OPIOID ANTAGONIST PRODRUGS AND FORMULATIONS FOR THE REVERSAL OF OPIOID OVERDOSES

CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Application No. 63/322,553 filed March 22, 2022, which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] Every day, more than 90 Americans die from opioid overdoses. These deaths often result from respiratory depression induced by opioid agonist effects on breathing. The potentially lethal respiratory depressive effects of prescription opioids and heroin can be rapidly reversed by the timely administration of a potent mu-opioid receptor antagonist (e.g., naloxone, nalmefene). [0003] Unfortunately, the prevalence of illicit, readily synthesized, highly potent, synthetic opioids such as fentanyl, ocfentanil, carfentanil, and nitazenes (50 to 5000 times more potent than heroin) continues to increase. Due to their high potency, physicochemical properties (i.e. hydrophobicity) and long plasma half-lives, exposures to synthetic opioids (e.g. fentanyl) are associated with a very high overdose risk. Currently available naloxone doses capable of reversing prescription-opioid or heroin overdoses are often ineffective at reversing the effects of synthetic opioids leading to hypoxic brain injury or death. The death toll associated with the increased prevalence of synthetic opioids is dramatically rising with over 90,000 deaths reported in in the U.S. in 2019.

[0004] Multiple factors contribute to the dangers posed by synthetic opioids. These include very high opioid receptor potencies, rapid onset of action, long half-lives, and ease of synthesis; this latter property translates to a lower cost of goods relative to heroin and prescription opioids. The dramatically increased potency and extended duration of action attending synthetic opioids renders them especially dangerous to abuse, and highly lethal when overdosed. These unique pharmacological aspects are key factors in the recent dramatic spike in overdose fatalities linked to fentanyl and related synthetic opioids. Further, based on 2017 estimates, synthetic opioids were linked to more than half of opioid-related deaths, far surpassing fatalities attributed to either heroin or prescription opioids. To further exacerbate the situation, the structure-activity relationships of piperidine-based and benzimidazole-based synthetic opioids are well understood. In addition, the piperidine-based chemotype common to fentanyl derivatives and the benzimidazole based-chemotype common to nitazenes are highly mutable via the application of simple, inexpensive, and high-yielding chemistry. As a result, more than 1400 synthetic opioid analogs have been described in the patent and scientific literature, with increasing numbers available on the illicit market. Based on these facts, and the significant financial incentives, it would be naive to assume that the most potent, and/or longest-acting synthetic opioid analog has pervaded into the illicit opioid market. This presents increasing challenges for effective treatment of acute overdoses by first responders armed only with short-acting naloxone.

[0005] 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. Thus, therapeutically effective plasma concentrations of 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. 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. 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.

[0006] 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) are needed to more effectively address the current and future risks posed by the increasing prevalence and abuse of deadly illicit synthetic opioids.

SUMMARY

[0007] In a first aspect, the present disclosure provides a compound according to Formula (I): D— E— L— P

Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

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; and

P is a polymer.

[0008] In some embodiments, the compound of Formula (I) is a compound of Formula (II):

Formula (II) or a pharmaceutically acceptable salt thereof, wherein

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.

[0009] In some embodiments, 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.

[0010] In some embodiments, P is and n is 1 to 1,000.

[0011] In some embodiments, m is 1 to 10.

[0012] In some embodiments, o is 2 to 10.

[0013] In some embodiments, the compound is according to Formula (Ila): Formula (Ila), or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, 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.

[0015] In some embodiments, D is nalmefene or a derivative thereof.

[0016] In some embodiments, the compound is according to Formula (III): polymer

Formula (III), or a pharmaceutically acceptable salt thereof, wherein Xi is CH ₂ or O;

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.

[0017] In some embodiments, the compound is according to Formula (IV):

Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R2 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.

[0018] In some embodiments, the compound is according to Formula (V):

Formula (V), or a pharmaceutically acceptable salt thereof, wherein X ₃ is CH ₂ or O;

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.

[0019] In some embodiments, the compound is according to Formula (VI):

Formula (VI), 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.

[0020] In some embodiments, the compound is according to Formula (VII):

Formula (VII), 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.

[0021] In some embodiments, 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.

[0022] In some embodiments, 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.

[0023] In some embodiments, the compound is selected from: , a pharmaceutically acceptable salt thereof.

[0024] In a second aspect, the present disclosure provides a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, as described herein, and one or more pharmaceutically acceptable excipient.

[0025] In some embodiments, the pharmaceutical composition is formulated for immediate release.

[0026] In some embodiments, the pharmaceutical composition is formulated for sustained release.

[0027] In some embodiments, 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.

[0028] In some embodiments, the pharmaceutical composition comprising a compound according to any one of the Formulas described herein, and an intranasal penetration enhancer. [0029] In some embodiments, 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.

[0030] In a third aspect, 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.

[0031] In another aspect, 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.

[0032] In another aspect, 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.

[0033] In another aspect, 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.

[0034] In yet another aspect, 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.

[0035] In a final aspect, 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.

[0036] In various embodiments of the methods as described herein, the subject is experiencing symptoms from overdose of opioid agonists. In some embodiments, the subject is suffering from opioid use disorder.

INCORPORATION BY REFERENCE

[0037] All publications, patents, and patent applications mentioned in this disclosure are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE FIGURES

[0038] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative and non-limiting embodiments, in which the principles of the present disclosure are utilized, and the accompanying figures of which:

[0039] FIG. 1 shows the ¹ HNMR spectrum of intermediate A.

[0040] FIG. 2 shows the ¹ HNMR spectrum of Compound 2.

[0041] 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).

[0042] 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.

DETAILED DESCRIPTION

[0043] 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.

[0044] There is a need for longer-acting opioid antagonists as the currently available reversal agents either require very high and/or repeated doses to manage synthetic opioid overdoses. There is also a marked disparity between the duration of actions of the currently available opioid antagonists vs. highly potent and long-lasting synthetic opioids. Furthermore, structurally unique classes of high potency synthetics (i.e. benzimidazoles exemplified by etonitazene and isotonitazene), with uncharacterized human pharmacokinetic profiles have emerged in the illicit drug markets. Thus, the development of a long-acting opioid antagonist would represent a prudent strategy for providing protection to military personnel and first-responders from the increasing threat of weaponized synthetic opioids.

[0045] Without being bound by theory, the present disclosure provides a 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. These important attributes include (i) the ability of the 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.

[0046] In another aspect, the present disclosure provides a composition comprising an opioid antagonist-polymer conjugate compound comprising the compound of formula I and an opioid antagonist. In some embodiments, the opioid antagonist-polymer conjugate is co-formulated with a penetration enhancer (e.g., alkyl-saccharide) to facilitate intranasal administration. In other embodiments, the opioid antagonist-polymer conjugate is formulated for parenteral administration (e.g., intravenous, subcutaneous or intramuscular injection). In yet another aspect of the present disclosure, the opioid antagonist-polymer conjugate is co-formulated with an opioid antagonist (e.g., nalmefene) to ensure rapid reversal of opioid overdose upon administration.

[0047] In yet other embodiments of the present disclosure, formulations comprising opioid antagonist-polymer conjugate compound are provided in a device configured to facilitate intranasal or parenteral administration.

[0048] In the following descriptions, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed present disclosure.

[0049] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

Definitions

[0050] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg (2004) “Advanced Organic Chemistry 4rd Ed.” Vols. A and B, Springer, New York. The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of mass spectroscopy, protein chemistry, biochemistry, synthetic organic chemistry, and pharmacology, within the skill of the art.

[0051] The term “average molecular weight” relates to the poly dispersity of a polymer, as the mass distribution of a polymer may be non-uniform. Most PEG polymers are polydisperse compounds and contain polymer chains of unequal length, and so the molecular weight is not a single value - the polymer exists as a gaussian distribution of chain lengths and molecular weights, with the most abundant species representing the average molecular weight.

[0052] The term “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.

[0053] The term “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.

[0054] 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.

[0055] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0056] “ oxo” refers to =0.

[0057] “enol” refers to C=C(— OH)

[0058] “Carboxyl” refers to -COOH.

[0059] “Hydroxyl” refers to -OH.

[0060] “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-

1-pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-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. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci-ealkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-ioalkyl. In some embodiments, the alkyl is a Ci-ealkyl. In some embodiments, the alkyl is a Ci-salkyl. In some embodiments, the alkyl is a C alkyl. In some embodiments, the alkyl is a Ci-3alkyl. Unless stated otherwise specifically in the specification, an alkyl 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 alkyl is optionally substituted with oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0061] “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. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1 -propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. [0062] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0063] “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.

[0064] “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. In some embodiments, the alkoxy is optionally substituted with halogen, - CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. [0065] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0066] “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. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6- membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. [0067] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0068] “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.

[0069] “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.

[0070] “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.

[0071] “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. In one aspect, 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. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such 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 . Unless stated otherwise specifically in the specification, 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. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0072] “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. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative 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). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran- 1-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol- 4-yl. The term 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. In some embodiments, 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. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0073] “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. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6- membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.

Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1- oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, 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. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, - OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. [0074] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0075] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0076] “ Treatment” of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, 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.

[0077] “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.

[0078] By “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.

[0079] As used herein, the term “subject” encompasses mammals and non-mammals. Examples of 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. Examples of nonmammals include, but are not limited to, birds, fish and the like. The term does not denote a particular age or gender.

[0080] The term an “opioid antagonist” refers to any molecule that blocks the action of an opioid agonist at one or more opioid receptor types, including so-called “agonist-antagonist” and “partial agonist” molecules that act as an antagonist for one opioid receptor type and an agonist for another receptor type, such as, for example, naloxone, naltrexone, nalorphine, buprenorphine, pentazocine, or samidorphan.

[0081] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0082] The term “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.

[0083] The term “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.

[0084] As used herein, the term “subject” encompasses mammals and non-mammals. Examples of 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. Examples of non- mammals include, but are not limited to, birds, fish and the like. The term does not denote a particular age or gender.

Compounds

[0085] In one aspect, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, according to Formula (I):

D— E— L— P

Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

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; and P is a polymer.

[0086] In some embodiments, the compound of Formula (I) is a compound of Formula (II):

Formula (II) or a pharmaceutically acceptable salt thereof, wherein

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-, -NR ¹¹ -, -O-, or absent;

R ¹¹ is optionally substituted Ci-Ce alkyl m is 1 to 100; and o is 2 to 100.

[0087] In some embodiments, 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. 'O'

[0088] In some embodiments, P is ⁿ and n is 1 to 1,000. In some embodiments, P is and n is 50 to 1,000. In some embodiments, P is and n is 100 to 700.

[0089] In some embodiments, m is 1 to 10.

[0090] In some embodiments, o is 2 to 10.

[0091] In some embodiments, the compound is according to Formula (Ila):

Formula (Ila), or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, 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.

[0093] In some embodiments, D is nalmefene or a derivative thereof.

[0094] In some embodiments, the compound of Formula (I) is a compound of Formula (III): polymer

Formula (III), or a pharmaceutically acceptable salt thereof, wherein:

Xi is CH ₂ or O;

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.

[0095] In some embodiments, the compound of Formula (I) is a compound of Formula (IV):

Formula (IV), or a pharmaceutically acceptable salt thereof, wherein

R2 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.

[0096] In some embodiments, the compound of Formula (I) is a compound of Formula (V):

N— R ₃

O L — polymer

Formula (V), or a pharmaceutically acceptable salt thereof, wherein

X ₃ is CH ₂ or O;

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.

[0097] In some embodiments, the compound of Formula (I) is a compound of Formula (VI):

Formula (VI), 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.

[0098] In some embodiments, the compound of Formula (I) is a compound of Formula (VII)

Formula (VII), or 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.

[0099] In some embodiments, the compound of Formula (I) is a compound of Formula (VIII)

Formula (VIII) or a pharmaceutically acceptable salt thereof, wherein

Z is -0-, -NH-, -NR ¹¹ -, -CH2-, or absent;

Q is -NH-, -NR ¹¹ -, -0-, or absent;

R ¹¹ is optionally substituted Ci-Ce alkyl m is 1 to 100; and o is 2 to 100.

[0100] In some embodiments, the compound of Formula (I) is a compound of Formula (IX)

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. [0101] In some embodiments, the compound is selected from: or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the compounds described herein are hydrolytically labile.

[0103] A representative synthesis for an opioid antagonist-polymer conjugate of the present disclosure is provided in Scheme I below.

Scheme I:

[0104] Table 1 below summarizes the compounds of Formulae I to IX.

[0105] 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 5,434,171, and derivatives, mixtures, salts, polymorphs, or prodrugs thereof

[0106] In one aspect of the present disclosure, 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.

[0107] In some embodiments, the molecular weight of the polymer can be about IK, about 2K, about 5K, about 10K, about 20K, about 40K, or about 60K.

[0108] In some embodiment, the linkage L can connect to the polymer moiety via ester, thioester, amide, amine, carbamate, carbonate, ether, thioether, and urea linkages.

Isomers/Stereoisomers

[0109] In some embodiments, 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, entgegen (E), and zusammen (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. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.

Pharmaceutically acceptable salts

[0110] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[OHl] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0112] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, di nitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6- dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate.

[0113] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l- carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, 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.

[0114] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (CI-4 alkyl)4, and the like. [0115] 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

[0116] In some embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods by administering such solvates. The present disclosure further provides for methods by administering such solvates as pharmaceutical compositions.

[0117] 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. In addition, 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

[0118] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described 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.

Pharmaceutical Compositions/F ormulations

[0119] 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. In one embodiment, 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.

[0120] In some embodiments, the pharmaceutical composition comprises a compound of any one of the Formulas described herein, an opioid antagonist, and one or more pharmaceutically acceptable excipients.

[0121] The opioid antagonist can be any suitable opioid antagonist as described herein. In some embodiments, the opioid antagonist is nalmefene, naloxone, or naltrexone. In some embodiments, the opioid antagonist is nalmefene. In some embodiments, the opioid antagonist is naloxone. In some embodiments, the opioid antagonist is naltrexone.

[0122] In some embodiments, the pharmaceutical composition comprises a compound of any one of the Formulas described herein, an intranasal penetration enhancer, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a compound of any one of the Formulas described herein and an intranasal penetration enhancer.

[0123] In some embodiments, 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).

[0124] In some embodiments, 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.

[0125] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0126] In some embodiments, the pharmaceutically acceptable excipient is selected from buffers, salts, preservatives, penetration enhancers, and any combinations thereof.

[0127] In some embodiments, the pharmaceutical composition is administered parenterally. In some embodiments, the pharmaceutical composition is administered via intravenously. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is administered intramuscularly. In some embodiments, the pharmaceutical composition is administered intranasally. In some embodiments, the pharmaceutical composition is administered buccally.

[0128] In some embodiments, the pharmaceutical composition is formulated as an aqueous solution. In some embodiments, the pharmaceutical composition is formulated as an aerosol. [0129] Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing and dissolving processes.

[0130] Pharmaceutical compositions for parental use are formulated as injections. In some embodiments, the pharmaceutical composition suitable for injection includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and any combinations thereof. In some embodiments, the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.

Dosing

[0131] The amount of a given agent that corresponds to a therapeutically effective amount varies depending upon factors such as the particular compound, condition of the subject, and/or the severity of the opioid overdose, the identity (e.g., weight, sex) of the subject in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. [0132] In general, however, doses employed for adult human treatment are typically in the range of 0.01 to 500 micromoles per dose, or more commonly 1 - 50 micromoles per dose of the opioid antagonist-polymer conjugate compound comprising formula I. In another aspect of the present disclosure, 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. In one aspect, doses employed for adult human treatment are conveniently administered in a single dose.

Routes of Administration

[0133] The compounds and compositions of the present disclosure can be administered intranasally or parenterally, including the intravenous, intramuscular, intraperitoneal, and subcutaneous routes of administration.

[0134] The compounds and disclosure of the present disclosure can be administered via a manufactured intranasal spray device designed to facilitate intranasal administration, or via a manufactured pre-filled injection device for parenteral administration.

Method of Treatment

[0135] In certain aspects, 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 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0136] In another aspect, 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 as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0137] In another aspect, 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.

[0138] In some embodiments, the subject is experiencing symptoms from overdose of opioid agonists. In some embodiments, the subject is suffering from opioid use disorder.

[0139] In some embodiments, compounds and compositions described herein may be used for the immediate and sustained reversal of the effects of opioid agonists in a subject. In some embodiments, this may involve the rapid reversal of potentially lethal respiratory depression induced by an overdose of an opioid agonist (e.g. fentanyl). In another embodiment, the compounds may be used to prevent the reassertion of opioid agonist effects (i.e. renarcotization) in a subject.

[0140] In some embodiments, the compounds and compositions described herein may be useful for transitioning individuals into an opioid use disorder treatment program as the ability of a treated subject to abuse opioid agonists will be impeded due to the sustained action of the opioid antagonist.

[0141] In some embodiments, the compounds and compositions described herein may be useful for providing military personnel and first-responders prophylactic protection against exposures to synthetic opioids.

EXAMPLES

[0142] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0143] As used above, and throughout the description of the present disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

Abbreviations

ACN acetonitrile

DCM dichloromethane

DIBAL diisobutylaluminum hydride

DIPEA N,N-diisopropylethylamine

DMA dimethylacetamide

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EtOAc ethyl acetate

HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyri dinium 3-oxide hexafluorophosphate

HEPES 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid

HMDS bis(trimethylsilyl)amide

HPLC high pressure liquid chromatography

IC50 half maximal inhibitory concentration

IPA isopropyl alcohol

LCMS liquid chromatography-mass spectrometry

MW micro wave

NMR nuclear magnetic resonance T3P propanephosphonic acid anhydride

TBAF tetra-n-butylammonium fluoride

TBDMS tert-butyldimethylsilyl

TBDPS tert-butyldiphenylsilyl

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin-layer chromatography

Example 1 - Synthesis and Characterizations of Compounds 1, 2, 3, and 4

Scheme 1 - Synthetic Scheme of Compounds 1, 2, 3, and 4

Synthesis of Intermediate A:

[0144] To a stirred solution of nalmefene hydrochloride (1 g, 2.66 mmol, 1.00 eq) in DCM (25.0 mL) at RT was added DIPEA (0.93 mL, 5.32 mmol, 2.00 eq) followed by the addition of adipic anhydride. The resulting solution was stirred at this temperature for 16h. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified by prep-HPLC (under neutral conditions) and the pure fractions collected were combined and lyophilized for 48h to afford the desired hemi-ester intermediate A (0.78 g, 63%) as white solid. ^T H NMR (500 MHz, DMSO-d6) 8 6.76 (d, J= 8.2 Hz, 1H), 6.65 (d, J= 8.2 Hz, 1H), 5.03 (t, J= 2.0 Hz, 1H), 4.96 (s, 1H), 4.79 (t, J= 2.2 Hz, 1H), 3.02 (dd, J= 12.1, 6.6 Hz, 2H), 2.64 (dd, J= 12.3, 4.7 Hz, 1H), 2.55 (t, J= 7.1 Hz, 3H), 2.33 (t, J= 6.7 Hz, 2H), 2.24 (t, J= 7.1 Hz, 3H), 2.05 (dt, J= 13.7, 3.5 Hz, 1H), 1.95 (td, J= 12.1, 3.8 Hz, 1H), 1.72 - 1.55 (m, 4H), 1.51 (dt, J= 12.9, 3.7 Hz, 1H), 1.26 (dd, J= 12.8, 3.7 Hz, 1H), 1.18 (td, J= 13.1, 3.8 Hz, 1H), 0.90 - 0.78 (m, 1H), 0.58 - 0.38 (m, 2H), 0.11 (dd, J = 4.9, 2.3 Hz, 2H). MS(ESI ⁺ ) m/z cak'd for [M+H] ⁺ [C ₂ 7H ₃₃ NO ₆ +H] ⁺ : 468.2 found: 468.5. General synthesis of nalmefene-PEG ester conjugate compounds 1, 2, 3, and 4 from intermediate A:

[0145] To a solution of NMF-hemiester A (1.00 eq), in DMF (25 mL/ mmol) and DCM (25 mL/ mmol) at RT was added HATU (1.20 eq) followed by the addition of PEG-NH2 (0.5 eq.). DIPEA (2.0 eq) was then added. The reaction mixture was stirred at RT for 16h. The reaction mixture was then diluted via slow addition of diethyl ether until a solid precipitated. The solid was filtered, washed with diethyl ether (2 x 20 mL), and dried under reduced pressure. This resulting solid was then dissolved in EtOH: DCM (1 : 1), and diethyl ether was added until the solid precipitated. The resulting precipitate was filtered, washed with diethyl ether (2 x 20 mL) and dried under reduced pressure to provide the desired Compound 2.

[0146] The polydisperse methoxy PEG reagents employed in the synthesis of the nalmefene- PEG ester conjugate compounds 1, 2, 3, and 4 were purchased from a vendor (NanoSoft Polymers, Winston-Salem, North Carolina) and were all white to off-white solids. The purity of the reagents was determined to be >95% using GPC, chemical identity was established by proton NMR, and all the reagents were reported to have a poly dispersity index of less than 1.09.

Determination of Percent Loading

[0147] To determine the percent loading of the nalmefene-PEG ester conjugate compounds 1, 2, 3, and 4, the conjugate compounds were initially individually analyzed using HPLC to confirm that no free nalmefene was present. Then 2 mgs of the individual compounds were dissolved in 200 microliters of 10% ethanol in water and subjected to ester hydrolysis via the addition of 50 microliters of 0. IM sodium hydroxide at room temperature. The hydrolyses were monitored by HPLC every 30 minutes, and the hydrolyses were continued until the resulting nalmefene peak achieved and maintained a constant peak area. The final concentration of nalmefene produced in the hydrolysis reactions was then determined using a reference standard curve comparison of HPLC peak areas. The resulting concentrations were then used to calculate the percent of released nalmefene from nalmefene-PEG ester conjugate compounds 1, 2, 3, and 4. The percent released values were then compared to calculated theoretical 100% values to determine the efficiency of the pegylation reactions used in Scheme 1 and to calculate correction factors for dosing nalmefene-PEG ester conjugate compounds 1, 2, 3, and 4 in subsequent in vitro and in vivo studies. The data is presented below in Table 2.

Example 2 - In Vitro Studies

[0148] The metabolic stability of representative nalmefene-PEG ester conjugate compound 4 in the presence of whole blood and liver microsomes from human, rat, and dog was evaluated. [0149] The assay was carried out in 96-well microtiter plates. Compounds were incubated (N=l) at 37°C separately in the presVence of fresh human and fresh dog blood. Reaction mixtures (50 pL) contained a final concentration of 1 pM test compound. The rate and extent of metabolism was calculated as the appearance of nalmefene vs. time, compared to the 0-min control nalmefene incubations. Propantheline was included as a positive control to verify assay performance.

[0150] At each of the time points, 50 pL of water was added to the blood samples before 300 pL of quench solution (100% acetonitrile with 0.1% formic acid) with internal standard (bucetin for positive ESI mode) was transferred to each well. Plates were sealed, vortexed, and centrifuged at 10°C for 15 minutes at 4000 rpm. The supernatant was transferred to fresh plates for LC/MS/MS analysis.

[0151] All samples were analyzed on LC/MS/MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analytical samples were separated using a Waters Atlantis T3 dC18 reverse phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL/min. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B). Elution conditions are detailed in the Table 3 below. Stability of Compound 4 in fresh human and dog liver microsomes

[0152] Liver microsomes tissue fractions were used for in vitro assessment of metabolic stability of various compounds by cytochrome P450 (CYP450) mediated phase I oxidation, and metabolism through other pathways. Human and dog liver microsomes tissue fractions were obtained from Corning Gentest.

[0153] The assay was carried out in 96-well microtiter plates. Compounds were seperately incubated (N=l) at 37°C in the presence of human and dog liver microsomes. Reaction mixtures (25 pL) contained a final concentration of 1 pM test compound, 0.5 mg/mL liver microsomes protein, and 1 mM NADPH in 100 mM potassium phosphate, pH 7.4 buffer with 3.3 mM MgC12. The rate and extent of metabolism was calculated as the appearance nalmefene vs. time, compared to the 0-min control reaction incubations. Verapamil was included as a positive control to verify assay performance.

[0154] At each of the four time points, 150 pL of quench solution (100% acetonitrile with 0.1% formic acid) with internal standard (bucetin for positive ESI mode) was transferred to each well. Plates were sealed and centrifuged at 10°C for 15 minutes at 4000 rpm. The supernatant was transferred to fresh plates for LC/MS/MS analysis.

[0155] All samples were analyzed on LC/MS/MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analytical samples were separated using a Waters Atlantis T3 dC18 reverse phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL/min. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B). Elution conditions are detailed in the Table 4 below.

[0156] Nalmefene demonstrated chemical stability in whole blood from all species tested, and in the presence of human and dog liver microsomes. Representative compound 4 was demonstrated to be stable in the presence of liver microsomes from all species tested and exhibited rapid conversion to nalmefene in rat whole blood (83% conversion to nalmefene at the 1-hour timepoint), and slower conversion to nalmefene in the presence of human and dog whole blood at the 1 -hour timepoint (2% and 5%, respectively).

Example 3 - In Vivo Studies in Dogs

[0157] An in vivo study was conducted whereby equimolar doses of Nalmefene (3.3 mg) and compounds 1, 2, 3, and 4 were formulated in an aqueous formulation then administered intramuscularly to dogs (N=3/dose group). Dogs were the species of choice for this study due to the close similarity of the in vitro metabolism profiles demonstrated between dog and human. [0158] All doses were well tolerated with no adverse events or clinical observations reported. Blood samples were collected at 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours post-dose for all groups. The dose groups for the NMF dog study are presented in Table 5 below. The samples were immediately stabilized with potassium oxalate and NaF upon blood collection, and then with 0.1% formic acid immediately post-processing to plasma, to insure complete deactivation of plasma esterase activity. The samples were analyzed directly for the presence of nalmefene using a LC/MS-MS method with a LLOQ of 0.1 ng/mL. In addition, collected plasma samples from dogs dosed with compounds 1, 2, 3, and 4 were pooled by timepoint, hydrolyzed via the addition of sodium hydroxide solution, then similarly analyzed for released nalmefene to extrapolate plasma concentrations of the intact prodrugs for each dose group. The resulting nalmefene plasma concentrations were measured at defined timepoints, as well as the nalmefene plasma concentrations measured after basic hydrolysis of the pooled samples by timepoint are presented below in Tables 6, 7, 8, 9, and 10 below. The resulting nalmefene plasma-concentration vs. time profile plots are presented in FIG. 3 and FIG. 4 respectively. [0159] Based on the data presented above, opioid antagonist-polymer conjugate compounds 1, 2, 3, and 4 demonstrate the desired attributes of representative opioid antagonist-polymer conjugate compounds of the invention. Specifically, (i) the ability of the opioid antagonist-polymer conjugate compound to rapidly deliver opioid antagonist to the systemic circulation following parenteral administration as depicted in FIG. 3, (ii) “depo-effects” involving controlled and sustained absorption from the site of administration and/or slow clearance from the systemic circulation as depicted in FIG. 4 modulated by the increasing size (i.e., molecular weight) of the PEG addend with molecular weights in the range of 5,000 to 30,000 being preferred, and (iii) controlled metabolism of the opioid antagonist-polymer conjugate compounds in the systemic circulation via hepatic and/or plasma enzymes to maintain a targeted exposure of the delivered opioid antagonist over a prolonged time period in stark contrast to nalmefene comparator (FIG. 3).

[0160] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in practicing the present disclosure. It is intended that the following claims define the scope of the present disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.