WO2015112168A2 - Compositions comprenant de la noribogaïne et un excipient pour faciliter le transport à travers la barrière hémato-encéphalique - Google Patents

Compositions comprenant de la noribogaïne et un excipient pour faciliter le transport à travers la barrière hémato-encéphalique Download PDF

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WO2015112168A2
WO2015112168A2 PCT/US2014/013063 US2014013063W WO2015112168A2 WO 2015112168 A2 WO2015112168 A2 WO 2015112168A2 US 2014013063 W US2014013063 W US 2014013063W WO 2015112168 A2 WO2015112168 A2 WO 2015112168A2
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noribogaine
compound
pharmaceutically acceptable
patient
pharmaceutical composition
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PCT/US2014/013063
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WO2015112168A3 (fr
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Deborah C. Mash
JR. Richard D. GLESS
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Demerx, Inc.
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Priority to EP14880182.2A priority Critical patent/EP3096794A2/fr
Priority to PCT/US2014/013063 priority patent/WO2015112168A2/fr
Priority to AU2014379612A priority patent/AU2014379612A1/en
Publication of WO2015112168A2 publication Critical patent/WO2015112168A2/fr
Publication of WO2015112168A3 publication Critical patent/WO2015112168A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • This invention relates generally to compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier.
  • Noribogaine is a well known derivative of ibogaine and is sometimes referred to as 12-hydroxyibogaine. It is a metabolite of ibogaine. US Patent No. 2,813,873 claims noribogaine albeit as "12-O-demethylibogaine" while providing an incorrect structural formula for ibogaine.
  • the structure of noribogaine has now been thoroughly evaluated and is found to combine the features of tyrptamine, tetrahydrohavaine and indolazepines.
  • Noribogaine can be depicted by the following Formula:
  • Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as non-addictive alkaloids 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 allosterically 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.
  • This invention relates to increased cranial delivery of noribogaine by use of a pharmaceutically acceptable excipient to enhance blood brain barrier penetration. It is contemplated that the excipient cooperatively increases the concentration of noribogaine in the brain of the treated patient thereby reducing the systemic concentration of noribogaine in the remainder of the patient's body. While not all drugs react cooperatively with blood brain barrier excipients, it is contemplated that noribogaine will show a significant increase in cranial concentration when used in conjunction with such an excipient. It is further contemplated that in view of such targeted delivery, the amount of noribogaine required to effect therapy will be reduced.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
  • the excipient which enhances the blood brain barrier penetration of noribogaine is a biocompatible dehydrating saccharide such as mannitol.
  • At least a portion of the mannitol or other dehydrating saccharide is bound to the noribogaine via a biocompatible, cleavable linking group. It is contemplated that such compounds will reduce the concentration of the saccharide necessary to enhance the blood brain barrier penetration of noribogaine.
  • a compound of Formula I there is provided a compound of Formula I:
  • R is hydrogen, alkyl, -C(0)-alkyl, or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide;
  • R 1 is hydrogen or the group -L-S where L is a covalent bond or is a biocompatible
  • cleavable linking group and S is a dehydrating saccharide or oligosaccharide; provided that at least one of R and R 1 is -L-S; or a pharmaceutically acceptable salt thereof.
  • R is hydrogen and R 1 is -L-S. In some embodiments, R is -C(0)-alkyl and R 1 is -L-S. In some embodiments, R is -L-S and R 1 is hydrogen. In some embodiments, both R and R 1 are -L-S.
  • this invention is directed to a
  • composition comprising a pharmaceutically acceptable excipient and a therapeutically acceptable amount of a compound of Formula I above.
  • R is hydrogen and R 1 is -L-S. In some embodiments, R is -L-S and R 1 is hydrogen. In some embodiments, R is -C(0)-alkyl and R 1 is -L-S. In some embodiments, both R and R 1 are -L-S. In some embodiments, the pharmaceutically acceptable excipient comprises mannitol.
  • a method for treating pain in a patient which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine or a pharmaceutically acceptable salt thereof and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
  • a method for treating addiction in a patient which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine or a
  • a method for treating pain in a patient comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
  • a method for treating addiction in a patient comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
  • compositions comprising noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an excipient to facilitate transport across the blood brain barrier.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • compositions comprising
  • noribogaine or a derivative or pharmaceutically acceptable salt thereof, and an excipient to facilitate transport across the blood brain barrier.
  • noribogaine refers to the compound:
  • noribog prepared by demethylation of naturally occurring ibogaine:
  • 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.
  • derivative refers to derivatives of noribogaine that maintain or enhance the activity of noribogaine, or are metabolized within the patient to form noribogaine. Suitable derivatives are disclosed in US Patent Application No.
  • the term "pharmaceutically acceptable excipient to enhance blood brain barrier penetration” refers to a substance that is capable of disrupting or penetrating the blood brain barrier.
  • the disruption is a transient disruption.
  • the amount of pharmaceutically acceptable excipient administered with the noribogaine or derivative thereof is the amount effective to disrupt the blood brain barrier and allow noribogaine to enter the brain.
  • biocompatible dehydrating saccharide refers to a saccharide or derivative thereof, having at least 6 carbon atoms (which may be linear, branched or cyclic) with an oxygen, nitrogen or sulfur atom bonded to each carbon atom.
  • biocompatible dehydrating oligosaccharides includes oligosaccharides containing from about 2-9 monosaccharide units.
  • Specific monosaccharides include C5 and above (preferably C 5 -C 8 ) saccharides such as ethritol, zylitol, galactose, lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol, sorbitol, glucose, arabinose, arabinose, celloboise, maltose, raffmose, rhamnose, melibiose, ribose, adonitol, arabitol, arabitol, fucose, lyxose, lyxose, lyxose, glucosamine, mannosamine, and galactosamine; di- and trisaccharides include saccharides having two or three monosaccharide units.
  • mannitol refers to (2R,3R,4R,5R)-hexane- 1,2,3, 4,5,6- hexol
  • Mannitol is a polyol and has been used as an osmotic diuretic agent and a weak renal vasodilator. It was originally isolated from the secretions of the flowering ash, called manna after their resemblance to the Biblical food, and is also be referred to as mannite and manna sugar. Mannitol and derivatives thereof are readily available from commercial sources or can be synthesized using procedures known in the art. In its pyranose or condensed form, mannitol becomes a 6 membered ring saccharide (sugar) of the formula:
  • saccharides are meant to include both their open forms as well as their pyranose forms including their naturally occurring D or L forms of the saccharide.
  • the term "pharmaceutically acceptable salt” refers to salts derived from organic or inorganic acids.
  • examples of such acids include, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, and the like.
  • biocompatible, cleavable linking group refers to a linking group that can be attached to noribogaine at any possible position such that 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.
  • the linking group should be sufficiently stable in the circulatory system (serum or blood), but is cleaved to release the noribogaine 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. pH, 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(O)O- or -OC(O)-), an amide-based cleavable linking group (-C(0)NR- or -NRC(O)-), or a phosphate -based cleavable linking group (-P(0)(OR)-0-, -O- P(S)(OR)-0-, -0-P(S)(SR)-0-, -S-P(0)(OR)-0-, -0-P(0)(OR)-S-, -S-P(0)(OR)-S-, -0-P(S)(OR)-S-, -S-P(S)(OR)-0-, -0-P(0)(R)-0-, -0-P(S)(R)-0-, -S-P(0)(R)-0-, -S-P(0)(R)-0-, -S-P(0)(R)-S-, or -0-0-
  • alkyl refers to a monovalent saturated aliphatic hydrocarbyl group having from 1 to 12 carbon atoms, or 1 to 6 carbon atoms.
  • Cx means an alkyl group with x carbon atoms.
  • one or more of the hydrogen atoms of the alkyl group can be replaced with a functional group such as - OH, -NH 2 , -SH, and the like.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-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 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • alkoxy refers to O-alkyl.
  • the term "therapeutically acceptable 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 excipient 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 drug dependency as well as alleviating drug cravings in addicts. Such symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
  • the term "patient” refers to mammals and includes humans and non-human mammals.
  • the blood brain barrier functions to protect the brain from exposure to toxins, both endogenous and exogenous.
  • BBB blood brain barrier
  • This protection severely limits the therapeutic ability of many of drugs by inhibiting their crossing from the circulatory system into the brain.
  • molecules In order for a drug to enter the brain and cross the BBB, molecules must either passively diffuse or be actively transported across the BBB.
  • Water soluble or polar compounds must be actively transported across the BBB, whereas it has been shown that drugs which passively diffuse into the brain have fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surfaces, reduced flexibility, and are small (i.e. less than 400 - 500 Da) (see Pardridge Molecular Interventions, 2003, 3:2, 90- 105, Deeken, et al.
  • a pharmaceutically acceptable excipient can be used to enhance blood brain barrier penetration (see Pan, et al. Acta Pharmacol Sin, 2000, 21 :7, 613-616).
  • This invention is relates to increased cranial delivery of noribogaine by use of a pharmaceutically acceptable excipient to enhance blood brain barrier penetration.
  • the pharmaceutically acceptable excipient cooperatively increases the concentration of noribogaine in the brain of the treated patient thereby reducing the systemic concentration of noribogaine in the remainder of the patient's body. While not all drugs react cooperatively with blood brain barrier excipients, it is
  • noribogaine will show a significant increase in cranial concentration when used in conjunction with such an excipient. It is further contemplated that in view of such targeted delivery, the amount of noribogaine required to effect therapy will be reduced. In addition, it is contemplated that the compositions disclosed herein provide for an increased serum half-life when compared to noribogaine alone.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
  • compositions of the present invention comprise an excipient capable of transiently disrupting the BBB and allowing noribogaine to penetrate the blood brain barrier.
  • the composition comprises a hypertonic solution which transiently disrupts the BBB by causing the cells which make up the BBB to dehydrate and shrink. This dehydration and shrinkage disrupts the BBB by compromising the tight junctions between the cells and thus forming passages into the brain.
  • the excipient which enhances the blood brain barrier penetration of noribogaine is a biocompatible dehydrating saccharide, such as mannitol.
  • a biocompatible dehydrating saccharide such as mannitol.
  • concentrations are known to those of skill in the art or can be readily determined using known methods.
  • concentration of mannitol in the composition is about 1.1 M.
  • mannitol is administered at a concentration of from about 0.1 mol/L to about 10 mol/L, or
  • excipients which are contemplated to be capable of enhancing penetration of noribogaine across the blood brain barrier include saccharides or saccharide derivatives (i.e. amino saccharides), bradykinin B2 receptor agonists (i.e. Cereport®), small fat- soluble molecules (i.e. ethanol or ethanol derivatives), naturally occurring or synthetic amino acids, choline, and purine bases or nucleosides or derivatives thereof.
  • Other blood brain barrier excipients can be used that are known to those of ordinary skill in the art.
  • Exemplary saccharides which can be used in the compositions and methods disclosed herein include, any one or more of ethritol, zylitol, galactose, lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol, sorbitol, glucose, arabinose, arabinose, celloboise, maltose, raffmose, rhamnose, melibiose, ribose, adonitol, arabitol, arabitol, fucose, lyxose, lyxose, lyxose, glucosamine, mannosamine, and galactosamine.
  • Excipients may also comprise one or more naturally occurring (endogenous or exogenous) or synthetic amino acid or derivative thereof, such as arginine, asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine, leucine, methionine, phenylalanine, proline, serine, threonine, glutamine, lysine, tryptophan, tyrosine, valine, taurine and L-dopa (a naturally occurring amino acid, dihydroxypheny alanine, found in broad beans).
  • Naturally occurring (endogenous or exogenous) or synthetic amino acid or derivative thereof such as arginine, asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine, leucine, methionine, phenylalanine, proline, serine, threonine, glutamine, lysine, tryptophan, tyrosine, valine, taurine and L-
  • the excipient capable of enhancing blood brain barrier penetration is bound to the noribogaine via a covalent bond or a biocompatible, cleavable linking group.
  • the covalent bond or linking group can be attached to the noribogaine at any possible position such the bond or biocompatible linker is readily cleaved in the body and does not inhibit or alter the desired physiological effect of noribogaine.
  • the linking group should be sufficiently stable in the circulatory system, but is cleaved to release the noribogaine upon entry into the brain.
  • the linking group is at least 2 time and preferably at least 10 times more reactive in the brain than in the circulatory system (i.e. in the blood or serum).
  • Suitable biocompatible, cleavable linking groups comprise a covalent 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. pH, 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 blood.
  • 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 cleavable 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 cleavable linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases.
  • Biocompatible, cleavable ester-based linking groups are cleaved by enzymes such as esterases and amidases in the brain.
  • Ester-based cleavable linking groups comprise a cleavable ester group of the general Formula -C(0)0- or -OC(O)-.
  • ester- based groups can be cleaved by esterases, for example.
  • Biocompatible, cleavable amide- based cleavable linking groups comprise amide bonds formed between amino acids and includes the amide group -C(0)NR- or -NRC(O)- where R can be hydrogen or alkyl.
  • Amide-based cleavable linking groups can be cleaved by enzymes such as peptidases and proteases.
  • Biocompatible, cleavable phosphate-based cleavable linking groups are cleaved by agents that degrade or hydrolyze the phosphate group, such as phosphatases.
  • Examples of phosphate-based linking groups can include -P(0)(OR)-0-, -0-P(S)(OR)-0-, -O- P(S)(SR)-0-, -S-P(0)(OR)-0-, -0-P(0)(OR)-S-, -S-P(0)(OR)-S-, -0-P(S)(OR)-S-, -S- P(S)(OR)-0-, -0-P(0)(R)-0-, -0-P(S)(R)-0-, -S-P(0)(R)-0-, -S-P(S)(R)-0-, -S- P(0)(R)-S-, -0-P(S)(R)-S- where R can be hydrogen or alkyl.
  • Exemplary linking groups are shown in Scheme 2.
  • 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.
  • R is hydrogen, alkyl, -C(0)-alkyl, or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide;
  • R 1 is hydrogen or the group -L-S where L is a covalent bond or is a biocompatible, cleavable linking group and S is a dehydrating saccharide or oligosaccharide; provided that at least one of R and R 1 is -L-S; or a pharmaceutically acceptable salt thereof.
  • R is hydrogen and R 1 is -L-S.
  • R is -C(0)-alkyl and R 1 is -L-S.
  • R is -L-S and R 1 is hydrogen.
  • R and R 1 are -L-S.
  • S can be a saccharide or saccharide derivative such as an amino saccharide, provided that the sachharide is capable of disrupting or penetrating the BBB.
  • S can be a saccharide or amino saccharide from the group consisting of ethritol, zylitol, galactose, lactose, xylose, dulcitol, myo-insoitol, fructose, mannitol, sorbitol, glucose, arabinose, arabinose, celloboise, maltose, raffinose, rhamnose, melibiose, ribose, adonitol, arabitol, arabitol, fucose, lyxose, lyxose, lyxose, glucosamine, mannosamine, and galactosamine.
  • S is mannitol, zylitol, galactose,
  • R is hydrogen, mannopyranose, glucopyranose, glucopyranose-0-(CH 2 )9C(0)-, ribofuranose,
  • R 1 is hydrogen, glucopyranose-O- (CH 2 ) 8 C(0)-, -C(0)0(CH 2 CH 2 0) 3 CH 3 , -C0 2 CH 2 CH 3 or mannitol
  • R is hydrogen, mannopyranose, glucopyranose, glucopyranose-O- (CH 2 ) 9 C(0)-, ribofuranose, ribopyranose or mannitol
  • R 1 is hydrogen.
  • R is hydrogen and R 1 is hydrogen, glucopyranose-0-(CH 2 ) 8 C(0)-,
  • R and R 1 are mannitol.
  • L is a suitable biocompatible, cleavable linking group comprising from 1 to 20 atoms selected from carbon, nitrogen, oxygen, sulfur, and phosphorus, and is, in general, susceptible to cleavage conditions or agents in the brain.
  • the linking group is an ester-based linking group.
  • the linking group is an amide-based linking group.
  • the linking group is a phosphate-based linking group.
  • L is a covalent bond.
  • composition comprising a
  • R is hydrogen and R 1 is -L-S.
  • R is -C(0)-alkyl and R 1 is -L-S.
  • R is -L-S and R 1 is hydrogen.
  • R and R 1 are -L-S.
  • S is mannitol.
  • S is mannose.
  • S is glucose.
  • Compounds of Formula I can be readily prepared from noribogaine by methods known to one of skill in the art.
  • Noribogaine can be synthesized via ibogaine O- demethylation. This may be accomplished, for example, by reacting ibogaine with boron tribromide/methylene chloride at room temperature and then purifying the product using known procedures.
  • noribogaine may also be obtained from the National Institute on Drug Abuse (Rockville, Md.).
  • Ibogaine may be obtained from natural or commercial sources, or can be synthesized by methods known in the art (see Huffman, et al, J. Org. Chem. 50: 1460 (1985)).
  • noribogaine can be reacted with a saccharide-linking group conjugate (LG-L-S, where LG is a leaving group such as alkoxy, halo, etc.) to form compounds of formula I.
  • LG-L-S saccharide-linking group conjugate
  • the phenol is protected with a suitable protecting group (PG-LG where LG is a leaving group such as alkoxy, halo, etc.) such that the indole nitrogen is derivatized with -L-S.
  • suitable protecting groups are well known in the art (see T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 4 th Edition, Wiley-Interscience, New York, 2006).
  • the indole nitrogen is protected with a suitable protecting group (PG) (see Greene et al, supra) such phenol that is derivatized with -L-S.
  • PG protecting group
  • both the indole nitrogen and the phenol are both derivatized with -L-S groups.
  • Saccharide-linking group conjugates for use in the reactions depicted in Scheme 1 (LG-L-S, where LG is a leaving group such as alkoxy, halo, etc.) can be synthesized using methods known in the art.
  • the starting compounds are commercially available from sources such as Aldrich® Chemical Company.
  • the saccharide-linking group conjugate for use in the reactions depicted in Scheme 1 is of the formula S-0-(CH 2 ) n -CO-OCH 3 where S is the saccharide, n is an integer from 0 to 16 and -OCH 3 is the leaving group (LG) (Scheme 2, where R is H or L-S) (see U.S. Patent No. 5,877,187).
  • n is an integer from 5 to 10.
  • the structures resulting from such functionalization include the following (where for illustrative purposes only a- D-mannopyranose is used as the saccharide):
  • Methods for preparing the compounds of Formula I wherein L is a covalent bond follow conventional saccharide chemistry. See, for example, U.S. Patent No. 5,877,187 which is incorporated herein by reference in its entirety.
  • the anomeric carbon atom at the 1 -position of a saccharide is chemically modified by conventional techniques to introduce a leaving group. Suitable leaving groups comprise halides, trichloroacetimidates, acetyl, thioglycosides, etc. The particular leaving group is selected relative to the functionality to which the saccharide is to be attached.
  • attachment of the saccharide to the indole nitrogen of noribogaine can be accomplished via the hydroxyl protected compound leaving only the amino group to couple with saccharide resulting in the formation of an N-linked sugar.
  • coupling of the saccharide to the hydroxyl group would entail reacting the N-protected noribogaine with the appropriate functionalized sugar.
  • using noribogaine and an excess of functionalized saccharides would provide for both the O- and N- functionalized noribogaine.
  • the structures resulting from such functionalization include the following (where for illustrative purposes only a-D-mannopyranose is used as the saccharide):
  • Exemplary compounds of this invention wherein L is a linking group can be prepared by the synthetic protocols illustrated below in Scheme 3.
  • Noribogaine (3-1) can be modified with a saccharide-linking group conjugate (3- 2), or a protected derivative thereof (e.g., the polyacetate or polybenzylate), to form a compound of formula I-l under conventional amidation conditions well known in the art.
  • a saccharide-linking group conjugate (3- 2) or a protected derivative thereof (e.g., the polyacetate or polybenzylate), to form a compound of formula I-l under conventional amidation conditions well known in the art.
  • the indole nitrogen of 3-1 or the hydroxyl groups of 3-2 can be protected using suitable protecting groups prior to the reaction of 3-1 with 3-2 and then subsequently deprotected using conditions known in the art.
  • Compound 3-2 can be prepared from reacting at least a stoichiometric amount and preferably an excess of compound 3-4 with a suitable saccharide (3-3).
  • the reaction can be conducted under conventional coupling conditions well known in the art as the anomeric carbon atom of the saccharide will preferably react with the hydroxyl group of the linker 3-2.
  • the reaction is conducted in a polar solvent.
  • the compounds 1-1 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like; or, alternatively, used without purification and/or isolation.
  • Compounds 3-5 for use in the reactions depicted in Scheme 3, can be prepared by reacting compounds 3-6 (LG is preferably, but not limited to alkoxy or halo) with 3-1 under conventional esterification conditions.
  • LG is preferably, but not limited to alkoxy or halo
  • the indole nitrogen of 3-1 can be protected using a suitable protecting group prior to the reaction of 3-1 with 3-6 and then subsequently deprotected using conditions known in the art.
  • Compound 3-5 can then be modified with 3-2 to form a compound of formula 1-2 under conventional amidation conditions well known in the art.
  • 1-2 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like; or, alternatively, used without purification and/or isolation.
  • hydroxyl groups of 3-3 or 4-1 can be protected using a suitable protecting group and then subsequently deprotected using conditions known in the art.
  • 1-3 or 1-4 can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like; or, alternatively, used without purification and/or isolation.
  • Noribogaine a metabolite of ibogaine, has properties that are well suited to the treatment of pain and to the withdrawal symptoms associated with drug dependency or abuse.
  • noribogaine binds to two classes of opioid receptors that have been associated with pain relief, the ⁇ and ⁇ receptors.
  • noribogaine acts as a full opiate agonist.
  • noribogaine elevates brain serotonin levels by blocking synaptic reuptake. It is believed that such levels (as well as ligand interactions at the ⁇ and ⁇ opiate receptors) play a role in the anxiety and drug cravings experienced by addicts during withdrawal.
  • One aspect of the present invention is directed to a method for treating pain in a patient.
  • 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 method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine.
  • the present invention is directed to a method for treating pain in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
  • Noribogaine has been known to be used to treat patients for alleviating the symptoms associated with withdrawal from drug dependency. Accordingly, the present invention is also directed to a method for treating addiction in a patient which method comprises administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof, and an effective amount of a pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine. In another embodiment, the invention is directed to a method for treating addiction in a patient which method comprises administering to said patient a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient.
  • the treatment of addiction in a patient comprises alleviating the symptoms associated with withdrawal from drug dependency.
  • symptoms include nausea, vomiting, anxiety, abdominal cramps, muscle pain, chills and headache.
  • noribogaine treatment 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 narcotics such as heroin and methadone. However, it is also useful in treating patients addicted to cocaine, alcohol, amphetamines and combinations of these drugs. Dosage and Routes of Administration
  • any route of administration and dosage form may be compatible with the pharmaceutical compositions and methods discussed above.
  • the compositions disclosed herein are designed to target the brain and penetrate the blood brain barrier, it is contemplated that the dosage of noribogaine administered to the patent can be decreased in comparison to the dose administered to a patient when using noribogaine alone. That said, the appropriate dosing regimen and route of administration can be readily determined by the attending clinician.
  • compositions suitable for oral, intravenous or intraarterial delivery will probably be used most frequently, other routes that may be used include peroral, pulmonary, rectal, nasal, vaginal, lingual, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes.
  • the composition can be administered transdermally 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. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
  • compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, 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, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like.
  • parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3- butanediol, ethanol, 1 ,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
  • the dosage required for treating pain may differ from the dosage required for treating addiction, however, the dosing regimen can be readily determined by the attending clinician based on the desired treatment. It is contemplated that for the treatment of pain, the dosage of noribogaine administered to a patient may be from about 0.1 to about 100 mg per kg of body weight and, preferably, from about 0.1 to about 30 mg per kg of body weight.
  • the dosage of noribogaine administered to a patient may be from about 0.1 to about 20 mg/ml.
  • kits of parts comprising a composition as disclosed herein and a means for administering the composition to a patient in need thereof.
  • the means for administration to a patient can include, for example, any one or combination of a syringe, a needle, an IV bag comprising the composition, a vial comprising the composition, etc.
  • the kit comprises a first and a second vial, wherein the first vial comprises the pharmaceutically acceptable excipient to enhance the blood brain barrier penetration of noribogaine and the second composition comprises a therapeutically effective amount of noribogaine, or a derivative or pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable excipient may be administered to the patient just prior to the noribogaine composition.
  • the pharmaceutically acceptable excipient is administered to the patient about 5 to 10 minutes prior to the noribogaine composition.
  • Oxalyl chloride (59 ⁇ , 0.68 mmol) was slowly added into a solution of acid 4-E (0.39 g, 0.57 mmol) in DCM (5 mL) at room temperature, followed by adding DMF (7xL). The resulting mixture was stirred at the temperature for 3 h, and then concentrated. The crude product 4-F was further dried under high vacuum and used in next reaction without purification.
  • TBAF (0.48 mL, 1.0 M solution in THF) was added to a solution of 7-A (114 mg, 0.19 mmol) in THF (5 mL) at -78 °C.
  • the resulting solution was stirred for 15 min at - 78 °C and 40 min at room temperature before it was concentrated and purified by column chromatography (dichloromethane/2-propanol/triethylamine, v/v, 10/1/0 to 100/20/1).
  • the resulting product was further purified by prep-HPLC to give pure 7-B (68 mg) as a slightly yellow solid.
  • Benzoyl chloride (1.76 mL, 15.2 mmol) was added dropwise to a solution of 1,2,3,4-0- diisopropylidene-D-mannidol 9-C (3.99 g, 15.2 mmol) in pyridine (20 mL) and DCM (50 mL) at - 78 °C.
  • the reaction mixture was stirred for one hour and then allowed to warm up to 0 °C. After 1.5 hours, the resulting mixture was poured into 150 mL of ice-cooled aq. 5N HCl, and extracted with DCM. The organic extract was washed with water, saturated NaHC0 3 , and brine. After drying over Na 2 S0 4 and concentration, 5.3 g of a colorless oil was obtained.
  • Epoxide 9-D (91 mg, 0.36 mmol) was added into a solution of noribogaine (90 mg, 0.3 mmol, free base) and Z-BuOK (34 mg, 0.3 mmol) in 6 mL of DMF at room temperature.
  • the reaction mixture was heated at 150 °C for 30 min in a microwave reactor.
  • the resulting dark solution was diluted with DCM and washed with water (2x) and dried over Na 2 S0 4 .
  • the mixture was purified by preparative TLC (2-propanol/DCM, v/v, 1/10) to afford 9-E (25 mg) and 9-F (35 mg), both as pale white solids.

Abstract

La présente invention porte d'une manière générale sur des compositions comprenant de la noribogaïne et un excipient pour faciliter le transport à travers la barrière hémato-encéphalique.
PCT/US2014/013063 2014-01-24 2014-01-24 Compositions comprenant de la noribogaïne et un excipient pour faciliter le transport à travers la barrière hémato-encéphalique WO2015112168A2 (fr)

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PCT/US2014/013063 WO2015112168A2 (fr) 2014-01-24 2014-01-24 Compositions comprenant de la noribogaïne et un excipient pour faciliter le transport à travers la barrière hémato-encéphalique
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Cited By (2)

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US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

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US5629307A (en) * 1989-10-20 1997-05-13 Olney; John W. Use of ibogaine in reducing excitotoxic brain damage
PT804200E (pt) * 1994-07-25 2006-09-29 Nda Int Inc Uso de derivados de noribogaina para tratamento de dependencia quimica em mamiferos
US5591738A (en) * 1994-10-14 1997-01-07 Nda International, Inc. Method of treating chemical dependency using β-carboline alkaloids, derivatives and salts thereof
US8637648B1 (en) * 2010-06-22 2014-01-28 Demerx, Inc. Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier

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US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10947257B2 (en) 2017-10-09 2021-03-16 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10954259B1 (en) 2017-10-09 2021-03-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11149044B2 (en) 2017-10-09 2021-10-19 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11180517B2 (en) 2017-10-09 2021-11-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11447510B2 (en) 2017-10-09 2022-09-20 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11505564B2 (en) 2017-10-09 2022-11-22 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11629159B2 (en) 2017-10-09 2023-04-18 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11851451B2 (en) 2017-10-09 2023-12-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11939346B2 (en) 2017-10-09 2024-03-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
US11738035B2 (en) 2019-04-17 2023-08-29 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

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