Treating Opioid Withdrawal

Abstract

The present invention relates to methods for treating, preventing, managing and / or controlling opioid withdrawal and / or symptoms associated with opioid withdrawal. Compounds, compositions, medicaments and kits that can be used in these methods are provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Australian Provisional Patent Application No. 2019903299, filed September 6, 2019, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to methods for treating and / or preventing opioid withdrawal. [Background technology]

[0003] Opioids and opiates are a useful class of analgesics that find widespread use in pain management.Opioids and opiates have also become substances of abuse, both by recreational users and by patients who develop opioid use disorder after opioid therapy.Also, cessation of opioid and / or opiate use can lead to opioid withdrawal.Opioid withdrawal is a physiological state that results from a subject's physical dependence on opioids and / or opiates, and can in some cases develop after a short period of exposure to opioids and / or opiates.

[0004] Iatrogenic opioid withdrawal syndrome (IOWS) frequently appears in patients who have been or are currently being treated with opioid analgesics for acute or chronic pain management. For example, it was reported in 2017 that 16.7% of adults in intensive care units (ICUs) who received opioid treatment for an average of approximately 6 days suffered from IOWS. In addition, in pediatric populations, IOWS was reported to occur in 10-57% of patients receiving opioids for more than 24 hours in the ICU. The proportion of patients suffering from IOWS increases dramatically when opioid treatment is longer term. For example, some randomized controlled trials (RCTs) reported that more than 80% of patients suffered from IOWS upon opioid dose tapering or discontinuation. IOWS poses a major challenge to treating physicians as it may impede successful cessation of opioid use and dramatically increases the risk of treatment-related adverse events and opioid misuse. In some populations, two-thirds of patients are unable to successfully discontinue opioid treatment, with withdrawal symptoms being a major factor in this failure.

[0005] Opioid withdrawal causes significant pain, physical and psychological suffering to sufferers. Therefore, providing an effective treatment for opioid withdrawal is desirable to provide acute relief to subjects in need thereof. Furthermore, the desire to escape opioid withdrawal symptoms plays a role in patients transitioning from prescribed use to abuse, and therefore, effectively preventing or treating opioid withdrawal may help prevent the development of opioid use disorder in individuals who may have initially used opioids and / or opiates in a prescribed manner. Overcoming opioid withdrawal symptoms is also typically the first major obstacle to recovery in individuals suffering from opioid use disorder. Therefore, effectively treating opioid withdrawal can help subjects achieve soberness.

[0006] In the context of opioid use disorder, existing management strategies for opioid withdrawal include substitution therapy, in which an opioid (typically buprenorphine or methadone) is administered as a replacement opioid. Opioid substitution therapy seeks to prevent or delay the onset of opioid withdrawal and / or minimize the severity of withdrawal syndrome that does occur. However, the opioids used in substitution therapy themselves often lead to opioid withdrawal, along with other side effects, after discontinuation or tapering of the dose. Furthermore, substitution therapy may be required for a long period of time, especially when a subject has developed an opioid use disorder.

[0007] Lofexidine is the first, and at the time of filing, the only non-opioid medication approved by the U.S. Food and Drug Administration (FDA) for the management of opioid withdrawal symptoms. However, in clinical trials, lofexidine therapy provided only modest improvements in acute opioid withdrawal symptoms and treatment retention while causing troublesome side effects including hypotension, bradycardia, and insomnia. Furthermore, lofexidine is only approved for use for a maximum of 14 days.

[0008] Thus, there is a continuing need to provide alternative options for managing opioid withdrawal.

[0009] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0010] The reference to prior art herein is not an admission or suggestion that that prior art forms part of the common general knowledge in any jurisdiction, or that that prior art could reasonably be expected to be understood, regarded as relevant, and / or incorporated into other pieces of prior art by those skilled in the art. Summary of the Invention [Means for solving the problem]

[0011] The present invention provides a method for treating opioid withdrawal and / or symptoms associated with opioid withdrawal, comprising administering to a subject in need thereof an effective amount of a compound according to formula (I). [ka] (In the formula: V is NH, CH, or a direct bond; W is NH, CH, or a direct bond; X is NH, CH, or a direct bond; Y is NH, CH2, or a direct bond; Z is selected from NH, O, S, S(O), SO2 or a direct bond; R 1 is H or C(O)R 4 Selected from; R 2 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 3 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 4 is an optionally substituted C 1~5 is alkyl; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1. or a pharma- ceutically acceptable salt or prodrug thereof, thereby treating opioid withdrawal and / or symptoms associated with opioid withdrawal in a subject.

[0012] The compound is: [ka] or a pharma- ceutically acceptable salt or prodrug thereof.

[0013] In some embodiments, the compound may be a hydrochloride salt of Compound 1, such as the dihydrochloride salt (CMPD1-2HCL).

[0014] In some embodiments, the compound may be a phosphate addition salt of Compound 1 (CMPD1-PO4). The phosphate addition salt may be referred to as a phosphate salt of Compound 1.

[0015] In another aspect, there is provided a method of treating a subject exposed to or at risk of being exposed to opioids and / or opiates, comprising administering to the subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof, thereby treating and / or preventing opioid withdrawal and / or symptoms associated with opioid withdrawal.

[0016] In another aspect, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof in the manufacture of a medicament for treating opioid withdrawal and / or symptoms associated with opioid withdrawal.

[0017] In another aspect, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof for treating opioid withdrawal and / or symptoms associated with opioid withdrawal.

[0018] In another aspect, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof for use in the treatment of opioid withdrawal and / or symptoms associated with opioid withdrawal.

[0019] In another aspect, there is provided a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof, and an opioid and / or an opiate.

[0020] In another aspect, there is provided a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof, and an effective amount of an opioid antagonist and / or partial agonist.

[0021] In another aspect, a kit is provided comprising, in separate parts: an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof, and Opioids and / or opiates.

[0022] In another aspect, a kit is provided comprising, in separate parts: an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof, and An effective amount of an opioid antagonist and / or partial agonist.

[0023] In some embodiments, these pharmaceutical compositions and kits can be used in any of the methods described herein.

[0024] In another aspect, there is provided a method of preventing opioid withdrawal and / or symptoms associated with opioid withdrawal, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof.

[0025] In another aspect, a method of treating pain is provided, comprising administering to a subject in need thereof an effective amount of an opioid and / or opiate and an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof. In some embodiments, the dose of the opioid and / or opiate can be decreased according to a tapering regimen. Administration of the compound of formula (I) can be maintained after cessation of administration of the opioid and / or opiate according to any of the methods of treating, preventing, managing and / or controlling opioid withdrawal and / or symptoms associated with opioid withdrawal described herein.

[0026] In another aspect, a method of treating opioid overdose is provided, the method comprising administering to a subject in need thereof an effective amount of an opioid antagonist, and an effective amount of a compound of formula (I), a pharma- ceutically acceptable salt and / or prodrug thereof.

[0027] As used herein, unless the context specifically requires, the term "comprise" and variations thereof, such as "comprising", "comprises" and "comprised", are not intended to exclude additional additives, ingredients, integers or steps.

[0028] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a symptom" and / or "at least one symptom" can include one or more symptoms, and so forth.

[0029] The term "and / or" can mean "and" or "or."

[0030] The term "(s)" following a noun intends either the singular or the plural, or both.

[0031] Various features of the present invention are described with reference to specific values ​​or ranges of values. These values ​​are intended to relate to the results of various suitable measurement techniques and should therefore be interpreted as including the margin of error inherent in any particular measurement technique. Some of the values ​​referred to herein are indicated by the term "about" to at least partially account for this variability. When the term "about" is used to describe a value, it can mean an amount within ±25%, ±10%, ±5%, ±1% or 20±0.1% of that value.

[0032] Unless specifically defined herein, chemical terms have their ordinary meanings known in the art.

[0033] As used herein, the term "C" used alone or in compound words 1~5 "Alkyl" refers to a monovalent straight or branched chain hydrocarbon group having one to five carbon atoms. As will be understood by those of skill in the art, the term "C 1~5 "Alkyl" means an alkyl chain having 1, 2, 3, 4 or 5 carbon atoms, or a range of carbon atoms including any two of the integers, including 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, and 4-5. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, iso-pentyl, and tert-pentyl. 1~4 Alkyl may be optionally substituted with one or more substituents. The substituents may be located at any position on the carbon chain. Suitable substituents include OH, NH, halogen, NH(C 1~5 alkyl), N(C 1~5 alkyl)2, CN, NO2, CO2H, or OC 1~5 Includes, but is not limited to, alkyl.

[0034] The terms "hydroxy" and "hydroxyl" refer to the group --OH.

[0035] As used herein, the term "OC 1~5 "Alkyl" refers to an alkoxy group having 1 to 5 carbon atoms. As will be understood by those of skill in the art, the term "OC 1~5 "Alkyl" means an alkoxy group having 1, 2, 3, 4 or 5 carbon atoms, or a range including any two of these integers, including 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5 and 4-5. 1~5Alkyl groups include, but are not limited to, methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, neopentyloxy, iso-pentyloxy, and tert-pentyloxy. 1~5 Alkyl may be optionally substituted with one or more substituents. The substituents may be located at any position on the carbon chain. Suitable substituents include OH, NH, halogen, NH(C 1~5 alkyl), N(C 1~5 alkyl)2, CN, NO2, CO2H, or OC 1~5 Includes, but is not limited to, alkyl.

[0036] As used herein, the terms "halo" or "halogen" refer to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

[0037] Further aspects of the invention, and further embodiments of the aspects described in the previous paragraphs, will become apparent from the following description, given by way of example and with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0038] [Figure 1] FIG. 1 is a chart of the distance traveled by C57BL / 6 mice over time after treatment with CMPD1-2HCL (results from Experiment 1 in Example 1). [Diagram 2]Figure 2A is a chart of jumping frequency in treatment groups (0, 2.5, 5 or 10 mg / kg CMPD1-2HCL) (four groups on the right) and C57BL / 6 mice not undergoing oxycodone withdrawal (group on the left) after inducing oxycodone withdrawal in C57BL / 6 mice by administration of naloxone (Jumping Results from Experiment 1.2 in Example 1). Figure 2B is a chart of paw tremor duration (duration in seconds) in treatment groups (0, 2.5, 5 or 10 mg / kg CMPD1-2HCL) (four groups on the right) and C57BL / 6 mice not undergoing oxycodone withdrawal (group on the left) after inducing oxycodone withdrawal in C57BL / 6 mice by administration of naloxone (Paw Tremor Results from Experiment 1.2 in Example 1). [Diagram 3] Figure 3a-h shows a series of charts of c-fos positive cell counts across eight brain regions (a. medial portion of the centrum amygdala; b. lateral parabrachial nucleus, c. periaqueductal gray matter; d. lateral habenula; e. nucleus accumbens shell; f. ventral portion of the lateral septum; g. ventral tegmental area; and h. dorsal raphe nucleus) in treatment groups (the two rightmost groups) and C57BL / 6 mice not undergoing oxycodone withdrawal (the two leftmost groups) following oxycodone withdrawal induction in C57BL / 6 mice by naloxone administration (c-fos results from Example 2). [Figure 4] FIG. 4 is a chart of fecal boli counts by treatment group (vehicle only, oxycodone, and oxycodone followed by CMPD1-2HCL) following induction of oxycodone withdrawal in C57BL / 6 mice by administration of naloxone (Fecal Results from Example 3). [Diagram 5] FIG. 5 is a chart of the frequency of jumping by treatment group (vehicle only, oxycodone, oxycodone followed by CMPD1-PO4, and oxycodone followed by CMPD1-2HCL) following induction of oxycodone withdrawal in C57BL / 6 mice by administration of naloxone in the three groups on the far right (Jumping Results from Example 4). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] The present invention provides a method of treating opioid withdrawal and / or symptoms associated with opioid withdrawal comprising administering an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof.

[0040] Surprisingly, the inventors have found that the compounds of the present invention can treat opioid withdrawal symptoms. Thus, a treatment comprising the administration of a compound of formula (I) may be useful for treating, preventing, managing and / or controlling opioid withdrawal and / or symptoms associated with opioid withdrawal.

[0041] Opioid withdrawal is a physiological phenomenon that may occur after a subject is exposed to opioids and / or opiates, and becomes physically dependent on opioids and / or opiates. Thus, opioid withdrawal may occur in a subject when opioids and / or opioid exposure is removed, and / or when exposed to opioid antagonists and / or opioid partial agonists. There are many diagnostic tools that have been developed in relation to opioid withdrawal. One such diagnostic tool is defined in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5 or DSM-V). According to DSM-5, opioid withdrawal can be diagnosed by either (1) cessation (or reduction) of heavy and prolonged (i.e., more than several weeks) opioid or opiate use; and / or (2) administration of an opioid antagonist after a period of opioid and / or opiate use. However, there are some notable documented instances of opioid withdrawal that are not included in the DSM-5 diagnostic criteria, including neonatal opioid withdrawal and some cases of IOWS.

[0042] In the methods of the present invention, the subject may be exposed to an opioid and / or opiate or at risk of being exposed to an opioid and / or opiate. In some embodiments, the subject has been administered an opioid and / or opiate. In some embodiments, the subject has been exposed to an opioid and / or opiate for at least about 1 day (d), 2d, 3d, 4d, 5d, 6d, 1 week (w), 2w, 3w, 4w or more. This administration may be in a clinical setting, for example, as described above for IOWS. The opioid and / or opiate may be capable of inducing physical and / or somatic withdrawal in the subject. These opioids and opiates include oxycodone, morphine, buprenorphine, codeine, fentanyl, opium, methadone, heroin, hydrocodone, hydromorphone, oxymorphone, meperidine, tramadol, propoxyphene, diphenoxylate, loperamide, nalbuphine, butorphanol, pentazocine, carfentanil and other fentanyl analogs, and combinations thereof. In some embodiments, these opioids and / or opiates can be referred to as opioid agonists, since they are all agonists or partial agonists of one or more opioid receptors.

[0043] In some embodiments, administration of a compound of formula (I) can be initiated after cessation of administration of an opioid and / or opiate, hi some embodiments, administration of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof is initiated within at least about 30 minutes (m), 45 minutes, 1 hour (h), 1.5 hours, 2 hours, 5 hours, 10 hours, 12 hours, 18 hours, or 24 hours of the last dose of an opioid and / or opiate.

[0044] In some embodiments, administration of the compound of formula (I) can be started before the administration of the opioid and / or opiate is stopped. In some embodiments, administration of the first dose of the compound of formula (I) is performed simultaneously with the last dose of the opioid and / or opiate. In some embodiments, administration of the first dose of the compound of formula (I) is performed at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more before the last dose of the opioid and / or opiate.

[0045] In some embodiments, administration of a compound of formula (I) may be initiated prior to administration of an opioid and / or opiate. Such methods may be useful, for example, prior to a surgical procedure where an opioid is likely to be required during the procedure or during recovery.

[0046] It will be appreciated that when a compound of formula (I) is administered prior to cessation or reduction of opioid and / or opiate use (including when administration of a compound of formula (I) precedes administration of an opioid and / or opiate), opioid withdrawal and / or symptoms associated with opioid withdrawal may be prevented in a subject. Thus, in some embodiments, the methods of the present invention are methods of preventing opioid withdrawal and / or symptoms associated with opioid withdrawal comprising administering to a subject at risk of opioid withdrawal an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof, thereby preventing opioid withdrawal and / or symptoms associated with opioid withdrawal.

[0047] In some embodiments, the method includes tapering the dose of the opioid and / or opiate. Tapering includes reducing the dose of the opioid and / or opiate in a stepwise manner over a period of time. The appropriate tapering regimen will depend on the particular opioid and / or opiate, as well as other factors that will be appreciated by those of skill in the art.

[0048] In some embodiments, administration of a compound of formula (I) is initiated prior to the initiation of opioid / opiate dose tapering.

[0049] In some embodiments, administration of a compound of formula (I) is initiated simultaneously with the initiation of an opioid / opiate dose taper. In these embodiments, a compound of formula (I) may be administered within about 15, 30, 60, or 120 minutes of the first dose of an opioid and / or opiate tapering regimen (e.g., the last maximum dose of the opioid and / or opiate).

[0050] In some embodiments, administration of a compound of Formula (I) is initiated during opioid / opiate dose tapering, for example, when the opioid and / or opiate dosage has decreased by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90% or 95%.

[0051] In some embodiments, administration of the compound of formula (I) is initiated after completion of the opioid / opiate dose taper, in some embodiments, administration of the compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof is initiated within at least about 30 minutes (min), 45 minutes, 1 hour (h), 1.5 h, 2 h, 5 h, 10 h, 12 h, 18 h, or 24 h of the final dose of opioid.

[0052] In some embodiments, administration of a compound of formula (I) may be maintained for at least about 1 week (w), 2w, 3w, 4w, 5w, 6w, 7w, 8w, 9w, 10w, 11w, 12w, or more. The length of time administration is maintained will depend on the opioid and / or opiate causing the withdrawal symptoms, the individual subject, and the length of any co-administration period. In some embodiments, administration of a compound of formula (I) may be stopped and resumed if the subject experiences the onset of symptoms of opioid withdrawal after the initial treatment period.

[0053] In some embodiments, the opioid withdrawal is neonatal opioid withdrawal. In these embodiments, exposure to opioids and / or opiates occurs in utero.

[0054] In some embodiments, opioid withdrawal can be induced by administering an opioid antagonist or partial agonist. Thus, the method can include administering an opioid antagonist or partial agonist. Typically, opioid antagonists include naloxone and naltrexone, and opioid partial agonists include buprenorphine. In these methods, the compound of formula (I) can be administered simultaneously with, before or after the administration of the opioid antagonist or partial agonist. Preferably, the compound of formula (I) is administered simultaneously with the opioid antagonist or partial agonist, since the administration of the opioid antagonist or partial agonist can induce opioid withdrawal.

[0055] Opioid antagonists may be used to treat opioid overdose. In some embodiments, the methods of the present invention may be used in a method of treating opioid overdose. Thus, the present invention also describes a method of treating opioid overdose, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof in combination with an effective amount of an opioid antagonist. The compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof may be administered to the opioid antagonist by the same or different route.

[0056] Also described herein are methods for treating pain, comprising administering an effective amount of an opioid and / or opiate and an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof. The pain may be any pain for which opioid and / or opiate therapy is effective. The administration of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof in these methods is intended to prevent or reduce the severity of opioid withdrawal and / or symptoms associated with opioid withdrawal. Thus, the administration of a compound of formula (I) in these methods may be by its administration in any of the methods for treating opioid withdrawal and / or symptoms associated with opioid withdrawal described herein.

[0057] compound The method of the invention comprises administering a compound of formula (I) [ka] (In the formula: V is NH, CH, or a direct bond; W is NH, CH, or a direct bond; X is NH, CH, or a direct bond; Y is NH, CH2, or a direct bond; Z is selected from NH, O, S, S(O), SO2 or a direct bond; R 1 is H or C(O)R 4 Selected from; R 2 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 3 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 4 is an optionally substituted C 1~5 is alkyl; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1).

[0058] In some embodiments, the compound of formula (I) may be provided as a compound of formula (Ia) [ka] (In the formula: Z is selected from NH, O, S, S(O) or SO2; R 1 is H or C(O)R 4 Selected from; R 2 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 3 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 4 is an optionally substituted C 1~5 (It is alkyl).

[0059] In some embodiments, the compound of formula (I) may be provided as a compound of formula (Ib) [ka] (In the formula: R 1 is H or C(O)R 4 Selected from; R 2 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 3 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC1~5 alkyl; R 4 is an optionally substituted C 1~5 (It is alkyl).

[0060] In some embodiments, the compound of formula (I) may be provided as a compound of formula (Ic) or a salt or prodrug thereof: [ka] (In the formula: Z is selected from NH, O, S, S(O) or SO2; R 1 is H or C(O)R 4 Selected from; R 2 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 3 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 4 is an optionally substituted C 1~5 (It is alkyl).

[0061] In some embodiments, the compound of formula (I) may be provided as a compound of formula (Id): [ka] (In the formula: Z is selected from NH, O, S, S(O) or SO2; R 1 is H or C(O)R 4 Selected from; R 2 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 3is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 4 is an optionally substituted C 1~5 (It is alkyl).

[0062] In some embodiments, the compound of formula (I) may be provided as a compound of formula (Ie): [ka] (In the formula: Z is selected from NH, O, S, S(O) or SO2; R 1 is H or C(O)R 4 Selected from; R 2 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 3 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 4 is an optionally substituted C 1~5 (It is alkyl).

[0063] In some embodiments, the compound of formula (I) may be provided as a compound of formula (If): [ka] (In the formula: Z is selected from NH, O, S, S(O) or SO2; R 1 is H or C(O)R 4 Selected from; R 2 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5alkyl; R 3 is H, OH, halogen, optionally substituted C 1~5 Alkyl or optionally substituted OC 1~5 alkyl; R 4 is an optionally substituted C 1~5 (It is alkyl).

[0064] In some embodiments, the compound of formula (I) is a compound of formula (Ia), or a salt or prodrug thereof.

[0065] In some embodiments, the compound of formula (I) is a compound of formula (Ib), or a salt or prodrug thereof.

[0066] In some embodiments, the compound of formula (I) is a compound of formula (Ic), or a salt or prodrug thereof.

[0067] In some embodiments, the compound of formula (I) is a compound of formula (Id), or a salt or prodrug thereof.

[0068] In some embodiments, the compound of formula (I) is a compound of formula (Ie), or a salt or prodrug thereof.

[0069] In some embodiments, the compound of formula (I) is a compound of formula (If), or a salt or prodrug thereof.

[0070] In some embodiments, V is NH.

[0071] In some embodiments, V is CH2.

[0072] In some embodiments, V is a direct bond;

[0073] In some embodiments, W is NH.

[0074] In some embodiments, W is CH2.

[0075] In some embodiments, W is a direct bond.

[0076] In some embodiments, X is NH.

[0077] In some embodiments, X is CH2.

[0078] In some embodiments, X is a direct bond.

[0079] In some embodiments, Y is NH.

[0080] In some embodiments, Y is CH2.

[0081] In some embodiments, Y is a direct bond.

[0082] In some embodiments, Z is NH.

[0083] In some embodiments, Z is O.

[0084] In some embodiments, Z is S.

[0085] In some embodiments, Z is S(O).

[0086] In some embodiments, Z is SO2.

[0087] In some embodiments, Z is a direct bond.

[0088] In some embodiments, R 1 is hydrogen.

[0089] In some embodiments, R 1 is C(O)R 4 For example, R 4is selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, iso-pentyl and tert-pentyl groups; 1~5 In some embodiments, R 4 is optionally substituted methyl.

[0090] In some embodiments, R 2 is hydrogen.

[0091] In some embodiments, R 2 is a hydroxyl group.

[0092] In some embodiments, R 2 is a halogen. For example, in some embodiments, R 2 is fluorine. In another embodiment, R 2 is chlorine.

[0093] In some embodiments, R 2 is an optionally substituted C 1~5 For example, R 2 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, iso-pentyl and tert-pentyl, 1~5 In some embodiments, R 2 is optionally substituted methyl.

[0094] In some embodiments, R 2 is optionally replaced by OC 1~5 For example, R 2 is selected from methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, neopentyloxy, iso-pentyloxy and tert-pentyloxy groups; 1~5In some embodiments, R 2 is an optionally substituted methoxy group.

[0095] In some embodiments, R 3 is hydrogen.

[0096] In some embodiments, R 3 is a hydroxyl group.

[0097] In some embodiments, R 3 is a halogen. For example, in some embodiments, R 3 is fluorine. In another embodiment, R 3 is chlorine.

[0098] In some embodiments, R 3 is an optionally substituted C 1~5 For example, R 3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, iso-pentyl and tert-pentyl, 1~5 In some embodiments, R 3 is optionally substituted methyl.

[0099] In some embodiments, R 3 is optionally replaced by OC 1~5 For example, R 3 is selected from methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, neopentyloxy, iso-pentyloxy and tert-pentyloxy groups; 1~5 In some embodiments, R 3 is an optionally substituted methoxy group.

[0100] In some embodiments, the compound of formula (I) is selected from: [ka] or a salt or prodrug thereof.

[0101] In another embodiment, the compound of formula (I) is selected from: [ka] or a salt or prodrug thereof.

[0102] In another embodiment, the compound of formula (I) is selected from: [ka] or a salt or prodrug thereof. For example, in some embodiments, the compound of formula (I) is: [ka] or a salt or prodrug thereof.

[0103] The method may include administering a compound of formula (I) in any pharma- ceutically acceptable form. In some embodiments, the compound of formula (I) is provided in the form of a pharma- ceutically acceptable salt, solvate, N-oxide, polymorph, tautomer, or prodrug thereof, or a combination of these forms in any ratio.

[0104] In some embodiments, the compound of Formula (I) is a salt, for example a pharma- ceutically acceptable salt.

[0105] Suitable pharma- ceutically acceptable salts include, but are not limited to, salts of pharma- ceutically acceptable inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid; or salts of pharma- ceutically acceptable organic acids, such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, isethionic acid, malic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid.

[0106] Base salts include, but are not limited to, those formed with pharma- ceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, and alkylammonium; salts formed with triethylamine; alkoxyammonium salts such as those formed with ethanolamine; and salts formed with ethylenediamine, choline, or amino acids such as arginine, lysine, or histidine. General information regarding the types of pharma- ceutically acceptable salts and their formation is known to those skilled in the art and can be found in "Handbook of Pharmaceutical salts" by P.H. Stahl, C.G. Wermuth, 1999, eds. st This is described in general textbooks such as Wiley-VCH, edition 2002.

[0107] The basic nitrogen-containing group in formula (I) (or the basic nitrogen-containing group in a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If)) is an alkyl halide, such as methyl, ethyl, propyl, and butyl chloride, bromide, and iodide. 1~6 They may be quaternized with agents such as dialkyl sulfates, such as dimethyl and diethyl sulfate; and others known in the art.

[0108] In some embodiments, the compound of formula (I) is a salt of a compound selected from: [ka]

[0109] In another embodiment, the compound of formula (I) is a salt of a compound selected from: [ka]

[0110] In another embodiment, the compound of formula (I) is a salt of a compound selected from: [ka]

[0111] For example, in some embodiments, the salt of a compound of formula (I) is [ka] is the salt of.

[0112] Meanwhile, in yet another embodiment, the salt of the compound of formula (I) is [ka] is the salt of.

[0113] In some embodiments, the compound of formula (I) is a hydrochloride salt.

[0114] In some embodiments, the hydrochloride salt is [ka] It is.

[0115] In some embodiments, the compound of formula (I) is a phosphate addition salt.

[0116] Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues, is covalently linked to the free amino, hydroxy, and carboxylic acid groups of the compounds of formula (I). The amino acid residues include the 20 naturally occurring amino acids commonly designated by their three-letter symbols, and include: 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds containing carbonates, carbamates, amides, and alkyl esters that can be covalently linked to the above substituents of formula (I) through the carbonyl carbon prodrug side chain. Prodrugs also include phosphate derivatives (such as acids, acid salts, or esters) of the compounds of formula (I) linked to the free hydroxyl of the compounds of formula (I) through a phosphorus-oxygen bond. It will be understood that the invention disclosed and defined herein extends to all alternative combinations of two or more of the individual features mentioned or apparent from the text or drawings, all of these different combinations constituting various alternative aspects of the invention.

[0117] The compound of formula (I) or its salt, tautomer, N-oxide, polymorph or prodrug can be provided in the form of a solvate. A solvate contains either a stoichiometric or non-stoichiometric amount of a solvent and can be formed during the process of crystallization with a pharma- ceutically acceptable solvent such as water, alcohol such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethylformamide (DMF), etc., and the solvate forms part of the crystal lattice by non-covalent bonding or by occupying a hole in the crystal lattice. A hydrate is formed when the solvent is water, and an alcoholate is formed when the solvent is alcohol. A solvate of the compound of the present invention can be conveniently prepared or formed during the process described herein. In general, a solvated form is considered equivalent to a non-solvated form for the purposes of the compounds and methods provided herein.

[0118] Compounds of formula (I) or their salts, tautomers, N-oxides, solvates and / or prodrugs that form crystalline solids may exhibit polymorphism. All polymorphic forms of the compounds, salts, tautomers, N-oxides, solvates and / or prodrugs may be used in the methods of the invention.

[0119] The compound of formula (I) can exhibit tautomerism. Tautomers are two interchangeable forms of a molecule that generally exist in equilibrium. Any tautomer of the compound of formula (I) can be used in the method of the present invention.

[0120] Methods for making compounds of formula (I) are described in PCT / AU2016 / 050588.

[0121] Administration The compounds of formula (I) as defined herein or a pharma- ceutically acceptable salt or prodrug thereof may be administered by any suitable means, for example, orally, rectally, nasally, vaginally, topically (including buccal and sublingually), parenterally, for example, subcutaneously, intraperitoneally, intravenously, intramuscularly, or intracisternally, by inhalation, insufflation, injection or implantation techniques (for example, as a sterile injectable aqueous or non-aqueous solution or suspension).

[0122] The compounds of the present invention may be provided as pharmaceutical compositions, including those for oral, rectal, nasal, topical (including buccal and sublingual), parenteral administration (including intramuscular, intraperitoneal, subcutaneous and intravenous), or in a form suitable for administration by inhalation or insufflation.Thus, the compounds of formula (I), or pharma-ceutically acceptable salts or prodrugs thereof, together with conventional adjuvants, carriers or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be used as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled therewith, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

[0123] The pharmaceutical composition for administration of the compound of the present invention can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy (see, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins). All methods include the step of combining the active ingredient, e.g., a compound defined by formula (I), or a pharmaceutically acceptable salt or prodrug thereof, with a carrier that constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately combining the active ingredient, e.g., a compound defined by formula (I), or a pharmaceutically acceptable salt or prodrug thereof, with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect. In some embodiments, the methods of the present invention include administering a medicament comprising a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier, diluent and / or excipient.

[0124] The compound of formula (I), or a pharma- ceutically acceptable salt or prodrug thereof, can be administered at a dose of about 0.001, 0.005, 0.01, 0.05, 0.1, 0.15, 0.2, 0.5, 1, 2, 3, 5, 10, 15, 20, 25, or 30 mg / kg of the subject's body weight. In some embodiments, the dose may be from any of these amounts to any other amount, such as from about 0.001 mg / kg to about 30 mg / kg, from about 0.2 mg / kg to about 30 mg / kg, or from about 0.2 mg / kg to about 10 mg / kg. However, it will be understood that the specific dose level and frequency of administration for any particular subject may vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the particular condition, and the host being treated.

[0125] The compound of formula (I), or a pharma- ceutically acceptable salt or prodrug thereof, may be provided in an "effective amount", for example, when the appropriate compound is added to a pharmaceutical composition. An "effective amount" is taken to mean an amount of compound that induces a desired biological or medical response in a tissue, system, animal, or human, as desired by a researcher, veterinarian, physician, or other clinician administering the compound of a composition comprising the compound. In some embodiments, the effective amount may be a "therapeutically effective amount", where the amount of the subject active compound is effective to treat a condition and / or symptoms thereof as manifested in a subject. In other embodiments, the effective amount may be a "prophylactically effective amount", where the amount of the subject active compound is sufficient to prophylactically treat and / or prevent the onset of a condition and / or symptoms associated with opioid withdrawal, or, if symptoms appear, reduce the level of severity of the condition and / or symptoms thereof, as compared to the average severity of the condition and / or symptoms thereof in a population of subjects not treated with the compound of formula (I) and / or a pharma- ceutically acceptable salt and / or prodrug thereof.

[0126] An "effective amount" is an amount of a compound of Formula (I) provided herein, or a pharma- ceutically acceptable salt or prodrug thereof, the administration of which to a subject, either in a single dose or as part of a series, is effective to manage and / or prevent one or more symptoms of opioid withdrawal. An amount is effective, for example, if its administration results in one or more of the following: cessation of symptoms of opioid withdrawal, reduction in the severity of symptoms of opioid withdrawal, reduction in the period over which the subject experiences withdrawal symptoms, prevention of the severity of symptoms that do occur, prevention of the onset of symptoms of opioid withdrawal, and / or prevention of the worsening of symptoms of opioid withdrawal.

[0127] An "effective amount" will depend on many factors, including the potency of the particular compound, the physical condition of the subject being treated, the severity of the opioid withdrawal symptoms, the formulation of the compound, and / or a professional evaluation of the medical situation. The weight and age of the subject may also be factors for one of skill in the art when determining the amount of compound that a subject should receive.

[0128] In some embodiments, the methods of the present invention treat symptoms of opioid withdrawal, including psychological symptoms, physical symptoms, and / or somatic symptoms.

[0129] Physical and somatic symptoms of opioid withdrawal include tremors, shaking, hot or cold flashes, goose bumps, sweating, rapid breathing, increased heart rate, increased blood pressure, body pain, vomiting, diarrhea, and fever. In some embodiments, the method treats a physical and / or somatic symptom of opioid withdrawal. In some embodiments, the physical and / or somatic symptom is selected from tremors and shaking.

[0130] Psychological symptoms of opioid withdrawal include dysphoria, anxiety, restlessness, irritability, insomnia, yawning, hallucinations, hyperalgesia, hyperkatifiteia, and anorexia. Although these symptoms are not physical / somatic, they are symptoms of opioid withdrawal and are believed to result from physiological changes caused by cessation or reduction of opioid administration and / or induced by administration of an opioid antagonist. In some embodiments, the method treats dysphoria.

[0131] Opioid withdrawal symptoms include dysphoria, anxiety, restlessness, irritability, insomnia, yawning, hallucinations, tremors, shaking, hot or cold flashes, goosebumps, sneezing, sweating, rapid breathing, elevated heart rate, elevated blood pressure, dilated pupils, piloerection, headache, body pain, muscle spasms, myalgia, bone pain, joint pain, hyperalgesia, hypercathytheia, watery discharge from eyes and nose (lacrimation and rhinorrhea), nausea, vomiting, diarrhea, abdominal pain, loss of appetite, and fever.As mentioned above, one of the diagnostic tools developed for opioid withdrawal is the DSM-5.DSM-5 specifies that for a subject to be diagnosed with opioid withdrawal, three of the following nine symptoms must appear within minutes to days of either the cessation (or reduction) of opioid exposure or the administration of an opioid antagonist or partial agonist. The DSM-5 symptoms are: (1) dysphoria, (2) nausea, (3) myalgia, (4) lacrimation or rhinorrhea, (5) dilated pupils, piloerection or sweating, (6) diarrhea, (7) yawning, (8) fever, and (9) insomnia. Thus, in some embodiments, the subject experiences at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 of these DSM-5 symptoms, and preferably, administration of a compound of formula (I) treats at least one of the symptoms experienced by the subject.

[0132] The severity of withdrawal symptoms depends on the opioid causing the dependence, the dose and duration of treatment or abuse, how quickly opioid use is discontinued, and subject characteristics such as age, sex, and weight.

[0133] Thus, in some embodiments, the method treats an opioid withdrawal symptom selected from the group consisting of tremors, shaking, hot or cold flashes, goose bumps, sweating, rapid breathing, increased heart rate, increased blood pressure, body pain, vomiting, diarrhea, fever, malaise, anxiety, restlessness, irritability, insomnia, yawning, hallucinations, hyperalgesia, hypercatheterism, and anorexia, or a combination thereof.

[0134] The phrases "administration of" and / or "administering" a compound should be understood to mean providing an active compound of interest (e.g., a compound of Formula (I) (or a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id) or Formula (Ie)), or a pharma- ceutically acceptable salt or prodrug thereof; an opioid and / or an opiate or an opioid antagonist or partial agonist) to a subject in need thereof.

[0135] As provided herein, beneficial or desired clinical results from the disclosed compounds of formula (I), or pharma- ceutically acceptable salts or prodrugs thereof, include, but are not limited to, cessation of opioid withdrawal symptoms, reduction in the severity of opioid withdrawal symptoms, prevention of the onset of opioid withdrawal symptoms, and / or management of opioid withdrawal symptoms, e.g., preventing the severity of opioid withdrawal symptoms from worsening, or reducing the severity of symptoms or cessation of symptoms within a shorter time than would be expected. Either therapeutic or preventative measures may be achieved. Those in need of treatment include those already experiencing opioid withdrawal and those in whom opioid withdrawal should be prevented. Treatment refers to inhibiting or reducing the increase in opioid withdrawal symptoms compared to when no treatment is administered, and does not necessarily refer to a complete cessation of the condition.

[0136] Thus, in general, the term "treatment" (and variations thereof, including "treating") means affecting a subject, tissue, or cell to obtain a desired pharmacological and / or physiological effect, including (a) cessation of opioid withdrawal symptoms, (b) reducing the severity of opioid withdrawal symptoms, (c) shortening the period over which a subject experiences withdrawal symptoms, (d) preventing the severity of symptoms that do occur, (e) preventing the onset of opioid withdrawal symptoms, and / or (f) preventing the worsening of opioid withdrawal symptoms. In some embodiments, the symptoms treated are physical and / or somatic symptoms of opioid withdrawal. Reference to managing opioid withdrawal in the context of the methods disclosed herein is intended to encompass treating opioid withdrawal by affecting any of these desired pharmacological and / or physiological effects, within the limits of the subject's tolerance to opioid withdrawal symptoms.

[0137] In another aspect, there is also provided a method of treating and / or managing opioid withdrawal, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof.

[0138] In another embodiment, there is also provided a method of treating and / or controlling opioid withdrawal symptoms, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof.

[0139] In another aspect, there is also provided the use of a compound of formula (I), or a pharma- ceutically acceptable salt or prodrug thereof, in the preparation of a medicament for: Treatment, management and / or control of symptoms associated with opioid withdrawal; and / or Treatment and / or management of opioid withdrawal.

[0140] In another aspect, there is also provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof for: Treatment, management and / or control of symptoms associated with opioid withdrawal; and / or Treatment and / or management of opioid withdrawal.

[0141] In another aspect, there is also provided a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof for use in: Treatment, management and / or control of symptoms associated with opioid withdrawal; and / or Treatment and / or management of opioid withdrawal.

[0142] In another aspect, there is also provided a composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof for use in: · Treating, managing and / or controlling physiological symptoms associated with opioid withdrawal; ·Treatment and / or management of opioid withdrawal.

[0143] Any of the embodiments described herein in relation to the administration steps or compounds of the invention may be used in these compounds, compositions, uses and / or methods.

[0144] kit A kit of parts is also provided, comprising in separate parts: a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof, and · instructions for its use in any of the methods of the invention.

[0145] A kit of parts is also provided, comprising in separate parts: A compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof, and Opioids and / or opiates.

[0146] In some embodiments, the portion comprising an opioid and / or opiate comprises the opioid and / or opiate in a multiple unit dosage form, such as one suitable for a tapering regimen.

[0147] A kit of parts is also provided, comprising in separate parts: A compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof, and ·Opioid antagonists and / or partial agonists.

[0148] In any of the kits disclosed herein, the compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof, and / or the opioid and / or opiate, and / or the opioid antagonist and / or partial agonist may be formulated as a pharmaceutical composition together with a pharma- ceutically acceptable carrier, diluent and / or excipient. The pharmaceutical composition may be formulated for administration by any route disclosed herein, including in a form suitable for oral, rectal, nasal, topical (including buccal and sublingual), parenteral (including intramuscular, intraperitoneal, subcutaneous and intravenous) administration, or administration by inhalation or insufflation.

[0149] composition In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof, and an opioid and / or an opiate.

[0150] Any compound of formula (I) described herein, or a salt and / or prodrug thereof, may be included in these compositions.

[0151] Any of the opioids and / or opiates described herein may be included in these compositions.

[0152] In some embodiments, the opioid and / or opiate are provided in an effective amount, which may be any amount that presents a subject with a risk of opioid withdrawal, hi other embodiments, the opioid and / or opiate are provided in an amount suitable for administration by a tapering regimen.

[0153] Pharmaceutical compositions comprising a compound of formula (I) or salts and / or prodrugs thereof, and an opioid and / or opiate, may be prepared in any of the forms described herein for administering a compound of formula (I), including for oral, rectal, nasal, topical (including buccal and sublingual), parenteral (including intramuscular, intraperitoneal, subcutaneous and intravenous) administration, or in a form suitable for administration by inhalation or insufflation.

[0154] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt and / or prodrug thereof, and an effective amount of an opioid antagonist and / or partial agonist.

[0155] Any compound of formula (I) described herein, or a salt and / or prodrug thereof, may be included in these compositions.

[0156] Any of the opioid antagonists and / or partial agonists described herein can be included in these compositions.

[0157] Pharmaceutical compositions comprising the compounds of formula (I) or salts and / or prodrugs thereof, and opioid antagonists and / or partial agonists may be prepared in any of the forms described herein for administering the compounds of formula (I), including for oral, rectal, nasal, topical (including buccal and sublingual), parenteral (including intramuscular, intraperitoneal, subcutaneous and intravenous) administration, or in a form suitable for administration by inhalation or insufflation.

[0158] The pharmaceutical composition typically further comprises a pharma- ceutically acceptable carrier, diluent and / or excipient. Any conventional carrier, diluent and / or excipient may be included as known in the art of pharmacy (see, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins).

[0159] The pharmaceutical compositions described herein may be used in any of the methods described herein. EXAMPLES

[0160] Example 1 This example describes experiments in a C57BL / 6 mouse model of opioid withdrawal (naloxone-induced withdrawal following oxycodone administration) and the potential of compounds of the invention to treat withdrawal symptoms.

[0161] [Table 1]

[0162] Drugs All drugs used in this study were dissolved in saline and administered in a volume of 10 ml / kg.

[0163] Experiment 1.1: Effects of CMPD1-2HCL on locomotor activity in an open-field study The aim of this experiment was to demonstrate that CMPD1-2HCL at doses of 5 and 10 mg / kg did not cause any potentially confounding effects on locomotor activity. N=18 adult male C57BL / 6 mice received 0, 5 or 10 mg / kg CMPD1-2HCL (ip; n=6 per condition). 15 min after receiving an intraperitoneal injection of CMPD1-2HCL, mice were placed individually in a new 40(l)×40(w)×40(h) cm locomotor testing arena. The session was captured by an overhead camera and the videos were analyzed by using the automated behavior tracking software CleverSys Topscan (CleverSys, Virginia, USA), which provided the distance traveled by each mouse in each 5-min time bin over the 60-min locomotor testing session. Data were analyzed by SPSS using mixed-model ANOVA.

[0164] The results of this experiment are shown in Tables 1 to 3 and FIG.

[0165] [Table 2]

[0166] [Table 3]

[0167] [Table 4]

[0168] The results of this experiment show that CMPD1-2HCL treatment does not significantly affect the locomotor activity of the subjects. Although there was a significant decrease in locomotor activity over time, this decrease was consistent across treatment groups (including controls), indicating that it was a time effect and not related to treatment. The amount of locomotor activity differed across 5-minute bins, averaged across treatment doses [F11,165=29.5, p<0.0001]. There was no significant main effect of CMPD1-2HCL dose [F2,15=0.997, p=0.392] or significant time by dose interaction effect on the distance traveled by mice throughout the test session [F22,165=1.358, p=0.143].

[0169] Experiment 1.2: Evaluation of the effects of CMPD1-2HCL on naloxone-induced oxycodone withdrawal Adult male C57BL / 6 mice (N=40) were assigned to one of five conditions (n=8 per condition): (1) Vehicle, 0 mg / kg CMPD1-2HCL; (2) oxycodone, 0 mg / kg CMPD1-2HCL; (3) oxycodone, 2.5 mg / kg CMPD1-2HCL; (4) oxycodone, 5 mg / kg CMPD1-2HCL; or (5) Oxycodone, 10 mg / kg CMPD1-2HCL.

[0170] Mice under oxycodone conditions received intraperitoneal injections of oxycodone for 5 days according to the schedule and doses shown in Table 1. Morning and afternoon doses were separated by 7 hours. Mice under vehicle conditions received injections of the vehicle saline instead of oxycodone. 1 hour and 45 minutes after the morning injection on the fifth day, mice were administered CMPD1-2HCL intraperitoneally. 15 minutes later, mice received an intraperitoneal injection of 10 mg / kg naloxone (oxycodone group) or saline (vehicle group) and immediately proceeded to testing.

[0171] [Table 5]

[0172] Testing involved placing mice individually in a 20(l) x 20(w) x 30(h) cm arena for 30 min. Sessions were captured via a side-view high-speed (120 fps), high-resolution (4K) camera. Number of jumps and total duration of paw tremor were scored from the video by an experienced experimenter blinded to condition.

[0173] Data were analyzed by SPSS using one-way ANOVA and planned contrasts.

[0174] jumping The jumping data are shown in Table 5 and FIG. 2A.

[0175] [Table 6]

[0176] The overall ANOVA assessing jumping was significant [F4,35=10.51, p<0.0001]. Planned contrasts revealed that mice undergoing oxycodone withdrawal jumped significantly more times during the test session [VEH 0CMPD1 vs. OXCD 0CMPD1, p<0.000001].

[0177] CMPD1-2HCL significantly inhibited oxycodone withdrawal-induced jumping at all doses tested [OXCD 0CMPD1 vs. OXCD 2.5CMPD1, p=0.023; OXCD 5CMPD1, p=0.018; OXCD 10CMPD1, p<0.001].

[0178] CMPD1-2HCL treated mice still showed elevated jumping compared to mice not undergoing oxycodone withdrawal [VEH 0CMPD1 vs. OXCD 2.5CMPD1, p=<0.001; OXCD 5CMPD1, p<0.001; OXCD 10CMPD1, p=0.011].

[0179] Foot tremors Paw tremor data are shown in Table 6 and FIG. 2B.

[0180] [Table 7]

[0181] The overall ANOVA assessing paw tremor was significant [F4,35=3.97, p<0.01]. Planned contrasts revealed that mice undergoing oxycodone withdrawal had paw tremors for significantly longer periods during the test session [VEH 0CMPD1 vs. OXCD 0CMPD1, p<0.01]. The highest dose of CMPD1-2HCL significantly inhibited oxycodone withdrawal-induced paw tremor [OXCD 0CMPD1 vs. OXCD 2.5CMPD1, p=0.898; OXCD 5CMPD1, p=0.083; OXCD 10CMPD1, p=0.033]. Mice treated with 5 and 10 mg / kg CMPD1-2HCL no longer had significantly elevated paw tremors compared to mice not undergoing oxycodone withdrawal [VEH 0CMPD1 vs. OXCD 2.5CMPD1, p=<0.01; OXCD 5CMPD1, p=0.204; OXCD 10CMPD1, p=0.4].

[0182] conclusion CMPD1-2HCL does not suppress locomotor activity in an open field locomotor test at the doses used in this study (Experiment 1). CMPD1-2HCL dose-dependently inhibited the dysphoric and somatic symptoms of oxycodone withdrawal (jumping and leg tremors) in Experiment 2. Overall, CMPD1-2HCL shows a significant and consistent therapeutic effect on withdrawal-induced jumping (a physical and / or somatic symptom of opioid withdrawal and escape behavior that reflects the intense dysphoric state induced by opioid withdrawal) and leg tremors (another somatic symptom induced by opioid withdrawal).

[0183] Example 2 In this example, the ability of Compound 1 to inhibit naloxone-induced opioid withdrawal-induced c-fos protein expression in the brain was studied. c-fos is a protein marker of neuronal activation. Compound 1 was administered in the dihydrochloride form (CMPD1-2HCL).

[0184] method N=40 male C57BL / 6 mice were assigned to one of four conditions: (1) VEH, VEH (n=10) (2) VEH, CMPD1-2HCl (n=10) (3) OXY, VEH (n = 10) (4) OXY, CMPD1-2HCl (n=10)

[0185] Mice under oxycodone (OXY) conditions received intraperitoneal injections of increasing doses of oxycodone at 9, 17.8, 23.7, and 33 mg / kg (twice a day on days 1-8, with increasing doses every other day) for 9 days. Morning and afternoon doses were separated by 7 hours. Mice under vehicle conditions (VEH) received injections of the vehicle saline instead of oxycodone. 1 hour 45 minutes after the morning injection on day 9, mice were administered an intraperitoneal dose of CMPD1-2HCL (10 mg / kg, injection volume 10 mg / ml) or VEH. 15 minutes later, mice received an intraperitoneal injection of 10 mg / kg naloxone (OXY group) or saline (VEH group) to induce withdrawal.

[0186] Seventy-five minutes after naloxone or saline injection, mice were euthanized by sodium pentobarbitone overdose and subjected to intracardiac puncture perfusion fixation with 4% paraformaldehyde, and then brains were collected for immunohistochemical processing.

[0187] Data were analyzed using two-way ANOVA and planned contrasts with SPSS.

[0188] result There was a statistically significant interaction between CMPD1-2HCL treatment and opioid withdrawal, identifying eight brain regions in which administration of CMPD1-2HCL also significantly inhibited withdrawal-induced neuronal activation.

[0189] The c-Fos count results obtained from these brain regions are shown in Figure 3a-h and include brain regions known to play an important role in the expression of opioid withdrawal symptoms.

[0190] Example 3 In this example, the ability of CMPD1-2HCL to inhibit gastrointestinal symptoms of opioid withdrawal was evaluated using a mouse model.

[0191] method Adult male C57BL / 6 mice (n=30) were assigned to one of four conditions (n=10 per condition): (1) VEH, VEH (n=10) (2) OXY, VEH (n = 10) (3) OXY, CMPD1-2HCL (n=10)

[0192] Mice under oxycodone condition (OXY) received intraperitoneal injections of oxycodone for 5 days according to the schedule and doses shown in Table 7. Morning and afternoon doses were separated by 7 hours. Mice under vehicle condition received injections of vehicle saline instead of oxycodone. 1 hour 45 minutes after the morning injection on the 5th day, mice were administered CMPD1-2HCL (10 mg / kg) intraperitoneally. 15 minutes later, mice received an intraperitoneal injection of 10 mg / kg naloxone (oxycodone group) or saline (vehicle group) and immediately proceeded to the test.

[0193] [Table 8]

[0194] The test involved placing mice individually in a 20(l) x 20(w) x 30(h) cm arena for 30 min. At the end of the session, feces were counted to determine whether the mice had diarrhea.

[0195] Data were analyzed using ANOVA and planned contrasts for feces and Fisher's exact test for diarrhea.

[0196] feces See Figure 4. Opioid withdrawal significantly increased the amount of feces produced during the 30 minute session (p<0.001), which was significantly inhibited by CMPD1-2HCL treatment (p<0.001).

[0197] diarrhea Opioid withdrawal significantly increased the number of mice suffering from diarrhea, which was inhibited by CMPD1-2HCL (see Table 8).

[0198] [Table 9]

[0199] Example 4 This example describes experiments in a C57BL / 6 mouse model of opioid withdrawal (naloxone-induced withdrawal following oxycodone administration) and the potential of Compound 1, in two different salt forms administered at the same free base equivalent dose, to treat withdrawal symptoms.

[0200] Experiment 2.1: Evaluation of the effects of CMPD1-2HCL and CMPD1-PO4 on naloxone-induced oxycodone withdrawal Two cohorts of adult male C57BL / 6 mice were evaluated for the effect of 7.3 mg / kg free base equivalent (FBE) IP Compound 1 in the dihydrochloride salt form (CMPD1-2HCL) and the phosphate addition salt form (CMPD1-PO4) on naloxone-induced withdrawal-induced jumping.

[0201] The first cohort of mice (N=30) was divided into the following conditions: (1) vehicle, 0 mg / kg (n=10); (2) oxycodone, 0 mg / kg 2HCl salt form of compound 1 FBE (n=10); (3) Oxycodone, 7.3 mg / kg 2HCl salt form of Compound 1 FBE (n=10).

[0202] A second cohort of mice (N=24) was divided into the following conditions: (1) vehicle, 0 mg / kg (n=8); (2) oxycodone, 0 mg / kg phosphate addition salt form of compound 1 FBE (n=8); (3) Oxycodone, 7.3 mg / kg phosphate addition salt form Compound 1 FBE (n=8).

[0203] Mice under oxycodone condition received intraperitoneal injections of oxycodone for 5 days according to the schedule and doses shown in Table 9. Morning and afternoon doses were separated by 7 hours. Mice under vehicle condition received injections of vehicle saline instead of oxycodone. 1 hour 45 minutes after the morning injection on the 5th day, mice were administered an intraperitoneal dose of Compound 1. 15 minutes later, mice received an intraperitoneal injection of 10 mg / kg naloxone (oxycodone group) or saline (vehicle group) and immediately proceeded to testing.

[0204] [Table 10]

[0205] Testing involved placing mice individually into a 20(l) × 20(w) × 30(h) cm arena for 30 min. Sessions were captured via a side-view high-speed (120 fps), high-resolution (4K) camera. Jumping counts were scored from the video by an experienced experimenter blinded to condition.

[0206] Data were analyzed by SPSS using one-way ANOVA and planned contrasts.

[0207] jumping Jumping data is shown in Figure 5. Data from cohort 1 mice are shown as square symbols and data from cohort 2 mice are shown as circle symbols.

[0208] The overall ANOVA assessing jumping was significant [F3,50=21.52, p<0.0001]. Planned contrasts revealed that mice undergoing oxycodone withdrawal jumped significantly more times during the test session [VEH_VEH vs. OXY_VEH, p<0.0001].

[0209] FBE compound 1 at 7.3 mg / kg significantly inhibited oxycodone withdrawal-induced jumping at all doses tested in both H3PO4 (CMPD1-PO4) and 2HCl (CMPD1-2HCL) addition salt forms [OXY_VEH vs. OXY_CMPD1-PO4, p<0.01; OXY_CMPD1-2HCL, p<0.001]. Moreover, the results after administration of FBE in the two salt forms did not significantly differ from each other in withdrawal-induced jumping [OXY_CMPD1-PO4 vs. OXY_2HCL, p=0.901] (see FIG. 5).

Claims

1. 2. An agent for treating opioid withdrawal or symptoms associated with said opioid withdrawal, comprising a compound of formula (Ia) (In the formula: Z is NH, O, S, S(O) or SO ２ Selected from: R １ is H or C(O)R ４ Selected from: R ２ H, OH, halogen, C １～５ Alkyl or O １～５ alkyl; R ３ H, OH, halogen, C １～５ Alkyl or O １～５ alkyl; R ４ is C １～５ is alkyl, Any C 1-5 alkyl group may be optionally substituted with one or more substituents selected from OH, NH 2 , halogen, NH(C 1-5 alkyl), N(C 1-5 alkyl) 2 , CN, NO 2 , CO 2 H, and OC 1-5 alkyl; Any OC 1-5 alkyl group may be optionally substituted with one or more substituents selected from OH, NH 2 , halogen, NH(C 1-5 alkyl), N(C 1-5 alkyl) 2 , CN, NO 2 , CO 2 H, and OC 1-5 alkyl. or a pharma- ceutically acceptable salt thereof.

2. The compound of formula (Ia) 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

3. 3. The method of claim 1, wherein the agent is for administration to a subject who has been exposed to an opioid and / or opiate, and the agent is for administration beginning after cessation of opioid and / or opiate exposure.

4. 3. The method of claim 1, wherein the agent is for administration to a subject who has been exposed to an opioid and / or opiate, and the agent is for administration beginning simultaneously with the last dose of the opioid and / or opiate.

5. 3. The method of claim 1, wherein the agent is for administration to a subject who has been exposed to an opioid and / or opiate, and the agent is for initiation of administration prior to cessation of the opioid and / or opiate exposure.

6. The agent according to any one of claims 1 to 5, further comprising an opioid and / or an opiate.

7. The agent according to any one of claims 1 to 6, wherein the agent is for administering opioids and / or opiates according to a tapering dosing regimen.

8. 8. The method of claim 7, wherein the agent is for administration beginning prior to the initiation of opioid / opiate dose tapering.

9. 8. The method of claim 7, wherein the agent is for administration commencing simultaneously with the initiation of an opioid / opiate dose taper.

10. 8. The method of claim 7, wherein the agent is for administration beginning after completion of opioid / opiate dose tapering.

11. The method of any one of claims 1 to 10, wherein the agent is for sustained administration for at least about one week.

12. 12. The agent according to any one of claims 1 to 11, wherein the symptoms are selected from the group consisting of tremors, shaking, hot or cold flashes, goose bumps, sweating, fast breathing, increased heart rate, increased blood pressure, body pain, vomiting, diarrhea, fever, discomfort, anxiety, restlessness, irritability, insomnia, yawning, hallucinations, hyperalgesia, hyperkatifyia and anorexia, or a combination thereof.

13. The agent according to any one of claims 1 to 12, comprising a pharma- ceutically acceptable carrier, diluent and / or excipient.

14. - a compound of formula (Ia) as defined in claim 1 or 2 or a pharma- ceutically acceptable salt thereof; and Opioids and / or opiates 13. A kit for treating opioid withdrawal or a symptom associated with said opioid withdrawal comprising in separate parts:

15. 15. The kit of claim 14, wherein the opioid and / or opiate is provided in multiple dosage forms suitable for a tapering regimen.

16. - a compound of formula (Ia) as defined in claim 1 or 2 or a pharma- ceutically acceptable salt thereof; and Opioid antagonists and / or partial agonists 13. A kit for treating opioid withdrawal or a symptom associated with said opioid withdrawal comprising in separate parts:

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