 are independently C C3 alkyi.
{012S] In one embodiment, 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
|ίΙ127| in one embodiment. L is selected from the group consisting of -P(0)(OR9)-0-, -O- P(S)(OR9)-0-, -0-P(S)(SR9).0-5 -S-P(0){OR9)-0., -0.p(0)(OR9)-S~5 -S-P(0)(OR9)-S-; -0-P(S)(OR9)-8-, ~5-P(S)(OE9)~0~, -0-P{0)(R*)-0-s ~0- {S K R -S-P(0)(R9)-0-, -S-P(S)(R9)-0-s -S-P{0)(R9)-S-s and -0-P(S)(R9)-S-, where R9 Is hydrogen or alkyl.
[0128] In one embodiment, R is hydrogen. L is a cova!ent bond or -(..'(()}-. and Rs is substituted alkyl. in one embodiment, Rf is alkyl substituted with -NR6R'' where R6 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,
[0129] In one embodiment, R is selected from the group consisting of ~C(0)NR3R4 and -C(0)OR5 and R! is hydrogen.
{0130} in one embodiment, the compound of Formula I is a compound wherein R1 is H, L and R1 are as defined in Table II below, and RI ! is Cp¾ alkyl optionally substituted with YH, YR12, YC(0)R12, C(0)YR!2, C(0) 1¾, C(0)NHR12, C(0)NR%13, NH2, NHR12, NR12R°, NHC(0)R12, or NR,2C(0)R13, where Y is O or S, R12 and R13 are independently C,- C¾ alkyl, or a pharmaceutically acceptable salt and/or solvate thereof.
[0131] In one embodiment, the compound of Formula Ϊ is a compound wherein Ri(' is H, L and R* are as defined in Table II below, and R11 is selected from H, CH2CH2OH,
CH2CH2OCH3, CH2CH2OCH2Ph, CH2CH2OC(0)alkyi, and
CH2CH20(CH2) O(CH2)qO(e¾)rCH3, or a pharmaceutically acceptable salt and/or solvate thereof.
Jill 32] !n one embodiment, the compound of Formula 1 is a compound wherein Rs0 is -OR, R, L and R1 are as defined in Table II below, and R11 is Cr(¾ alkyl optionally substituted with YH, YR12, YC(0)Rn, C(0)YR12, C(0)NH2, C(0)NHR12, C(0) RI2Rt3, H¾ NHR12, NRI2R13, NHC(0)R12, or NR,2C(0)R13, where Y is O or 8, R12 and R are independently C r C3 a!kyl, or a pharmaceutically acceptable salt and/or solvate thereof.
[0133] In one embodiment, the compound of Formula I is a compound wherein Rs0 is -OR, R. L and R1 are as defined in Table II below, and Rl ! is selected from H. CH2CH2OH,
CH2CH2OCH3, CH2CH20CH2Ph, CH2CH2OC(0)alkyl5 and CH2CH20(CH2)pO(CH2)ciO(CH2)rCH3, or a pharmaceutically acceptable salt and/or solvate thereof.
{0134] In one embodiment, the compound of Formula I is a compound wherein R'° is -OR, R, L and R1 are as defined in Table II below, and R! 1 is selected from H, CH2CH2OH,
CH2CH2OCH3, CH2CH2OCH2PI1, CH2CH2OC(0)aIkyl, and
CH2CH20(CH2)pO{CH2)qO(CH2)rCH3, or a pharmaceutically acceptable salt and/or solvate thereof.
{0135J In one embodiment, the compound of Formula I is a compound wherein R."J is -OR, R, L and R3 are as defined in Table II below, and R! 1 is H, or a pharmaceutically acceptable salt and/or solvate thereof.
{0136) In one embodiment, the compound of Formula I is a compound wherein R'° is -OR, R» L and R¾ are as defined in Table II below, and R1 ' is CH2CH2OH, or a pharmaceuticaliy acceptable salt and/or solvate thereof.
f§137| In one embodiment, the compound of Formula I is a compound wherein R! 0 is -OR, R, L and R1 are as defined in Table II below, and R' 1 is CH2CH2OCH3, or a pharmaceuticaliy acceptable salt and/or solvate thereof.
{0J38J in one embodiment, the compound of Formula 1 is a compound wherein R10 is -OR, R, L and R1 are as defined in Table II below, and R" is CH2OCH3, or a pharmaceutically acceptable salt and/or solvate thereof,
[0139] In one embodiment, the compound of Formula I is a compound wherein R 10 is -OR, R. L and R1 are as defined in Table 11. below, and Rn is (Ί i20 fTX'i Ph.. or a
pharmaceutically acceptable salt and/or solvate thereof.
[0140] In one embodiment, the compound of Formula I is a compound wherein Ri0 is -OK, R, L and R1 are as defined in Table II below, and R! ! is CH2CH20C(0)alk l, such as Ci2 alkyi, or a pharmaceutically acceptable salt and/or solvate thereof.
[0141] In one embodiment, the compound of Formula I is a compound wherein RUj is -OR, R, L and R1 are as defined in Table ΪΙ below, aid R! ! is
CH2CH20(CH2¾,0(CH2)qO(CH2)fCH3, or a pharmaceutically acceptable salt and/or solvate [0142] In one embodiment, the compound of Formula Ϊ is a compound wherein Ri 0 is -OR, R, L and R1 are as defined in Tabie II below, and R1 1 is methyl or a pharmaceutically acceptable salt and/or solvate thereof.
I if ! 431 In one embodiment, the compound of Formula I is a compound wherein R'° is -OR, R, L and R1 are as defined in Table II below, and Rf 1 is C\ alkyi, or a pharmaceutically acceptable salt and/or solvate thereof.
Tabie II
Figure imgf000028_0001
Figure imgf000029_0001
J0144J In one erabodimeni, provided are compounds represented by Formula II below:
Figure imgf000029_0002
TT
wherein
R is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of -C(0)R\ -C(0)NR3R4 and -C(0)OR\ where R2 is selected from the group consisting of hydrogen, alkyL substituted aikyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, RJ and R4 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, R5 is selected from the group consisting of aikyl, substituted alkyf, alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that is not a saccharide or an oligosaccharide;
L is selected from the group consisting of a covaient bond and a eleavab!e linker group;
! 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;
or pharmaceutically acceptable salts thereof,
provided thai when L is a covaient bond and R5 is hydrogen, then R is selected from the group consisting of -C(0)NR.3R4 and -C(0)OR5; and
further provided that when R is hydrogen or -C(0)Rz and L, is a covaient bond, then R! is not hydrogen,
[0145] In one embodiment, R is hydrogen and L is a cleavable group,
[0146J in one embodiment, L is a suitable biocompatible, cleavable linking group. Suitable biocompatible, cleavable linking groups comprise a covaient 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.). Generally, 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. Examples of 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.
101 71 In general, 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. Thus one can determine the relative susceptibility to cleavage between a first and a second condition, where the first is indicative of cleavage in the brain and the second is indicative of cleavage in serum, blood or other non- target tissue, Such evaluations can be carried out in cell-free systems, in cells, in cell culture, in organ or tissue culture, or in whole animals. In preferred embodiments, the cleavable linking group is cleaved at least 2, 4, 10 or 100 times faster in the brain as compared to serum, blood or other non-target tissue,
{0148} In one embodiment, 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.
{§149} In one embodiment, 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
fMSOJ In one embodiment, L is seiected from the group consisting of -P(0)(OR9)~0-, -O- P(5){OR9)-Q-, -G-P(S){8R9)-{ , -S-P(0){OR9)-C)-, ~0-P(G)(GR9)-g-, ~8~P(0)(OR9)-S~, .0-P(S)iC)R9)~S~; -S-P($)(OR' 0-. -0-P{0)(R9)-0-5 ~0-P(S K RVO-, -S-P(0)(R9)«0-, -S-P(S)(R9)-0-5 -S-P(G){R9>$-, and -Q-P(8)(R9)-S-, where R9 is hydrogen or alkyl.
J0151J In. one embodiment, R is hydrogen, L is a covalent bond or -C(0)-s and R1 is substituted alkyl. Preferably R1 is alkyl substituted with -NR6R; where R6 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,
[0I52J ' In one embodiment, R is selected from the group consisting of -C(0)NR3R4 and -C(0)OR3 and R1 is hydrogen.
[01531 In one embodiment, 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
Figure imgf000031_0001
10 .QXfpiCH2CH2N ¾j2 j -CH3
Figure imgf000032_0001
Figure imgf000033_0001
3» Methods of Use
{0154] 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>RJ groups are cleaved in vtvo to produce nori oga ne or a noribogaine derivative. In a preferred embodiment, 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,
Treatment of Pain
[OlSSj In one of its method aspects, 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
pharmaceutical composition comprising a compound of this invention and a pharmaceutically acceptable exeipient. 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.
JO 1 6 j In another of its method aspects, 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
ANALGESICS'", which is incorporated herein by reference in its entirety. Treatment of Addiction
[0157] in another of its method aspects, 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.
fill 581 In certain embodiments, 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. In addition, it is contemplated that 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. It is contemplated that the compositions disclosed herein are especially useful in the treatment of addiction to opioids such as heroin and methadone. However, it is also useful in treating patients addicted to other substances, including cocaine, alcohol, amphetamines, tobacco, caffeine, opioid-like drugs, cannabinoids, benzodiazepines, and any other illicit, prescription, or generally available addictive substance, as we'd as combinations of these drags.
[0159J 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. In addition, 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, However, 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. [0160] 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.
pl61] The use of nori ogaine for acute and long-term treatment of drag abuse and withdrawal symptoms is described, for example, in U.S. Patent Application Serial
Nos.14/214,157, 14/346,655, 14/195,822; and U.S. Provisional Patent Application Serial Nos. 61/941,390, filed February 18, 2014 and titled "LOW DOSE NORIBOGAINE FOR TREATING NICOTINE ADDICTION AND PREVENTING RELAPSE OP NICOTINE USE"; 61/952,731, filed March 13, 2014 and titled "METHODS FOR ACUTE AND LONG- TERM TREATMENT OF ALCOHOL DEPENDENCE"; and 61/952,727, filed March 13, 2014 and titled "METHODS FOR ACUTE AND LONG-TERM TREATMENT OF
SUBSTANCE ABUSE"; each of which is incorporated herein by reference in its entirety.
Treatment of Depression
[0162] In another of its method aspects, 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. The use of 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.
Treatment of Stress and/or Anxiety
[0163] In another of its method aspects, 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.
|0164] 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! negative outlook, excessive worrying, moodiness, irritability, agitation, inability to relax, feeling lonely, isolated or depressed, aches and pains, diarrhea or constipation, nausea, dizziness, chest pain, headache, rapid heartbeat, eating too much or not enough, sleeping too much or not enough, social withdrawal, procrastination or neglect of responsibilities, increased alcohol, nicotine or drug consumption, and nervous habits such as pacing about or nail-biting. Stress can develop into a disabling disorder of excessive and irrational fears, such as obsessive-compulsive disorder, panic disorder, acute stress disorder and post traumatic stress disorder (PTSD).
[0165] 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.
f0166] 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.
[0167] The use of noribogaine for treatment of PI'SD 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. Combination therapy
{0168] Compounds of this invention maybe used alone or in combination with other compounds to treat the diseases or disorders described above. When administered with another agent, the co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Thus, 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. However, 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.
[0169] In some embodiments, 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,
4. Compositions
[0170] In another aspect, 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. J0171] Although 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. In addition, it is contemplated that 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). Other 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,
{01721 The compositions are comprised of in general, a compound of this invention or a mixture thereof in combination with at least one pharmaceutically acceptable exeipient.
Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention. Such 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.
[0I73J 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.
{0174] 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
Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990). [0175] The 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. 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.
[0176] 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. Preferably, the compound is present at a level of about 1 to 80 wt %. in a liquid composition, a compound of this invention should generally be present in such compositions at a concentration of between about 0.1 and 20 rng/rnl. 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.
[0177] The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the compound can be formulated as liquid solution, suspensions, aerosol propellents or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDi) and dry powder inhalers (DPI). 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. 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. 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,
JO! 78} Recently,, pharaiaceuticai formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size, For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crossiinked matrix of
nraeromolecules. 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.
[0179] In a preferred embodiment, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
[0180] In some embodiments, 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, In a preferred embodiment, 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),
ISIJ Generally, 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. For example, for administration to a 70 kg person, the dosage range would preferably be about 70 to 210 mg per day, In some embodiments, 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. In other embodiments, 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.
[0182] In some embodiments, 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. In a preferred embodiment, 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. In an especiaily preferred embodiment, the patient's QT interval is monitored before and during treatment with the compound. Methods for pre-screening a patient before treatment can be found, for example, in U.S. Provisional Patent Application Serial No. 61/952,744, filed March 13, 2014 and tided "METHODS AND COMPOSITIONS FOR PRE-SCREENING PATIENTS FOR TREATMENT WITH NORIBOGAJNE," which is incorporated herein by reference in its entirety.
{0183] In addition to the methods discussed above, the present invention is directed to a pharmaceutical composition, preferably in unit dose form, comprising a compound of this invention. When administered to a patient, 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,
[0J84] The amount of the composition administered will depend on a number of factors, including but not limited to the desired final concentration of the compound, the
pharmacokinetic and pharmacodynamic properties of the compound, the size, age, and physiological profile of the patient, and the like. 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.
{0185} Determination of dosages is well within the empiric knowledge of persons skilled in the art; nonetheless, it can be appreciated that estimates of final dosages can be made by approximating the concentration of compound necessary to achieve a desired therapeutic activity, such as treatment of pain and/or addiction. Extrapolation to a specified mammalian dosage range, or more particularly a human dosage range is well within the skill of the practitioner.
(§186) In some embodiments, 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,
5. Synthetic Methods
[0187J 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.
101.88] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T, W. Greene and G. M. Wilts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999» and references cited therein.
[0189} Furthermore, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as 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.
{0190} Still -further, some of the compounds defined herein include vinyl groups which can exist in cis, trans or a mixture of cis and trans forms. All combinations of these forms are within the scope of this invention,
I ίί 1911 The starting 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 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). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 15 (John Wiley and Sons, 1991 ), Rodd's Chemistry of Carbon Compounds, Volumes 1 5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes i 40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4.sup.th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
[0192J Compounds of Formula II can be readily prepared from noribogaine by methods described herein and those known to one of skill in the art, A skilled artisan would appreciate that the reactivity of the hydroxy group and the indole nitrogen is different so that selectivity can be achieved by selecting suitable reagents and suitable reaction conditions for one of them to react but leaving the other intact to form the desired product. For example, the hydroxy group is expected to selectively react with an acid Κ20(Ο)ϋΗ in the presence of triphenylphosphine (PhjP) and diethyl azodicarboxylate (DEAD) to give compound 1-1 and 1-3. Thus, as shown in Scheme I, 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. In other embodiments (i.e. when R is H), 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-R1. Suitable protecting groups are well known in the art (see T. W. Greene. P. G. M. Wuts, Protective
Groups in Organic Synthesis, 4 Edition, Wiley-Interscience, New York, 2006). in another alternative embodiment (i.e. when L is a bond and R1 is H), the indole nitrogen is protected with a suitable protecting group, PG (see Greene et aL supra), such phenol that is derivatized with R.
Figure imgf000044_0001
[0193J Alternatively, as shown in Scheme 2, compounds of this invention wherein L-R is not hydrogen may be prepared by reacting ibogaine with LG-L-R5 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
Figure imgf000045_0001
|01 4] Compounds described herein can also be prepared as shown in any of Schemes 3-5, wherein R, R1, L, R1 and R! " are as defined herein, LG is a leaving group such as hydroxy, alkoxy, halo, etc., and X is iodo (I) or bromo (Br) . Compounds 3-1 and 4-1 can be prepared according to procedures described in, for example, U.S. Patent 6,21 1,360 or U.S. Patent Publication No. 2013/0165647.
[0195] In Scheme 3, Compound 3-1 reacts with LG-L-R1 to give compound 3-2,
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
enantiomerically pure 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-R1 to give compounds of ibis invention.
[0196] in Scheme 4, Compound 4-1 is halogenated to compound 4-2. When 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). 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". When X is iodo or bromo, 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. 'ΆΏ Improved Cu- Based Catalyst System for the Reactions of Alcohols with Aryl Halides" Altman et al.5 J, Org. Chem., 2008, 73, 284-286, incorporated herein by reference), or CuBr (U.S. Patent No, 4,422,955, incorporated herein by reference) useful for incorporating an -OR group, such as, benzyloxy or substituted benzyloxy group. Compound 4-3 reacts with LG-L-R1 to give compound 4-4, which is de-carboxylated by methods described herein or known in the art to provide compound 4-5,
|0197j In Scheme 5. compound 4-1 is de-carboxyiated by methods described herein or known in the art to provide compound 5-1. Compound S- l is halogenated to compound 5-2, which reacts with ROH to provide compound 5-3, followed by reaction with LG-L-R1 to give com ound 4-5 using methods described herein.
Figure imgf000046_0001
Scheme 5
Figure imgf000047_0001
5-3 4-5
Scheme 6
Figure imgf000047_0002
Ph!(OH)OTs
Figure imgf000047_0003
Scheme 7
7-1 7-2 7-3
Esterification with
c irai caroxy!ic acid Retro sid s! FTCOOH. wherein R*
is chirai roup
Figure imgf000048_0002
y,
etc.
Examples
(0198] The present invention is further defined by reference to the following examples. It will be appareni to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the current invention.
Table HI. List of abbreviations and acronyms.
Abbreviatio n Meaning
°C Degree Celcius
Ac Acetyl
bs Broad singlet
ca. Approximately
CD! Ν,Ν'-Carbonyl diimidazole
d Doublet
dd Doublet of doublets
DEAD Diethyl azodicarboxyiate
DiPEA Ν, -Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DMF Dimethylformami de
Et Ethyl.
σ o Gram
h Hour
HPLC High-performance liquid chromatography
Hz Hertz
i,v. intravenous
Kg Kilogram
M Molar
Muliiplet Abbreviation i Meaning
Μ+ί Mass peak
Me Methyl
Milligram
MHz Megahertz
min Minute
niL Milliliter
mmol Milliraole
MS Mass spectrometry
N Normal
NaHDMS Sodium hexamethyidisilazane
NMR Nuclear magnetic resonance
Ph Phenyl
q Quartet
q.s. Sufficient amount
r.t./rt Room temperature
s Singlet
t Triplet
TBAF Tetra-n-butyiamraonium fluoride
TBS tert-Bulyldimethyistlyl
TBSC1 tert-Butyldimethyisiiyl chloride
td Triplet of doublets
THF Tetrahydroruran
TLC Thin layer chromatography
v/v Volume/volume
wt% Weight percent
δ Chemical shift
μΤ Microliter
[0199] Compounds of the invention can be prepared from readily available starting materials using, for example, the following general methods and procedures, it will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0200] Additionally, as will he apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular 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. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA), Others may be prepared by procedures, or obvious modifications thereof described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1 89), Organic Reactions, Volumes 1 -40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001 ), and Larock's Comprehensive Organic Transformations (VCH Publishers inc. 1989).
Example 1, Preparation of Compound 3
Figure imgf000050_0001
[0201] Compound 1 may be prepared by reacting noribogaine with at least two equivalents of (CH3)2NCH?.CH2C(0)C1 in the presence of a base in a suitable solvent. In one
embodiment, the reaction is conducted in a polar solvent. Upon reaction completion, 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.
Example 2, Preparation of Compound 2
Figure imgf000050_0002
102021 Compound 2 may prepared by reacting noribogaine with at least one equivalent of (CH3)2NC¾CH2CC0)C1 in the presence of a base in a suitable solvent to give an intermediate product. In one embodiment, 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, Upon reaction completion, 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.
Example 3. Preparat on of Com ound 3
Figure imgf000051_0001
{0203] Compound 3 may prepared by reacting noribogaine with one equivalent of
(CH3)2NC1¾C¾C(Q)C1 in the presence of a base, such as pyridine, in a suitable solvent, or with one equivalent oftCI¾)2N(¾CH2C(0)OH in the presence of triphenylphosphine (Ph3P) and diethyl azodicarboxylate (DEAD), In one embodiment, the reaction is conducted in a polar solvent. Upon reaction rational completion, compound 3 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or. altematively, used without purification and/or isolation.
Example 4, Preparation of Compound 8
Figure imgf000051_0002
) Preparation ofTBS-Noribogaine 8-A
[0204] A suspension of noribogaine hydrochloride (852 mg, 2.56 mmoi), TBS-CI (444 mg, 2.94 mraol) and imidazole (227 mg, 3.33 mmol) in DMF (6 irtL) was stirred at room temperature for 20 h. The resulting clear solution was diluted with 10% 2- propano!/dicMoromethane and washed with water and brine. The aqueous phase was extracted with EtOAc. The combined organic layers were concentrated and purified by column chromatography (EtOAc/Hexanes,, v/v, 2/1) to give compound 8-A (911 mg, 87%) as a white solid.
{0205] MS calculated for (C25H3eN2OSi): 410; MS found, (M+l ): 41 1 .
b) Preparation of Compound 8-B
(0206J NaHMDS (0.75 ml.., 1.0 M solution, in THF) was added into a solution of TBS- noribogaine 8-A (205 mg, 0.5 mmol) in THF (10 ml.) at -78 X. The resulting soiution was stirred for 10 min at -78 °C then a solution of 4-nitrop enyl cMoroformate (182 mg, 0.9 mmol) in THF (8 nxL, pre-cooled to -78 °C) was added quickly. The reaction mixture was allow to warm to room temperature and stir for 1 hour, followed by the addition of N,N- dimetliyleth leiiediamine (0.22 ttiL, 2.0 mmol). After stirring at room temperature for an additional hour, the reaction mixture was diluted with 10% 2-propanol/dichloromcthane and washed with water and brine. The aqueous phase was extracted with EtOAc, The combined organic layers were concesitrated and purified by column chromatography (EtOAc Hexanes, v/v, 2/1 to 99:1 EtOAc rtriethylamine). The desired product compound 8-B (138 mg, 53%) was obtained as white solid.
J0207J MS calculated for (C3oH4gN402Si): 524; MS found, (M+l): 525.
c) Preparation of Compound 8
f«208J TBAF (0.68 mi.. 1.0 M solution in THF, 0.68 mmol) was added to a solution of compound 8-B (178 mg. 0.34 mmol) in THF (12 mL) at -78 °C. The resulting soiution was stirred for 40 min at -78 °C before it was quenched by addition of IN aqueous HQ (2 ml). The reaction mixture was allowed to warm to room temperature and was concentrated. The residue was purified by Preparative-HPLC to give compound 8 as the hydrochloride salt (1 10 mg, HO salt, 72%) as a white solid.
[02091 MS calculated for (C24H3 N4O2): 410; MS found, (M+l): 41 1. Ή NMR (300 MHz, CD3OD) δ 8.20 (hs, 1H), 7.49 (d, 1H), 6.87 (s, 1H), 6.80 (d, 1 H), 3.50 - 3.92 (m, 6H>, 3.36 - 3.58 (m, 4H), 3.00 - 3.36 (m, 2H) , 2.80 - 3.00 (m, 6H), 2.50 (td, IH), 1 .85 - 2.20 (m, 3H), 1.48 - 1.82 (m, 3 i f ), 1.22 - 1.46 (m, 1 H), 1.04 (t, 3H). Example 5» Preparation of Compound 15
Figure imgf000053_0001
Figure imgf000053_0002
a) Preparation ofNoribogaine acetate 15 -A
[0210J A mixture of noribogame (300 mg, 0.9 tnmol) and DMAP (10 mg, 0.09 mrnol) in acetic anhydride (6 mL) was heated at 40 °C for 16 h. The acetic anhydride was eo- evaporated with toluene at 40 6C under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), and the resulting solution was stirred with saturated NaHCO;? solution (50 mL) at rt for 2 h. The organic phase was separated and concentrated under reduced pressure. The crude product was purified by chromatography on silica gei (ethyl aeetate/hexane : =1 /2) to give compound 15- A (280 mg, 90%) as white solid.
1021 i f MS calculated for (CatHaeNA ; 338; MS found, (M+l): 339. !H NMR (3G0 MHz, CD3OD) δ 7.18 (4 J=8.4 Hz, III), 7,06 (d, J=2.4 Hz, 1H), 6.7 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 3.38 (rn, lH), 3.1 <m, 4H), 2.95 (in, 2H), 2.65 (m, 1H), 2.27 (s, 3H), 2.14 (m, 1 H), 1 .88 (!TL 21 f). 1.64-1.45 (m, 4H), 1.23 (m, 1H), 0.94 (t, J=7.5 Hz, 3H),
b) Preparation of Compound 15
[0212] To a solution of Ν,Ν-diraethylethanolamme (0.6 mL, 6 intnol) in THF (1.4 mL) was added sodium (46 mg, 2 mmol) at rt. The reaction mixture was stirred at rt until the sodium disappeared. The resulting solution of sodium Ν,Ν-dime ylethanoiamine was used for the reaction below,
[0213J To a solution of compound 1 S-A (200 mg, 0.59 mmol) in THF (2 mL) was added dropwise NaHMDS (0.59 mL, 0.59 mrnol) at -78 °C. The reaction mixture was stirred at -78 "C for 10 min, and then, the resulting reaction mixture was transferred via a cannula to a solution of 4-nitrophenyl chforoformate (143 mg, 0,71 mmol) in THF (1 mL) at -78 °C. The reaction mixture was allowed to warmed to it and stirred for 30 rain. The reaction mixture was then cooled to -78 °C, and sodium Ν,Ν-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
acetate/rnethaiiol/triethylainme : =100/5/1). The resulting yellow oil was further purified by prep-HPLC to give compound 15 (66 mg, 30%) as a white solid.
10214] MS calculated for (i/,.d l :, .;Ο^ : 41 1 ; MS found, (M+I): 412. Ή NMR (300 MHz, CD3OD) S 7.79 (d, J-8.7 Hz, 1 H), 6.7 (d, J 2.4 Hz, 1H), 6.66 (dd, J-2.4 and 8.7 Hz, 1H), 4.4 (m, 3H), 3.75 (m, 1 H), 3.0 (m, 3H), 2.87 (m, 2H), 2.8 (m, 211), 2.7 (m, 3H), 2.5 (m, 3H), 2.29 (s, 6H), 2.14 (m, lH), 1.85 (m, 2H), 1.61-1.23 (m, 5H), 1.1 (m, IE), 0.94 (t, J=7.2
Hz, 3H),
Example 6. Preparation of Compound 16
Figure imgf000054_0001
[0215] To a solution of compound 15-A (330 mg, 0,92 mmol) in THF (3 mL) was added dropwise NaHMDS (0.87 mL, 0.87 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 10 min, and then the resulting reaction mixture was transferred via a cannula to a solution of 4-nitrophenyl chioroformate (185 mg, 0.92 mmoi) in THF (1 mL) at -78 °C. The reaction mixture was allowed to warm to rt and stirred for 30 min. The reaction mixture was recooled to -78 °C» and N,N-dimethyI e&yJenediamine (79 mg, 0.9 mmol) was added. The reaction mixture w s warmed 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 Chromatogaphy (ethyl acetate methanol ttiethyiamine : =100/5/1 ). The resulting yellow oil was further purified by prep-HPLC to give compound 16 (50 mg, 14%) as a white solid. [0216] MS calculated for (C^H^N ) : 452; MS found, (M+l )r 453. Ή NMR (300 MHz, CDjOD) δ 7.5 (d, J==8,7 Hz. !H), 7,12 (d, J=2.4 Hz, IH), 6,8 (dds J=2.4 and 8.7 Hz, 11-1), 3.5 i . 3H), 3.4 (m, i l l). 3.2 (m, 211). 3.0 (m, 311). 2.8 (m, 111 ). 2.6 (m. 3H), 2.3 (s, οϊ ί >, 2.27 (s, 3H), 2.14 (m, IH), 1.85 (m, 2H), 1.61-1.23 (m, 5H), 1.1 (m, 1H), 0.94 (t, 3=6.9 Hz, 3H).
Example 7. Preparation of Compound 38
Figure imgf000055_0001
a) Preparation of Compound 38-A
[0217] To a solution of compound 15- A (42 mg. 012 mmol) in THF (1 ml.) was added drop ise NaHMDS (0.14 mL, 0.14 mmol) at -78 °€. The reaction mixture was stirred at -78 °C for 10 min and then 4-nitropheny 1 chloroformate (27 mg, 0.14 mmol) was added at -78 °C. The reaction mixture was allowed to warm to rt and stirred for 1 h. Saturated NaHC(¼ solution (5 mL) was added, and the reaction mixture was extracted with ethyl acetate (2 x 10 raL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetaie/¾exane--l /l) to give compound 38-A (20 mg) as a yellow oil in 33% yield.
[0218] MS calculated for (C2gH29Nj06)+: 503; MS found, (M+l): 504.
b) Preparation of Compound 38
\9219] A reaction mixture of compound 2 (150 mg, 0.3 mmol) and tnethylamine (1 raL, 33 wt% in ethano!) in€¾<¾ (5 mL) was stirred at rt for 1 h. The reaction mixture was washed with saturated NaH.C<¾ solution, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl acetate/methanoytriethyf amine : 100/2/1) to give compound 3 (80 mg) as a yellow oil in 80% yield,
[02201 MS calculated for
Figure imgf000056_0001
353; MS found, (M+l ); 354.
Example 8, Preparation of Compound 18
Figure imgf000056_0002
[0221 j A reaction mixture of compound 38 (80 mg, 0.22 rnmol) and DMAP (10 mg. 0.09 mmol) in acetic anhydride (3 mL) was heated at 40°C for 16 h. The acetic anhydride was co- evaporated with toluene at 40°C under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the resulting solution was stirred with saturated NaHCQj solution (50 ml,) at rt for 30 min. The organic phase was separated and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (ethyl
acetate/methanol/triethylamine : =100/2/1) to afford a crude residue, which was further purified by preparative HPLC give compound 18 (50 mg, 60%) as a yellow solid.
10222] MS calculated for (C23H29N3O3)"' : 395; MS found, (M+ l): 396. Ή NMR (300 MHz, CD3OD) δ 7.44 (d, J=8.7 Hz, 1 H), 7.13 (d, J=2.4 Hz, 1H), 6.7 (dd, J=2.4 and 8.7 Hz, i M>. 3.2 Cm. 1H), 3.05 (m, 4H), 2.98 (s, 311). 2,95 (m, 211). 2.83 (m, 1 H). 2,6 (tn, H i), 2.27 (s, 3H), 2.14 (m, 1H), 1.88 (m, 2H), 1.64-1,45 (m. 4H), 1.23 (m, 1H), 0.92 ( J=7.2 Hz, 3H).
Example 9. Preparation of Com ea ed 31
Figure imgf000056_0003
[0223] To a solution of compound 15-A (200 mg, 0.59 rnmol) in THF (2 mL) was added dropwise NaHMDS (0,68 mL, 0.68 mmol) at -78 °C, The reaction mixture was stirred at -78 °C for 10 min, and then methyl choroformate (78.6 uL, 0.68 mmol) was added at -78 °C. The reaction mixture was allowed to warm to rt and stirred for 1 h. Saturated NaHCOj solution (5 niL) was added, and the reaction mixture was extracted with ethyl acetate (2 x 20 mL), The combined organic extracts were concentrated under reduced pressure to afford a crude product which was purified by preparative- HPLC to give compound 31 (1 1 6 mg, 55%) as a white solid.
f§224] MS calculated for (C23H28N204)+: 396; MS found, (M+l): 397. IH NMR (400 MHz. CD3OD) 5 7.95 (d, 3=92 Hz, 1H), 7.06 (d, J=1.2Bz, 1 H), 6.7 (dd, J .2 Hz, J=1.2 Hz, 1H)S 4.84 (ss 3H), 3.8 (m, IH), 3.1 (m, 3H), 2.99 (in, 2H), 2.8 (m, i H), 2.68 (m. I H), 2.15 (s, 3H), 2.14 (m, I H), 1 .85 (m, 2H), 1.61 (m, 2H), 1.58 (m, I H), 1.46 (m, li l), 1.23 (ra, I H), 0.94 (t, J=7.2 Hz, 3H).
Example 10. Preparation of Com ound 39
Figure imgf000057_0001
a) Preparation ofTBS-Noribogaim 8-A
[0225] A suspension of noribogaine hydrochloride (852 mg, 2.56 mmol), TBS-Ci (444 mg, 2.94 mmol) and imidazole (227 mg, 3.33 mmol) in DMF (6 mL) was stirred at room temperature for 20 h. The resulting clear solution was diluted with 10% 2- propanol/dichloromethane and washed with water and brine. The aqueous phase was extracted with EtOAc, The combined organic extracts were concentrated and purified by column chromatography (EtOAc/Hexanes, v/v, 2/1) to give compound 8-A (91 1 mg, 87%) as a white solid,
[0226] MS calculated for (CasHsgNaOSi): 410; MS found, (M+ 1 ): 41 1 .
h) Preparation of Compound 9- A
[0227] NaHMDS (0.9 mL, 1.0 M solution in THF, 0,9 mmol) was added into the solution of compound 8-A (246 nig, 0.6 mmol) in THF (6 mL) at -78 °C, The resulting solution was stirred for 15 min at -78 °C before ethyl chloroformate (0.12 mL, 1.2 mmol) was added. The reaction mixture was warmed up to room temperature and stirred for 1 hour, then it was partitioned between EtOAc and water. The organic layer was washed with brine and dried over a^SO^. The crude product was obtained as a pale yellow oil after concentration, which was used in the next step without further purification,
f 02283 MS calculated for (C2«H 2N2(¼Si): 482; MS found, (M+l); 483.
c) Preparation of Compound 39
{0229J TBAF (1.5 mL, 1.0 M solution in THF) was added into a solution of compound 9-A (crude, ca. 0,6 mmol) in THF (12 mL) at -78 °C. The resulting solution was stirred for 20 min at -78 °C before it was allowed to warm to room temperature. After one hour, the reaction mixture was diluted with 10% 2-propanol dichlororaethane and washed with water and brine. The aqueous phase was extracted with EtOAc. The combined organic layers were concentrated and purified by column chromatography (dichloromethane MeOH, v/v, 10/1 } to give compound 39 (187 rag, 85% over two steps) as a white solid.
[0230] MS calculated for (C22f r^O.;)' 368; MS found, (M+l): 369. ¾ NMR (300 MHz, CD3OD) S 7.83 (d, 1H), 6.82 (s, 1H), 6.78 (d, 1H), 4.49 (q, 2H), 4.08 (dd. Hi), 3.65 - 3.92 (m, 2H), 3,40 - 3.62 (m, 2H), 3, 15 - 3.20 (m, 1H) , 2.95 - 3.07 (m, 2H), 2.42 - 2.62 (m, IH), 2.20 (bs, ! Hi 1.80 - 2.10 (m. 2H), 1.40 1.80 (m, 4H), 1.48 (t, 3H). 1.05 (t, 3H),
Example 11. Preparation of Compound 32
Figure imgf000058_0001
[0231] A solution of compound 39 (137 mg, 0.37 mmol) and CD! (181 mg, 1.12 mol) in THF (10 mL) was stirred at 50 "C for two hours. The mixture was then cooled to room temperature, and N-methyipiperizme (0.27 mL, 0.24 mmol) was added. After one hour, the reaction mixture diluted with 10% 2-propanol dichiorometbane and washed with water and brine. The aqueous phase was extracted with EtOAc, The combined organic extracts were concentrated and purified by preparative-HPLC to give compound 32 as the hydrochloride salt (159 mg, HC1 salt, 81%) as a white solid,
(02321 MS calculated for (CaH3e 404): 494; MS found, (M+1 ): 495. !H NM (400 MHz, CD3OD) δ 8.07 (d, 1H)S 7.35 (s, IH), 7.09 id, IH), 4.57 (q, 211), 4.40 - 4.60 (m, 1H): 4.25 - 4.40 (m, IH), 4.12 (dd» 1H), 3.80 - 3,92 (m, IH), 3.84 (s, 1H), 3.42 - 3.62 (m, 5H)S 3.16 - 3.42 (m, 5H), 2,98 (s, 3H), 2.S7(td5 \ E% 2.24 (bs, IH), 1.98 - 2.11 (m, 2.H), 1.50 ~ 1.82 (m, 3H), 1.42 - 1.50 (m, 2H), 1.51 (t, 3H), 1.05 (t, 3H).
Example 12. Preparation of Compound 40
Figure imgf000059_0001
1S-A
[0233] To a solution of compound 15-A (200 nig, 0.59 mmol) in. THF (2 mL) was added dropwise NaHMDS (0.68 mL, 0.68 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 10 mill, and then methyl choroformate (78.6 ,uL, 0.68 mmol) was added at -78 °C. The reaction mixture was allowed to warm to rt and stirred for 1 fa, Saturated NaHC<¾ solution (5 mL) was added, and the reaction mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were concentrated under reduced pressure to afford a crude product which was purified by preparative-HPLC to give compound 40 (1 16 nig, 55%) as a white solid.
[0234] MS calculated for (C23I½K¾04f: 396; MS found, (M+1); 397. lH NMR (400 MHz, CD3OD) 5 7.95 (d, J=9.2 Hz, IB), 7.06 (d, J-l .2Hz, HI), 6,7 (dd, J=9.2 Hz, J«l .2 Hz, IH), 4.84 (s, 3H), 3.8 (m. 1H), 3.1. (m, 3H), 2.99 (m, 2H), 2.8 (m, IH), 2.68 (m, IH), 2.15 (s, 3H), 2.14 (m, IH), 1.85 (in. 2H), 1.61 (tn, 2H), 1.58 (m, IH), 1.46 (m, I H), 1.23 (m, IH),
0.94 (t, J=7.2 Hz, 3H). Example 13. Preparation of Compound 36
Figure imgf000060_0001
a) Preparation of Compound 36-A
|023S} NaHMDS (1.05 mL, 1.0 M solution In THF) was added into a solution of TB8- noribogaine 8-A (288 mg, 0,7 mmoi) in 8 ml. of THF at -78 °C, The resulting solution was stirred for 10 min at -78 °C before a solution of chlorodimethyi phosphate (0.15 mL, 1.4 mmol) in 2 mL of THF was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour, before it was diluted with 5% 2- propanol/dichlorornethane and washed with water and brine. The aqueous phase was extracted with EtOAe. The combined organic extracts were concentrated and purified by column chromatography (EtOAc/Hexanes, v/v, 2/1 to pure EtOAe). The desired product compound 36-A (305 mg, 84%) was obtained as a white solid.
102361 MS calculated for (C2?H 3N204PSi): 518; MS found, (M+l): 51 .
b) Preparation of Compound 36
{§237 j TBAF {1.1 mL, 1.0 M solution in THF) was added into a solution of compound 36- A (305 mg, 0.59 mmol) in 8 mL of THF at -78 °C. The resulting solution was stirred for 40 niiii at -78 °C before it was quenched by addition of 2 mL of IN aqueous HC1, The reaction mixture was diluted with 5% 2-propanol/dicMorometriajne and washed with water and brine. The aqueous phase was extracted with EfOAc. The combined organic layers were concentrated and purified by column chromatography (dicWoromethane/2-propanoI, v v, 15/1 to 1.0/1) and then preparative-HPLC to give pure compound 36 as..the hydrochloride. salt (220 mg, HCi salt, 85%) as a white solid,
102381 MS calculated for (C2i¾N20 P): 404; MS found, (M+l): 405, !B NMR (300 MHz, CDC ) δ 10.38 (bs, 1H)» 7,45 (d, IH), 6.97 (s, IH), 6,91 (d, IB), 3.98 - 4,15 (m, IH), 3.40 - 3.85 (m, 1 OH), 2.70 - 3.20 (m, 3H) , 2,40 - 2,60 (ro, IH), 2.18 (bs, IH), 1.72 - 2.05 (m, 4H), 1.38 - 1.50 (in. 1 H), 0.95 (L 3H).
Example 14» Preparation of Compound 41
Figure imgf000061_0001
(0239J A solution of compound 36 (44 mg, 0.1 1 mmol), CD! (54 mg, 0.33 mol) and one drop of DIPEA in 2 mL of THF was stirred at 50 °C for two hours, before it was cooled down to room temperature. N-methy!piperizine (3 drops) was added. After one hour, the reaction mixture was concentrated and purified by preparative TLC (dichioromethane/
MeOH/triethylarriine. v/v, 200/20/1). Pure compound 41 (28 mg, 48%) was obtained as a white solid.
{02401 MS calculated for (C27H39N4Q5P): 530; MS found, (M+l): 531 , Ή NMR (300 MHz, CDCh) δ 7.95 (d. I H), 7,13 (s, 1H), 6.95 (d, IH), 3,65 - 3,82 (m, 8H), 3.55 - 3.65 (m, 3H), 3,47 (s, 1H), 3.40 - 3.45 (m, IH) , 2.96 - 3.40 (m, 5H), 2,72 - 2,95 (m, IH), 2.40 - 2.70 (m, 4H), 2.35 (s, 3H), 2.08 - 2.25 (in. IH), 1.78 - 1.95 (m, 2H), 1.38 - 1.70 (m, 2H), 1.15 - 1.20 (m, 2H), 0.89 (t, 3H). Example 15
[0241 J The following example illustrates how to treat an opioid addicted patient having an immediate craving for the opioid. In particular, 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.
Example J 6
10242] The following example illustrates how to treat severe pain in a patient. In particular, 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.
Example 17: Tablet formulation
[0243] The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient itity i >er tebl et, mg 1
Compound of Formal* I 40
Cornstarch 50
Croscarmellose sodium ? J i Lactose
Magnesium stearate
Example 18; Capsule formulation
[0244] The following ingredients are mixed intimately and loaded into a. hard-shell gelatin capsule, ...Ιί!1£*ί!£ ?.! Quasi tit y per caps yJe, rsig |
Compoun of Formula I j 20 j
Lactose, sgray-drted 148
Magoesiuisi stearate 2
Example 19: Suspension formulatioii
j 245| The following ingredients are mixed to form a suspension for oral administration (q.s. = sufficient amount).
Figure imgf000063_0002
Example 20; injectable formulation
102461 The followin ingredients are mixed to form an injectable formulation.
Figure imgf000063_0001
Example 21; Suppository formulatio
(0247] 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;
Riches-Nelson, Inc., New York), and has the following composition:
Ingredient Quantity
Compound of Formula I 500 rng
•" Wste sof® Η-Ϊ5 balance

Claims

What is claimed is:
A compound of Formula I or Formula 11:
Figure imgf000064_0001
wherein L is selected from the group consisting of a covalenf bond and a cleavable linker group;
R' is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycioalkyl, substituted cycioalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic provided that R! is not a saccharide or an oligosaccharide;
10 is hydrogen or -OR;
R11 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, (CH2)mOC(0)alkyl, (CH2)mOH, (CH2)mOaikyl CH2-X-alkyl or
(CH2.)mO(CH2)pO(CH2)qO{CH2)rCH35 where each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2, X is O or NH;
R is selected from the group consisting of hydrogen, a hydroiysable group selected from the group consisting of ~C(0)R2, ~C(0)NR3R4 and -€'(0)OR\ where R": is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that R is not a saccharide or an oligosaccharide;
R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and
R* is selected from, the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl heterocyclic and substituted heierocyciic provided that R is not a saccharide or an oligosaccharide;
or a pharmaceutically acceptable salt and/or solvate thereof,
provided that when L is a covalent bond and R : is hydrogen, then R is selected from the group consisting of -C(0)NR3R4 and -C(0)ORs; and
further provided that when R is hydrogen or -C(0)R2 and L is a covalent bond, then R! is not hydrogen,
2. The compound of claim 1 , wherein Rn is selected from the group consisting of hydrogen, CJ-CJ alkyl, substituted Cr-C3 alkyl, Ci-Ca alkoxy and substituted CrQ? alkoxy.
3. The compound of claim 1, wherein L is hydrogen or a biocompatible, cleavable linking group and Rn is C1-C3 alkoxy optionally substituted with YH, YR , YC(0)R12, C(0)YRi 2, C(0)NH2, C(0)NHR12, C(0)NRl2R13, N¾, NHR12, NR,2R13, NHC(0}R! or NR, 2C(0)R13, where Y is O or S, R12 and Ru are independently C 1 -C3 alkyl
4. The compound of claim 1, wherein R is hydrogen, L is a co valent bond or -C(0>, and R1 is alkyl substituted with -NR6R'' where R° and R7 are independently selected from the group consisting of hydrogen, alkyl. aikenyl, substituted alkenyL alkynyl, substituted alkynyl, aryi, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic,
5. The compound of claim 1, wherein R1 ' is selected from H, CH2CH2OH,
CH2CH2OCH3, CH2CH2OCH2Pfa, CH2C¾OC(0)alkyl, and
CH2CH20(CH2)pO(CH2)qO(CH2)rCH3, wherein p, q, and r are independently 0, 1, 2, or 3, or a pharmaceutically acceptable salt and/or solvate thereof.
6. The compound of claim 1, wherein IIs ! is H5 or a pharmaceutically acceptable salt and/or solvate thereof.
7. The compound of claim 1 , wherein R! or R¾0 is H, or a pharmaceutically acceptable salt and/or solvate thereof,
8. The compound of claim 1 , wherein R is hydrogen and L is a cleavable group,
9. The compound of claim 1, wherein L is a biocompatible, cleavable linking group comprising from 1 to 20 atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus,
10. The compound of claim 1 , wherein L is -C(0)-. 11, The compound of claim 1, wherein L is -C(0)0-.
12, The compound of claim 1, wherein L is -C(0)NR-f where R is hydrogen or alkyt
13, The compound of claim 1, wherein L is selected from the group consisting of ••PiOKOR/'KK -0~PiS)iORV<>-. -0-P(S)(SR9)-0-, -S-P{0)(OR9)-0-, -0-P(0)(OR9)-S-, -S-P(0)(OR9)-S»} ~0-P(8)(OR9)~S~, -S-P(S)(OR9)-0-5 -0-P(0)(R9)-0-, -0-P(S)(R9)-0-, -S-P(0)(R9)-0-, -S~P(S)iR9KX••S-P(0)(R);-S-. ·0·Ρ(8χ! ν)·· · where R9 is hydrogen or alkyl.
14, The compound of claim 1, wherein R is hydrogen, L is a cova!ent bond or -C(O), and
R1 is substituted aikyl.
15, The compound of claim 14, wherein R' is alkyl substituted with -NR6R'' and where R6 and R7 are independently selected from the group consisting of hydrogen, aikyl, alkenyl, substituted alkenyl, aikynyl, substituted aikynyl, aryi, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted faeteroaryl, heterocyclic, and substituted heterocyclic.
] 6. The compound of claim 1, wherein R is selected from the group consisting of -C(0)NR3R4 and -C(G)OR3 and R¾ is hydrogen.
The compound of claim 1 selected from the group consisting of
Figure imgf000066_0001
Figure imgf000067_0001
or a pharmaceutically acceptable salt and/or solvate thereof.
18, A composition comprising a compound of any one of claims 1-1 1 and pharmaceuticaiiy acceptable recipient,
1 . A inethod for treating a pain in a patient which method comprises administering to said patient a compound of any one of claims 1-1 1 ,
20. A method for treating addiction to at least one addictive substance in a patient which .method comprises administering to said patient a compound of any one of claims 1-1 1.
21. 'Πκ method of claim 20, wherein the at least one addictive substance Is chosen from the group consisting of an opioid, an opioid-like drug, cocaine, alcohol, an amphetamine, a methamphetamine. tobacco, caffeine, a caasabinoid, and a benzodiazepine,
22. A method for treating stress in a patient which method comprises administering to said patient a compound of any one of claims 1- 1 ,
23. ' The method of claim 22, wherein the stress is post traumatic stress disorder.
24. A method for treating depression in a patient which method comprises administering to said patient a compound of any one of claims I - 11.
25. A method for treating anxiety in a patient which method comprises administering to said patient a compound of any one of claims 1-1 1,
26. A method for screening a patient to determine the patient's tolerance for a therapeutic dose of a compound of a y one of claims 1-1 1 , the method comprising:
measuring the patient's pre-administration QT interval;
administering to the patient a subtherapeutic dose of the compound; and
measuring the patient's post-administration QT interval.
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