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WO2023183795A1 - Promédicaments antagonistes des opioïdes et formulations pour l'inversion des surdoses d'opioïdes - Google Patents

Promédicaments antagonistes des opioïdes et formulations pour l'inversion des surdoses d'opioïdes Download PDF

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WO2023183795A1
WO2023183795A1 PCT/US2023/064757 US2023064757W WO2023183795A1 WO 2023183795 A1 WO2023183795 A1 WO 2023183795A1 US 2023064757 W US2023064757 W US 2023064757W WO 2023183795 A1 WO2023183795 A1 WO 2023183795A1
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compound
formula
pharmaceutically acceptable
pharmaceutical composition
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Thomas E. Jenkins
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Elysium Therapeutics Inc
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    • 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
    • A61P25/36—Opioid-abuse
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33303—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group
    • C08G65/33317—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group heterocyclic

Definitions

  • Synthetic opioids present multiple challenges for first responders attempting to rescue overdose victims. Because of the complexity of an opioid overdose, and the difficulty obtaining accurate rescue data, the quantity of naloxone that must be administered by first responders to reverse a suspected overdose with a synthetic opioid remains empirical and symptom driven. The disparity between the elimination half-lives of naloxone ( ⁇ 1 hour); and many fentanyl derivatives (e.g. fentanyl, 8-10 hours; carfentanil, 7.7 hours; sufentanil, 6-9 hours) can complicate the medical management of overdose. High-potency long-acting synthetic opioid overdoses often require very high, or repeated, doses of short-acting naloxone to effect a successful rescue.
  • naloxone With its relatively short elimination half-life, are often not adequately sustained in the presence of long- duration synthetic opioids, leading to a rapid recurrence of symptoms (i.e. re-narcotization) resulting in potentially lethal respiratory depression and/or hypoxic brain injury.
  • re-narcotization a rapid recurrence of symptoms
  • the potential for life-threatening re-narcotization following an initial reversal with naloxone has been discussed in the peer reviewed literature for over 20 years.
  • An opioid antagonist with a longer duration of action could minimize the potential for relapse following rescue from an opioid overdose and would be especially useful for administration by friends or family with no medical training, and for overdose victims who either refuse transportation to a hospital following rescue, or are discharged following a brief emergency room stay.
  • opioid overdose In some areas with a high incidence of opioid overdose, more than one-third of patients treated in the field for opioid overdose refused transport to the emergency department. Due to the short duration of action of naloxone, individuals may require repeated rescues from multiple overdoses in a single day. The need for a longer acting opioid antagonist is especially acute in rural areas that constitute -72% of U.S. land mass (and contain roughly 15% of the population, over 46 million individuals), where access to an emergency department could be delayed for several hours.
  • New and improved high-potency opioid antagonists with rapid onset, and a longer duration of action than currently available short-acting reversal agents e.g., naloxone, nalmefene
  • currently available short-acting reversal agents e.g., naloxone, nalmefene
  • the present disclosure provides a compound according to Formula (I): D— E— L— P
  • D is an opioid antagonist
  • E is an ester group formed via functionalization of a hydroxyl, enol or carboxyl group present on D;
  • L is a covalent linkage between E and the polymer P
  • P is a polymer
  • the compound of Formula (I) is a compound of Formula (II):
  • D is an opioid antagonist compound comprising one or more groups selected from -OH, - COOH, and -SH;
  • P is a polymer
  • Y is O or S
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent;
  • Q is -NH-, -O-, -NR 11 -, or absent;
  • R 11 is optionally substituted Ci-Ce alkyl; m is 1 to 100; and o is 2 to 100.
  • D is buprenorphine, cyclazocine, cyclorphan, naloxone, N- methylnaloxone, naltrexone, N-methylnaltrexone, nalmefene, 6-amino-6-desoxo-naloxone, levallorphan, nalbuphine, naltrendol, naltrindole, nalorphine, nor-binaltorphimine, oxilorphan, pentazocine, samidorphan, derivatives thereof, or mixtures thereof.
  • P is and n is 1 to 1,000.
  • m is 1 to 10.
  • o is 2 to 10.
  • the compound is according to Formula (Ila): Formula (Ila), or a pharmaceutically acceptable salt thereof.
  • n is about 50 to about 1,000. In some embodiments, n is about 100 to about 900. In some embodiments, n is about 200 to about 800. In some embodiments, n is about 300 to about 700. In some embodiments, n is about 400 to about 600. In some embodiments, n is about 100. In some embodiments, n is about 200. In some embodiments, n is about 300. In some embodiments, n is about 400. In some embodiments, n is about 500. In some embodiments, n is about 600. In some embodiments, n is about 700.
  • D is nalmefene or a derivative thereof.
  • the compound is according to Formula (III): polymer
  • Ri is cyclopropyl methyl or allyl.
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent Q is -NH-, -NR 11 -, -O-, or absent;
  • R 11 is optionally substituted Ci-Ce alkyl; m is 1 to 100; and o is 2 to 100.
  • the compound is according to Formula (IV):
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent Q is -NH-, -NR 11 -, -O-, or absent;
  • R 11 is optionally substituted Ci-Ce alkyl; m is 1 to 100; and o is 2 to 100.
  • the compound is according to Formula (V):
  • R3 is cyclopropyl methyl or allyl
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent
  • Q is -NH-, -NR 11 -, -O-, or absent;
  • R 11 is optionally substituted Ci-Ce alkyl; m is 1 to 100; and o is 2 to 100.
  • the compound is according to Formula (VI):
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent
  • Q is -NH-, -NR 11 -, -O-, or absent;
  • R 11 is optionally substituted Ci-Ce alkyl; m is 1 to 100; and o is 2 to 100.
  • the compound is according to Formula (VII):
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent Q is -NH-, -NR 11 -, -O-, or absent;
  • R 11 is optionally substituted Ci-Ce alkyl; m is 1 to 100; and o is 2 to 100.
  • the compound is according to Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent
  • Q is -NH-, -NR 11 -, -O-, or absent;
  • R 11 is optionally substituted Ci-Ce alkyl; m is 1 to 100; and o is 2 to 100.
  • the compound is according to Formula (IX): or a pharmaceutically acceptable salt thereof, wherein
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent Q is -NH-, -NR 11 -, -O-, or absent;
  • R 11 is optionally substituted Ci-Ce alkyl; m is 1 to 100; and o is 2 to 100.
  • the compound is selected from: , a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, as described herein, and one or more pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for immediate release.
  • the pharmaceutical composition comprises a compound according to any one of the Formulas described herein, an opioid antagonist, and one or more pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprising a compound according to any one of the Formulas described herein, and an intranasal penetration enhancer.
  • the pharmaceutical composition comprises a compound according to any one of the Formulas described herein, an opioid antagonist, an intranasal penetration enhancer, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating acute respiratory distress syndrome in a subject, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
  • the present disclosure provides a method of treating acute respiratory distress syndrome in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the present disclosure provides a method of treating respiratory arrest syndrome in a subject, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
  • the present disclosure provides a method of treating respiratory arrest syndrome in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the present disclosure provides a method of preventing opioid abuse or overdose in a subject, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
  • the present disclosure provides a method of preventing opioid abuse or overdose in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the subject is experiencing symptoms from overdose of opioid agonists. In some embodiments, the subject is suffering from opioid use disorder.
  • FIG. 1 shows the 1 HNMR spectrum of intermediate A.
  • FIG. 2 shows the 1 HNMR spectrum of Compound 2.
  • FIG. 3 depicts the nalmefene plasma-concentration vs. time profiles following equimolar intramuscular doses of nalmefene and nalmefene-PEG ester conjugate compounds 1, 2, 3, and 4 in the dog demonstrating a distinct correlation between the molecular weight of the PEG addend and the plasma clearance rate of delivered opioid antagonist (e.g. nalmefene).
  • delivered opioid antagonist e.g. nalmefene
  • FIG. 4 depicts the nalmefene plasma-concentration vs. time profiles following equimolar intramuscular doses of nalmefene and nalmefene-PEG ester conjugate compounds 1, 2, 3, and 4 in the dog after the individual plasma samples were pooled by timepoint then hydrolyzed via the addition of sodium hydroxide solution to release available nalmefene from the nalmefene-PEG ester conjugates present in the plasma.
  • This data demonstrates a distinct correlation between the molecular weight of the PEG addend and the plasma clearance rate of nalmefene-PEG ester conjugate compounds 1, 2, 3, and 4.
  • the present disclosure provides a composition that significantly reduces the risks of hypoxic brain injury and/or death following an opioid overdose.
  • This disclosure describes novel opioid antagonist polymer conjugates and compositions thereof that (i) rapidly reverse the effects of opioid agonists in a subject, (ii) provide long-lasting plasma levels of opioid antagonists to effectively prevent re-narcotization following an overdose rescue, and (iii) provide long-lasting prophylactic protection from the effects of opioid agonists to first-responders and military personnel.
  • composition comprising an opioid antagonist-polymer conjugate compound comprising the compound of formula I whereby several key unanticipated attributes of the opioid antagonist-polymer conjugate compound, the linkage of the polymer addend to the opioid antagonist, and the specific size and type of the polymer addend have been demonstrated.
  • opioid antagonist-polymer conjugate compound to rapidly deliver opioid antagonist to the systemic circulation following parenteral or intranasal administration, (ii) “depo-effects” involving controlled and sustained absorption from the site of administration and/or slow clearance from the systemic circulation, and (iii) controlled metabolism of the opioid antagonist- polymer conjugate compound in the systemic circulation via hepatic or plasma enzymes to release opioid antagonist over a sustained time period.
  • the present disclosure provides a composition comprising an opioid antagonist-polymer conjugate compound comprising the compound of formula I and an opioid antagonist.
  • the opioid antagonist-polymer conjugate is co-formulated with a penetration enhancer (e.g., alkyl-saccharide) to facilitate intranasal administration.
  • the opioid antagonist-polymer conjugate is formulated for parenteral administration (e.g., intravenous, subcutaneous or intramuscular injection).
  • the opioid antagonist-polymer conjugate is co-formulated with an opioid antagonist (e.g., nalmefene) to ensure rapid reversal of opioid overdose upon administration.
  • formulations comprising opioid antagonist-polymer conjugate compound are provided in a device configured to facilitate intranasal or parenteral administration.
  • modulator means a molecule that interacts with a target.
  • the interactions include, but are not limited to, agonism, antagonism, and the like, as defined herein.
  • agonist means a molecule such as a compound, a drug, an enzyme activator or a hormone that enhances the activity of another molecule and/or the activity of the target receptor.
  • the term “antagonist” means a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone, that diminishes and/or prevents the action of another molecule or the activity of the target receptor.
  • Haldroxyl refers to -OH.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2- propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-
  • 2-pentyl 2,2-dimethyl-l -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, secbutyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2.
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, - NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, - OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, - OMe, -NH2, or -NO2.
  • the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl).
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cisdecalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo.
  • halogen is fluoro or chloro.
  • halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2- dibromoethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, - CH2CH2OCH2CH2OCH3, -CH(CH 3 )OCH 3 , -CH2NHCH3, -CH 2 N(CH 3 )2, -CH2CH2NHCH3, or - CH 2 CH 2 N(CH3) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.
  • Heterocycloalkyl refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl).
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • Treatment of an individual e.g. a mammal, such as a human
  • a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
  • treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
  • “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, nonhuman primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • nonmammals include, but are not limited to, birds, fish and the like. The term does not denote a particular age or gender.
  • esterase includes any enzyme that hydrolyzes an ester moiety into its respective carboxylic acid and alcohol components.
  • a “plasma esterase” is an esterase that primarily exerts its catalytic action in the blood stream.
  • prodrug refers to a derivative of an active agent that requires a transformation within the body to release the active agent. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
  • the term “subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, nonhuman primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non- mammals include, but are not limited to, birds, fish and the like. The term does not denote a particular age or gender.
  • the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, according to Formula (I):
  • E is an ester group formed via functionalization of a hydroxyl, enol or carboxyl group present on D;
  • L is a covalent linkage between E and the polymer P; and P is a polymer.
  • the compound of Formula (I) is a compound of Formula (II):
  • P is a polymer
  • Z is -O-, -NH-, -NR 11 - CH2, or absent;
  • m is 1 to 10.
  • the compound of Formula (I) is a compound of Formula (III): polymer
  • Z is -O-, -NH-, -NR 11 -, -CH2-, or absent;
  • Q is -NH-, -NR 11 -, -O-, or absent;
  • X 3 is CH 2 or O
  • Q is -NH-, -NR 11 -, -O-, or absent;
  • the compound of Formula (I) is a compound of Formula (IX)
  • An opioid antagonist is a molecule that blocks the action of an opioid agonist at one or more opioid receptor types.
  • the opioid antagonist preferably exhibits no agonist activity for an opioid receptor type and preferably exhibits antagonist activity for the mu-receptors.
  • Suitable opioid antagonists include, but are not limited to, buprenorphine, cyclazocine, cyclorphan, naloxone, N-methylnaloxone, naltrexone, N-methylnaltrexone, nalmefene, 6-amino-6-desoxo- naloxone, levallorphan, nalbuphine, naltrendol, naltrindole, nalorphine, nor-binaltorphimine, oxilorphan, pentazocine, samidorphan, and piperidine-N-alkylcarboxylate opioid antagonists such as those described in U.S. Patent Nos. 5,159,081, 5,250,542, 5,270,328, and 5,434,17
  • an opioid antagonist-polymer conjugate of the present disclosure may comprise a water-soluble polymer such as poly(ethylene glycol), or related linear, dendrimeric, or branched polyalkylene glycol covalently attached directly via an ester linkage, or via a suitable intervening linker, to the opioid antagonist.
  • a water-soluble polymer such as poly(ethylene glycol), or related linear, dendrimeric, or branched polyalkylene glycol covalently attached directly via an ester linkage, or via a suitable intervening linker, to the opioid antagonist.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds of the present disclosure may be administered to animals.
  • the compounds can be administered intranasally or parenterally, including the intravenous, intramuscular, intraperitoneal, and subcutaneous routes of administration.
  • the pharmaceutical composition comprises a compound of any one of the Formulas described herein, an opioid antagonist, and one or more pharmaceutically acceptable excipients.
  • the opioid antagonist can be any suitable opioid antagonist as described herein.
  • the opioid antagonist is nalmefene, naloxone, or naltrexone.
  • the opioid antagonist is nalmefene.
  • the opioid antagonist is naloxone.
  • the opioid antagonist is naltrexone.
  • the intranasal penetration enhancer is an alkyl-saccharide. In some embodiments the intranasal penetration enhancer is an alkyl-maltoside. In some embodiments, the intranasal penetration enhancer is dodecyl-maltoside (DDM) or tetradecyl-maltoside (TDM). In some embodiments, the intranasal penetration enhancer is dodecyl-maltoside (DDM). In some embodiments, the intranasal penetration enhancer is tetradecyl-maltoside (TDM).
  • DDM dodecyl-maltoside
  • TDM tetradecyl-maltoside
  • the pharmaceutical composition comprises a compound of any one of the Formulas described herein, an opioid antagonist, an intranasal penetration enhancer, and one or more pharmaceutically acceptable excipients.
  • the opioid antagonists can be any suitable opioid antagonist described herein.
  • the intranasal penetration enhancer can be any suitable intranasal penetration enhancer described herein.
  • the pharmaceutically acceptable excipient is selected from buffers, salts, preservatives, penetration enhancers, and any combinations thereof.
  • the formulation of the opioid antagonist-polymer conjugate compound comprising formula I may be co-formulated with 0.01 to 500 micromoles of an opioid antagonist per dose, or more commonly 1 - 50 micromoles of the opioid antagonist-polymer conjugate per dose.
  • doses employed for adult human treatment are conveniently administered in a single dose.
  • the present disclosure provides a method of preventing opioid abuse or overdose in a subject, comprising administering to the subject a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

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Abstract

La présente invention concerne des composés antagonistes opioïdes et des promédicaments. L'invention concerne également des compositions et des formulations comprenant des composés antagonistes des opioïdes et des promédicaments, ainsi que des procédés d'utilisation desdits composés, compositions et formulations pour l'inversion de la surdose d'opioïdes.
PCT/US2023/064757 2022-03-22 2023-03-21 Promédicaments antagonistes des opioïdes et formulations pour l'inversion des surdoses d'opioïdes Ceased WO2023183795A1 (fr)

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