Organic compounds

Abstract

The present invention relates to specific enantiomers of the substituted heterocyclic fused gamma-carbolines described herein in free, solid, pharma- ceutical acceptable salt and / or substantially pure form, pharmaceutical compositions thereof, and 5-HT 2A The present invention relates to methods of use in treating diseases associated with receptors and pathways related to the dopamine D1 and D2 receptor signaling systems.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to and the benefit of U.S. Provisional Application No. 63 / 269,304, filed March 14, 2022, the contents of which are hereby incorporated by reference in their entirety.

[0002] The present invention relates to certain substituted heterocyclic fused gamma-carbolines, in free, solid, pharma- ceutical acceptable salt and / or substantially pure form, as described herein, pharmaceutical compositions thereof, and 5-HT 2A The present invention relates to methods of use and combinations with other agents for the treatment of diseases or disorders such as those associated with receptors, serotonin transporter (SERT), pathways associated with dopamine D1 and / or D2 receptor signaling systems, and / or μ-opioid receptors, such as anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, pain-related conditions (including head pain, neuropathic pain, and as acute analgesic), fibromyalgia, chronic fatigue, social phobia, gastrointestinal disorders, such as gastrointestinal motility dysfunction and obesity; depression and mood disorders, such as those associated with psychosis or Parkinson's disease; psychosis, such as schizophrenia associated with depression; bipolar disorder; drug dependence, such as opioid dependence and alcohol dependence, drug withdrawal symptoms; obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD) and related disorders; and other psychiatric and neurological conditions. In some embodiments, the disease or disorder may include treatment-resistant depression, cocaine and / or amphetamine dependence, opioid use disorder, and symptoms of opioid withdrawal. [Background technology]

[0003] Substituted heterocyclic fused gamma-carbolines have been shown to inhibit the 5-HT2 receptor, particularly the 5-HT 2AThese compounds are known to be agonists or antagonists of the 5-HT receptor. These compounds are disclosed in U.S. Patent Nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, 7,183,282, U.S. Patent Reissue No. 39,680 and U.S. Patent Reissue No. 39,679. 2A They have been disclosed as novel compounds useful for treating disorders associated with receptor modulation, such as obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, conditions associated with head pain, social phobia, gastrointestinal disorders, such as gastrointestinal motility dysfunction and obesity. U.S. Patent No. 8,309,722 and U.S. Patent No. 7,081,455 also disclose methods for making substituted heterocyclic fused gamma-carbolines, and the use of these gamma-carbolines as serotonin agonists and antagonists useful for controlling and preventing central nervous system disorders, such as addictive behaviors and sleep disorders.

[0004] One particular fused heterocyclic gamma carboline, 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, now known as lumateperone, is disclosed, for example, in US 8,598,119, US 11,053,245, US 11,124,514 and US 9,956,227 for treating a variety of neurological disorders. This compound is a potent serotonin 5-HT 2A It is a receptor antagonist, a dopamine receptor D1 and D2 modulator, and a serotonin transporter (SERT) antagonist. New indications for this compound based on recent evidence indicate that it may also act in part through NMDA receptor antagonism via mTOR1 signaling in a manner similar to that of ketamine, as disclosed in US2021 / 060009, the contents of which are hereby incorporated by reference in their entirety.

[0005] Nos. 10,245,260 and 10,799,500 disclose novel fused heterocyclic gamma-carbolines that have been unexpectedly found to exhibit a potent combination of serotonin receptor inhibition, SERT inhibition, dopamine receptor modulation and mu-opiate receptor biased agonism, the contents of which are hereby incorporated by reference in their entireties.

[0006] The compound of formula A shown below is disclosed in these patents, as well as in US2021 / 0145829. This compound is a potent serotonin 5-HT 2A It is a receptor antagonist and a mu-opiate receptor partial or biased agonist. This compound also interacts with dopamine receptors, specifically the dopamine D1 receptor, but has only weak SERT antagonist activity.

[0007] [ka]

[0008] It is also believed that the compounds of formula A, via their D1 receptor activity, may enhance NMDA and AMPA mediated signaling through the mTOR pathway.The compounds of formula A are therefore useful for treating or preventing central nervous system disorders.

[0009] The enantiomer of the above compound is formula B below and is disclosed in WO2020 / 132474 and US2022 / 0056031. [ka]

[0010] It has been unexpectedly discovered that the compound of formula B, which is an enantiomer of the compound of formula A, has no SERT activity, moderately strong D1 receptor binding and serotonin receptor inhibition, and only weak mu receptor activity. To put this in perspective, the binding affinities of the compounds of formula A and formula B can be qualitatively compared as follows: [ka] Thus, the compound of formula A is a 5-HT 2A In contrast to compounds of formula A, compounds of formula B have similar potency at 5-HT 2A It is well known that enantiomers of a pharmacologically active compound have different or opposite activities, e.g., one enantiomer is active and the other inactive, but the compound of formula B may have the same activity as its enantiomer, compound of formula A, only at the D1 and D2 receptors, and furthermore has the same activity as 5-HT 2A It is unexpected and unpredictable that the compound of formula B may have completely different relative activities at the SERT and mu-opiate receptors. Moreover, the pharmacological profile of the compound of formula B is also completely different from that of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, which has a somewhat similar structure and is also known as lumateperone. Summary of the Invention [Problem to be solved by the invention]

[0011] In yet another new and unexpected development, it has been discovered that diastereoisomers of the compounds of formula A and B, which have trans-stereochemistry across the central bridge, have unexpectedly unique activities compared to both cis-stereoisomers. Unlike the compounds of formula A and B, the compounds of formula I of the present disclosure inhibit serotonin 5-HT 2A It has no receptor activity and no SERT activity, but has very strong mu-opiate receptor binding and dopamine D1 receptor binding, and moderate D2 receptor binding.

[0012] This unexpected activity profile shows a relative increase at mu and D1 receptors, weak D2 receptor activity, and 5-HT 2A Based on this pharmacological activity, which is lacking in SERT activity, new means for treating diseases are provided. For example, these compounds can be used in combination with a compound of formula A or B and another antidepressant (e.g., a SERT inhibitor or a 5-HT 2A This can be useful when additive effects of different inhibitors (such as ribozymes) may be undesirable. [Means for solving the problem]

[0013] In a first aspect, the disclosure provides a compound of formula I, in free or salt form (e.g., a pharma- ceutically acceptable salt form): [ka] The compound of formula I relates to a compound having trans-stereochemistry across the 6b-10a ring fusion (Compound I). The compound of formula I is understood to include both of the following diastereoisomers, compounds of formulas IA and IB, and any combinations thereof (including racemic, 50:50 combinations), in free or salt form (e.g., pharma-ceutically acceptable salt form).

[0014] [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present disclosure provides further exemplary embodiments of compounds of formula I, in free or salt form (e.g., a pharma- ceutically acceptable salt form), e.g., isolated or purified free or salt form (e.g., a pharma- ceutically acceptable salt form), including: 1.1 Compound I, wherein the compound is in free form (free base form). 1.2 Compound I, wherein the compound is in the form of a salt. 1.3 Compound I, wherein the compound is in the form of a pharma- ceutically acceptable salt. 1.4 Compound I, wherein the compound is in the form of an acid addition salt, for example in the form of a hydrochloric acid or toluenesulfonic acid addition salt. 1.5 Compound I or any of 1.1-1.4 in a solid form, e.g., a crystalline form. 1.6 Compound I or any of 1.1-1.5, wherein the compound is a compound of formula 1A, e.g., free or substantially free of a compound of formula 1B. 1.7 Compound I or any of 1.1-1.5, wherein the compound is a compound of formula 1B, e.g., free or substantially free of a compound of formula 1A. 1.8 "Substantially free" means that the compound has less than 10 wt.%, or less than 8 wt.%, or less than 6 wt.%, or less than 5 wt.%, or less than 4 wt.%, or less than 3 wt.%, or less than 2 wt.%, or less than 1 wt.% of the isomer that is substantially free of compound 1.6 or 1.7. 1.9 Compound 1.6 or 1.7, in which the ratio between the isomers in favor of the dominant isomer is at least 90:10, or 92:8, or 94:6, or 95:5, or 96:4, or 97:3, or 98:2, or 99:1, or greater than 99:1 by weight. 1.10 Compound I or any of 1.1-1.5, wherein compound I is a mixture of compounds of formula IA and IB. 1.11 Compound I is racemic, for example, compound 1.10, in a 50:50 molar ratio of compound of formula IA to compound of formula 1B. 1.12 Compound 1.10, in which compound I has a molar excess of compounds of formula 1A, for example at least 55 mol%, or at least 60 mol%, or at least 65 mol%, or at least 70 mol%, or at least 75 mol%, or at least 80 mol%, or at least 85 mol%, or at least 90 mol%, or at least 95 mol% of compounds of formula 1A, measured from the total amount of compounds of formula I (i.e. not taking into account any compounds other than the compounds of formulae 1A and 1B). 1.13 Compound 1.10, in which compound I has a molar excess of compounds of formula 1B, for example at least 55 mol%, or at least 60 mol%, or at least 65 mol%, or at least 70 mol%, or at least 75 mol%, or at least 80 mol%, or at least 85 mol%, or at least 90 mol%, or at least 95 mol% of compounds of formula 1B, measured from the total amount of compounds of formula I (i.e. not taking into account any compounds other than the compounds of formulae 1A and 1B). 1.14 Compound I or any of 1.1-1.5, wherein compound I is a substantially pure diastereoisomer of a compound of formula 1A, e.g., having 5 mol % or less of a compound of formula 1B, e.g., 4 mol % or less, or 3 mol % or less, or 2 mol % or less, or 1 mol % or less, or 0.5 mol % or less, or 0.25 mol % or less, or 0.15 mol % or less, or 0.1 mol % or less, or 0.05 mol % or less, or 0.01 mol % or less of a compound of formula 1B, measured from the total amount of compounds of formula I (i.e. not taking into account any compounds other than compounds of formulae 1A and 1B). 1.15 Compound I or any of 1.1-1.5, wherein compound I is a substantially pure diastereoisomer of a compound of formula 1B, e.g., having 5 mol % or less of a compound of formula 1A, e.g., 4 mol % or less, or 3 mol % or less, or 2 mol % or less, or 1 mol % or less, or 0.5 mol % or less, or 0.25 mol % or less, or 0.15 mol % or less, or 0.1 mol % or less, or 0.05 mol % or less, or 0.01 mol % or less of a compound of formula 1A, measured from the total amount of compounds of formula I (i.e. not taking into account any compounds other than the compounds of formulae 1A and 1B). 1.16 Compounds 1.6-1.9, or any of 1.14 or 1.15, wherein the compound is prepared using an asymmetric synthesis process. 1.17 Compound I or any of 1.1-1.16, where the compound is prepared using a synthetic process that includes an enantiomer separation step(s), e.g., chiral chromatography or diastereoisomeric resolution. 1.18 Compound I or any of 1.1-1.17, wherein the compound is substantially free of any of the Compounds of Formula A, e.g., having e.g., 5 wt.% or less of compounds of formula A, measured based on the total weight of the compound, e.g., 4 wt.% or less, or 3 wt.% or less, or 2 wt.% or less, or 1 wt.% or less, or 0.5 wt.% or less, or 0.25 wt.% or less, or 0.15 wt.% or less, or 0.1 wt.% or less, or 0.05 wt.% or less, or 0.01 wt.% or less of compounds of formula A. 1.19 Compound I or any of 1.1-1.18, wherein the compound is substantially free of any of the Compounds of Formula B, e.g., having 5 wt.% or less of compounds of formula B, measured based on the total weight of the compound, e.g., 4 wt.% or less, or 3 wt.% or less, or 2 wt.% or less, or 1 wt.% or less, or 0.5 wt.% or less, or 0.25 wt.% or less, or 0.15 wt.% or less, or 0.1 wt.% or less, or 0.05 wt.% or less, or 0.01 wt.% or less of compounds of formula B. 1.20 Compound I or any of 1.1-1.19, wherein the compound is in substantially pure form, e.g., at least 90%, or at least 95%, or at least 98%, or at least 99% pure relative to all compounds or impurities present other than any compound of formula I.

[0016] As used hereinafter, "a compound of the invention" refers to a compound of any of Formulas I or 1.1-1.20.

[0017] In a second aspect, the disclosure provides a pharmaceutical composition (Pharmaceutical Composition I) comprising a compound according to any one of Formula I or compounds 1.1-1.20, e.g., in admixture with a pharma- ceutically acceptable diluent or carrier. In certain embodiments, the compound of Formula I or any one of Formulas 1.1-1.20 is in a pharma- ceutically acceptable salt form. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule, e.g., for gastrointestinal absorption (i.e., absorption through the stomach and / or the large and small intestines). In some embodiments, the pharmaceutical composition is an oral transmucosal composition, e.g., an orally dissolving tablet, wafer, film, gel, or spray. For example, the composition can be a fast dissolving sublingual or buccal tablet, wafer, film, or gel. In some embodiments, the pharmaceutical composition is formulated for intranasal or pulmonary administration (e.g., as an aerosol, mist, or powder for inhalation). In some embodiments, the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous, or intraperitoneal injection. In particular, pharmaceutical compositions for intramuscular or subcutaneous injection may be in the form of long-acting injectable or depot compositions, e.g., which provide sustained or delayed release of the compounds of the invention into the bloodstream and body tissues. Alternatively, particularly when formulated for intravenous, intrathecal, intraperitoneal or subcutaneous injection, the compositions may be immediate-acting compositions, e.g., which immediately release most or all of the dose into the body fluids.

[0018] In further embodiments, the pharmaceutical compositions of the present disclosure are for sustained or delayed release formulations (pharmaceutical composition 1-A), such as depot formulations. In some embodiments, the compound of any of formulas I or 1.1-1.20 is provided in the form of an injectable depot that provides sustained or delayed release of the compound, preferably in free or pharma- ceutical acceptable salt form, in admixture with a pharma- ceutical acceptable diluent or carrier.

[0019] In certain embodiments, pharmaceutical composition 1-A comprises a compound according to any one of Compound I or 1.1-1.16 in free base or pharma- ceutically acceptable salt form, optionally in crystalline form, where the compound is ground into microparticles or nanoparticles, e.g., particles or crystals having a volumetric particle size (e.g., diameter or Dv50) of 0.5 to 100 microns, e.g., 5 to 30 microns, 10 to 20 microns, 20 to 100 microns, 20 to 50 microns, or 30 to 50 microns, or the compound is crystallized into said size. Such particles or crystals can be combined with a suitable pharma- ceutically acceptable diluent or carrier, e.g., water, to form a depot formulation for injection. For example, the depot formulation can be formulated for intramuscular or subcutaneous injection with a dosage of drug suitable for 4 to 6 weeks of treatment. In some embodiments, the particles or crystals are ground into microparticles or nanoparticle ...1 to 5 microns, e.g., 5 to 3 2 / g, e.g. 0.5 to 3.3m 2 / g or 0.8 to 1.2m 2 / g surface area.

[0020] In another embodiment, the present disclosure provides pharmaceutical composition IB, which is pharmaceutical composition I, and the compound of formula I is a polymer matrix. In one embodiment, the compound of the present disclosure is dispersed or dissolved in the polymer matrix. In a further embodiment, the polymer matrix comprises a polymer selected from standard polymers used in depot formulations, such as polyesters of hydroxy fatty acids and their derivatives, or polymers of alkyl alpha-cyanoacrylates, polyalkylene oxalates, polyorthoesters, polycarbonates, polyortho-carbonates, polyamino acids, hyaluronic acid esters and mixtures thereof. In a further embodiment, the polymer is selected from the group consisting of polylactide, poly d,l-lactide, polyglycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymers. In another embodiment, the polymer is selected from poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactones, polydioxanones, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactones), polyorthoesters, poly(glycolic acid-caprolactones), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as glycerol mono- and distearate. In a preferred embodiment, the polymer matrix comprises poly(d,l-lactide-co-glycolide), such as PLGA having a molar ratio of 50:50 to 90:10. In some embodiments, the PLGA is miscible with a solvent carrier, such as an aqueous solvent, an aqueous emulsion, or a non-aqueous organic solvent (preferably a pharma- ceutically acceptable organic solvent). Suitable organic solvents may include propylene glycol, polyethylene glycol, ethanol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycofurol, solketal, glycerol formate, acetone, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate, or mixtures thereof, depending on the amount used for injection.

[0021] Pharmaceutical composition IB is particularly useful for sustained or delayed release, and the compound of the present disclosure is released when the polymer matrix is ​​degraded.These compositions can be formulated (e.g., as a depot composition) for controlled and / or sustained release of the compound of the present disclosure for up to 180 days, for example, from about 14 to about 30 days, about 180 days.For example, the polymer matrix can degrade and release the compound of the present disclosure for about 30, about 60 or about 90 days.In another example, the polymer matrix can degrade and release the compound of the present disclosure for about 120 or about 180 days.

[0022] In yet another embodiment, Pharmaceutical Composition I or IA or IB may be formulated for administration by injection, for example, as a sterile aqueous or non-aqueous solution.

[0023] In another embodiment, the present disclosure provides a pharmaceutical composition (pharmaceutical composition IC) comprising the compound of the present invention described above in an osmotic controlled release oral delivery system (OROS) as described in US2001 / 0036472 and US2009 / 0202631, the contents of each of which are incorporated by reference in their entirety. Thus, in one embodiment, the present disclosure provides a pharmaceutical composition or device (pharmaceutical composition P.1) comprising: (a) a gelatin capsule containing a compound of the present invention in free or pharmaceutical acceptable salt form, optionally mixed with a pharmaceutical acceptable diluent or carrier; (b) a multi-layered wall superimposed on the gelatin capsule, the multi-layered wall comprising, from the outside of the capsule in order: (i) a barrier layer, (ii) an expandable layer, and (iii) a semi-permeable layer, and (c) an orifice formed or formable through the wall.

[0024] In another embodiment, the present invention provides a pharmaceutical composition comprising a gelatin capsule containing a compound of the present invention in liquid, free or pharma- ceutical acceptable salt form, optionally miscible with a pharma- ceutical acceptable diluent or carrier, the gelatin capsule being surrounded by a composite wall comprising a barrier layer in contact with the exterior surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall (pharmaceutical composition P.2).

[0025] In yet another embodiment, the present invention provides a composition (Pharmaceutical Composition P.3) comprising a gelatin capsule containing a compound of the present invention in liquid, free or pharma- ceutical acceptable salt form, optionally miscible with a pharma- ceutical acceptable diluent or carrier, the gelatin capsule being surrounded by a composite wall comprising a barrier layer in contact with the exterior surface of the gelatin capsule, an expandable layer in contact with the barrier layer, a semipermeable layer encompassing the expandable layer, and an exit orifice formed or formable in the wall, the barrier layer forming a seal between the expandable layer and the environment at the exit orifice.

[0026] In yet another embodiment, the present invention provides a composition (Pharmaceutical Composition P.4) comprising a gelatin capsule containing a compound of the present invention in liquid, free or pharma- ceutical acceptable salt form, optionally miscible with a pharma- ceutical acceptable diluent or carrier, the gelatin capsule being surrounded by a barrier layer in contact with the exterior surface of the gelatin capsule, an expandable layer in contact with a portion of the barrier layer, a semipermeable layer that encompasses at least the expandable layer, and an exit orifice formed or formable in the dosage form that extends from the exterior surface of the gelatin capsule to the environment of use. The expandable layer may be formed in one or more distinct locations, for example, two locations located on opposite sides or ends of the gelatin capsule.

[0027] In certain embodiments, the compound of the present invention in the osmotic-controlled release oral delivery system (i.e., compositions P.1-P.4) is in a liquid formulation, which may be a neat liquid active agent, a solution, a suspension, an emulsion, or a liquid active agent in a self-emulsifying composition, etc.

[0028] Further information about osmotically-controlled release oral delivery system compositions, including the characteristics of gelatin capsules, barrier layers, expandable layers, semipermeable layers; and orifices, can be found in US 2001 / 0036472, the contents of which are incorporated by reference in their entirety.

[0029] Other osmotic-controlled release oral delivery systems for the compounds of the invention or pharmaceutical compositions of the present disclosure can be found in US2009 / 0202631, the contents of which are incorporated by reference in their entirety. Thus, in another embodiment, the present invention provides a composition or device comprising: (a) two or more layers, said two or more layers comprising a first layer and a second layer, said first layer comprising a compound of the invention in free or pharma- ceutical acceptable salt form, optionally miscible with a pharma- ceutical acceptable diluent or carrier, and said second layer comprising a polymer; (b) an outer wall surrounding said two or more layers; and (c) an orifice in said outer wall (Pharmaceutical Composition P.5).

[0030] Pharmaceutical composition P.5 preferably utilizes a semipermeable membrane surrounding a three-layer core: in these embodiments, the first layer, referred to as the first drug layer, contains a small amount of drug (e.g., a compound of the invention) and an osmotic agent, e.g., a salt; the middle layer, referred to as the second drug layer, contains a larger amount of drug, excipients, and no salt; and the third layer, referred to as the push layer, contains an osmotic agent and no drug (Pharmaceutical composition P.6). At least one orifice is drilled through the membrane on the first drug layer end of the capsule-shaped tablet.

[0031] Pharmaceutical composition P.5 or P.6 may include a membrane defining a compartment and surrounding an inner protective subcoat, at least one outlet orifice formed or formable therein, and at least a portion of the membrane being semipermeable; an expandable layer located in the compartment away from the outlet orifice and in fluid communication with the semipermeable portion of the membrane; a first drug layer located adjacent to the outlet orifice; and a second drug layer located in the compartment between the first drug layer and the expandable layer and comprising a compound of the invention in free or pharma- ceutical acceptable salt thereof (pharmaceutical composition P.7). Depending on the relative viscosities of the first and second drug layers, different release profiles are obtained. It is essential to identify the optimal viscosity for each layer. In the present invention, the viscosity is adjusted by adding a salt, sodium chloride. The delivery profile from the core is determined by the weight, formulation and thickness of each of the drug layers.

[0032] In certain embodiments, the present invention provides pharmaceutical composition P.7, where the first drug layer comprises a salt and the second drug layer does not contain a salt. Pharmaceutical compositions P.5-P.7 may optionally include a flux-promoting layer between the membrane and the drug layer.

[0033] The pharmaceutical compositions P.1 to P.7 are generally referred to as osmotic pressure-controlled release oral delivery compositions.

[0034] In a third aspect, the present invention provides a method (Method 1) for treating or preventing a central nervous system disorder, comprising administering to a patient in need thereof a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, e.g., any of Pharmaceutical Compositions I, IA, IB, IC, or P.1-P.7. In certain embodiments, Method 1 comprises administering: 1.1 Compound I in free form or any of 1.1 to 1.20 1.2 Compound I or any of 1.1 to 1.20, in the form of a pharma- ceutically acceptable salt. 1.3 Compound I or any of 1.1 to 1.20 in the form of an acid addition salt. 1.4 Pharmaceutical Composition I 1.5 Pharmaceutical Composition IA, IB or IC 1.6 Any of the pharmaceutical compositions P.1 to P.7, or 1.7 Any of the osmotic controlled release oral delivery system compositions described above.

[0035] Substance use disorders and substance-induced disorders are two categories of substance-related disorders defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), 5th edition. Substance use disorders are a pattern of symptoms resulting from the use of a substance that an individual continues to use despite the resulting problems. Substance-induced disorders are disorders that are induced by use if the substance. Substance-induced disorders include addiction, withdrawal, and substance-induced psychiatric disorders, including substance-induced psychosis, substance-induced bipolar and related disorders, substance-induced depressive disorders, substance-induced anxiety disorders, substance-induced obsessive-compulsive and related disorders, substance-induced sleep disorders, substance-induced dysfunction, substance-induced delirium, and substance-induced neurocognitive disorders.

[0036] DSM-5 includes references for classifying substance use disorder as mild, moderate or severe. In some embodiments of the methods disclosed herein, the substance use disorder is selected from mild substance use disorder, moderate substance use disorder or severe substance use disorder. In some embodiments, the substance use disorder is mild substance use disorder. In some embodiments, the substance use disorder is moderate substance use disorder. In some embodiments, the substance use disorder is severe substance use disorder.

[0037] Anxiety and depression are very common comorbid disorders in patients who are treated for substance use or substance abuse. A common treatment for substance abuse disorders is the combination of buprenorphine, a partial opioid agonist, and naloxone, an opioid antagonist, but neither of these drugs have any significant effect on anxiety or depression, leading to the common result that a third drug, such as an anti-anxiety drug of the benzodiazepines or an SSRI antidepressant, must also be prescribed. This makes treatment regimen and compliance more difficult. In contrast, the compounds of the present disclosure provide opioid antagonism along with serotonin antagonism and dopamine modulation. This provides a significant improvement in the treatment of patients with substance use or abuse disorders accompanied by anxiety and / or depression.

[0038] The compound of the present invention can have anxiolytic properties that alleviate the need to treat patients with anxiolytic drugs, and said patients suffer from comorbid anxiety.Thus, in some embodiments, the present disclosure provides a method for treating substance addiction, substance use disorder and / or substance-induced disorder, or substance abuse disorder, for example, in patients who suffer from symptoms of anxiety or who are diagnosed with anxiety as a comorbid disorder or as a residual disorder, without further administration of anxiolytic drugs, such as benzodiazepines.Benzodiazepines are GABA-modulating compounds.

[0039] The compounds of the present invention may be particularly effective and useful in the treatment of pain, and the patient suffers from gastrointestinal and / or pulmonary disorders. Traditional opioid analgesics suffer from two major side effects: gastrointestinal disorders (including nausea, vomiting and constipation) and respiratory depression. 90 to 95% of patients taking opioids for long-term pain treatment develop severe constipation, requiring long-term use of laxatives and / or enemas. Stronger opioids, such as morphine, oxycodone and hydromorphone, produce more severe constipation than other opioids. Respiratory depression is the most serious adverse effect of opioid treatment, especially when patients combine (intentionally or inadvertently) prescribed opioid analgesics with other legal or illegal respiratory depressants (including alcohol), resulting in a risk of death. Patients who require pain treatment, especially chronic pain treatment, are therefore at particular risk of adverse effects when they suffer from pre-existing gastrointestinal or pulmonary disorders. Unlike traditional opioid analgesics, the compounds of the present invention provide analgesic relief without significant adverse gastrointestinal effects and without significant respiratory depression.Thus, such compounds can provide improved safety and efficacy to patients with these existing GI and pulmonary disorders who require pain treatment.In a further embodiment, the compounds of the present invention can be combined with traditional opioid agents to obtain improved pain control (and reduced risk of associated adverse effects) with dose-sparing effects for traditional opioid agents.

[0040] In some embodiments, the pain is caused by postherpetic neuralgia. Postherpetic neuralgia (PHN) is a neuropathic pain caused by damage to peripheral nerves caused by reactivation of the varicella zoster virus.

[0041] In some embodiments, the pain is caused by fibromyalgia, e.g., the pain is a symptom of fibromyalgia. Fibromyalgia is a complex syndrome of uncertain cause or origin. It is classified as a pain processing disorder, specifically the processing of pain signals within the central nervous system. It is therefore often considered as a central neuropathic pain syndrome and an example of "central sensitization." Fibromyalgia is characterized by chronic widespread pain that often includes allodynia. In the United States, only pregabalin and duloxetine are approved for the management of fibromyalgia, and existing painkillers are generally ineffective.

[0042] Patients suffering from neuropathy who can be otherwise treated with opioid analgesics or other drugs with high risk of abuse may be contraindicated for such treatment if they suffer from substance use or abuse disorder, or if they have a history of opioid addiction, opioid withdrawal or opioid overdose, or if they have a history of substance or alcohol abuse.Therefore, there is a need for alternative non-addictive treatment methods, such as those described herein, especially in such patients.

[0043] In some embodiments of the methods described herein below, pharmaceutical compositions comprising a compound of the invention may be administered for controlled and / or sustained release of the compound of the invention over a period of about 14 days to about 30 to about 180 days, preferably about 30, about 60 or about 90 days. Controlled and / or sustained release is particularly useful to avoid premature discontinuation of treatment, especially for antipsychotic treatments where non-compliance or non-adherence to medication regimes is a common occurrence.

[0044] In some embodiments of the methods described herein below, the pharmaceutical composition comprising a compound of the present invention may be a depot composition of the present disclosure administered for controlled and / or sustained release of the compound of the present invention over time.

[0045] In a further embodiment of the third aspect, the disclosure provides Method 1 or any of Methods 1.1-1.7, wherein the method is as further described as follows. 1.8 Central nervous system disorders include serotonin 5-HT 2A Any of Method 1 or Methods 1.1-1.7, wherein the disorder involves a receptor, the dopamine D1 receptor and / or D2 receptor system, and / or the serotonin reuptake transporter (SERT) pathway, and / or the mu-opioid receptor pathway. 1.9 Central nervous system disorders include obesity, anxiety (including general anxiety, social phobia and panic disorder), depression (e.g. refractory depression and MDD), psychosis (including psychosis associated with dementia, e.g. hallucinations or paranoid delusions in advanced Parkinson's disease), schizophrenia, sleep disorders (particularly sleep disorders associated with schizophrenia, and other psychiatric and neurological disorders), sexual disorders, pain and pain-related conditions including migraine, head pain, idiopathic pain, chronic pain (e.g. moderate to moderately severe chronic pain, e.g. in patients requiring treatment for another illness over 24 hours), neuropathic pain, dental pain, fibromyalgia, chronic fatigue, agoraphobia, social phobia, agitation in dementia (e.g. agitation in Alzheimer's disease), Any of Method 1 or Methods 1.1-1.8, wherein the disorder is selected from the group consisting of agitation in autism and related autistic disorders, gastrointestinal disorders, e.g., dysfunction of gastrointestinal motility and dementia, e.g., dementia of Alzheimer's disease or Parkinson's disease; mood disorders; drug dependence, e.g., opioid dependence and / or alcohol dependence, and withdrawal from drug or alcohol dependence (e.g., opioid dependence); opioid overdose; comorbidities associated with drug dependence, e.g., depression, anxiety and psychosis; binge eating disorder; and obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD) and related disorders; or opioid use disorder (OUD), or any combination thereof. 1.10 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a disorder selected from: (i) psychosis in a patient suffering from depression, e.g., schizophrenia; (2) psychosis, e.g., depression in a patient suffering from schizophrenia; (3) psychosis and / or substance dependence, e.g., mood disorder associated with schizophrenia or Parkinson's disease; (4) psychosis, e.g., sleep disorder associated with schizophrenia or Parkinson's disease; and (5) substance addiction, substance use disorder, and / or substance induced disorder, where the patient may suffer from residual symptoms of anxiety or an anxiety disorder and where the depression is treatment resistant depression. 1.11 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a psychosis, e.g., schizophrenia, and said patient is a patient suffering from depression. 1.12 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is depression and said patient is a patient suffering from a psychosis, e.g., schizophrenia or Parkinson's disease. 1.13 Any of Methods 1 or 1.1-1.8, wherein the disorder is a substance dependence disorder which may be accompanied by any of the aforementioned disorders, e.g., the disorder is opioid dependence, cocaine dependence, amphetamine dependence, alcohol dependence, or withdrawal from any drug or alcohol dependence (e.g., withdrawal from opioid, cocaine or amphetamine dependence), or the disorder is an opioid use disorder or opioid overdose, or the method is a method for treating or preventing opioid addiction relapse (e.g., for detoxification and maintenance treatment of opioid addiction, or for preventing relapse of opioid addiction). 1.14 Method 1.13, wherein the patient also suffers from a comorbid condition, such as anxiety, depression or psychosis, or residual symptoms of anxiety or an anxiety disorder, and / or mood changes (e.g., depression), and further wherein the patient suffers from opioid overdose. 1.15 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a disorder selected from obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), generalized anxiety disorder, social phobia, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, pathological grooming disorder, kleptomania, pyromania, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorders and related disorders, and combinations thereof. 1.16 Method 1 or any one of Methods 1.1-1.8, wherein the central nervous system disorder is selected from obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), social phobia, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, and impulse control disorder. 1.17 Method 1 or any one of Methods 1.1 to 1.8, wherein the central nervous system disorder is obsessive-compulsive disorder (OCD) or obsessive-compulsive personality disorder (OCPD). 1.18 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is a pain disorder, e.g. a pain-related condition, such as head pain, idiopathic pain, neuropathic pain, chronic pain (e.g. moderate to moderately severe chronic pain in patients requiring treatment for other illnesses over a 24 hour period), fibromyalgia, dental pain, traumatic pain, or chronic fatigue. 1.19 Method 1 or any of Methods 1.1-1.8, wherein the central nervous system disorder is opioid use disorder, opioid withdrawal or opioid dependence, and / or the method results in relief from withdrawal-induced symptoms (e.g., gastrointestinal symptoms, including diarrhea, anxiety, depression, pain, sleep disorders, or any combination thereof). 1.20 Method 1 or any of methods 1.1-1.8, wherein the central nervous system disorder is chronic pain and / or neuropathic pain. 1.21 Method 1.20, wherein the pain is caused by a peripheral neuropathy (e.g. mononeuropathy, plexopathy, radiculopathy or polyneuropathy) or caused by a central neuropathy (e.g. deafferented pain or sympathetically maintained pain, e.g. complex regional pain syndrome (CRPS)). 1.22 Any of methods 1.20 to 1.21, wherein the pain is chronic pain. 1.23 Any of methods 1.20 to 1.21, wherein the pain is neuropathic pain. 1.24 Method 1.22 or 1.23, wherein the pain is chronic neuropathic pain. 1.25 Any of methods 1.20-1.24, wherein the pain is caused by a mononeuropathy (e.g., a monofocal mononeuropathy), such as a focal mononeuropathy, a compressive mononeuropathy, or an entrapment mononeuropathy (e.g., carpal tunnel syndrome). 1.26 Any of methods 1.20-1.24, wherein the pain is caused by radiculopathy, for example caused by a herniated spinal disk, or caused by diabetic ischemia. 1.27 Any of methods 1.20-1.24, wherein the pain is caused by a plexopathy, e.g., a plexopathy caused by nerve compression, e.g., nerve compression by a neuroma, tumor, or herniated disc. 1.28 Any of methods 1.20-1.24, wherein the pain is caused by multiple mononeuropathy or polyneuropathy, e.g., diabetic polyneuropathy. 1.29 Any of methods 1.20-1.24, wherein the pain is caused by a central neuropathic pain syndrome, such as deafferentation pain or complex regional pain syndrome (CRPS), or by fibromyalgia. 1.30 Any of methods 1.20-1.24, wherein the pain is caused by postherpetic neuralgia (PHN) or by fibromyalgia. 1.31 Any of methods 1.20-1.24, wherein the pain is caused by drug-induced neurotoxicity (e.g. due to doxorubicin, etoposide, gemcitabine, ifosfamide, interferon alpha, platinum chemotherapy agents (e.g. cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin, phenanthriplatin, picoplatin, satraplatin) or vinca alkaloids (e.g. vinblastine, vincristine, vindesine, vinorelbine or vinpocetine) or antiretroviral nucleosides (e.g. didanosine, stavudine, zalcitabine)). 1.32 Any of methods 1.20 to 1.31, wherein the neuropathy is an axonal neuropathy (i.e., axonopathy). 1.33 Any of methods 1.20-1.32, wherein the patient has fibromyalgia, diabetes, human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS), or cancer. 1.34 Any of methods 1.20-1.32, where the patient is receiving or has been previously treated with an antiretroviral nucleoside, platinum-based antineoplastic agent, or vinca alkaloid antineoplastic agent. 1.35 Any of methods 1.20-1.34, wherein the pain is associated with allodynia and / or hyperalgesia. 1.36 The patient also suffers from anxiety (including generalized anxiety, social phobia and panic disorder), depression (e.g. refractory depression and MDD), psychosis (including psychosis associated with dementia, e.g. hallucinations or paranoid delusions in advanced Parkinson's disease), schizophrenia, migraine, substance abuse disorder, substance use disorder, opiate use disorder or other drug dependence, e.g. stimulant dependence and / or alcohol dependence, any of methods 1.20-1.35. 1.37 Method 1 or any of methods 1.1 to 1.8, wherein the central nervous system disorder is a sleep disorder. 1.38 Method 1.37, wherein the sleep disorder is selected from insomnia, frequent awakenings, and waking up feeling unrefreshed. 1.39 Method 1.37, wherein the sleep disorder is in a patient suffering from or at risk of dyskinesia, e.g., a patient receiving a dopamine agonist, e.g., selected from levodopa and levodopa adjuvants (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists and anticholinergics, e.g., a patient receiving levodopa. 1.40 The patient also has Parkinson's disease, any of methods 1.37 to 1.39. 1.41 Method 1 or any of Methods 1.1-1.8, wherein said disorder is a sleep disorder and said patient suffers from depression. 1.42 Method 1 or any of Methods 1.1-1.8, wherein said disorder is a sleep disorder and said patient suffers from a psychosis, e.g., schizophrenia. 1.43 Method 1 or any of Methods 1.1-1.8, wherein said disorder is a sleep disorder and said patient is suffering from Parkinson's disease. 1.44 Method 1 or any of Methods 1.1-1.8, wherein said disorder is a sleep disorder and said patient suffers from depression and psychosis, e.g., schizophrenia and / or Parkinson's disease. 1.45 Method 1 or any of methods 1.1-1.8, wherein the disorder is dyskinesia, e.g., in a patient receiving a drug selected from dopamine agonists, e.g., levodopa and levodopa adjuvants (carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists and anticholinergics, e.g., levodopa. 1.46 Any of methods 1 or 1.1-1.46, wherein the patient suffers from any combination of the disorders listed in methods 1.1-1.45. 1.47 Any of Methods 1 or 1.1-1.46, wherein the method is for treating or preventing any combination of the disorders listed in Methods 1.1-1.45. 1.48 The patient suffers from a pre-existing or concomitant gastrointestinal and / or pulmonary disorder, either method 1 or 1.1-1.47. 1.49 Method 1.48, wherein the pre-existing or co-existing disorder is selected from the group consisting of irritable bowel syndrome, pelvic floor disorders, diverticulitis, inflammatory bowel disease, colon or colorectal cancer, celiac disease, non-celiac gluten sensitivity, asthma, chronic obstructive pulmonary disease (COPD), dyspnea, pneumonia, congestive heart failure, interstitial lung disease, pneumothorax, bronchitis, pulmonary embolism and traumatic chest injury (e.g., broken sternum or ribs, bruised intercostal muscles). 1.50 Any of Methods 1.1-1.49, wherein the patient has been diagnosed with a substance use or abuse disorder, e.g., opioid use disorder (OUD). 1.51 The patient is taking an opiate or opioid drug, such as morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, any of Methods 1.1-1.50, having a history of prior substance use or abuse with benzodiazepine, benzoylcholine ... 1.52 Any of Methods 1 or 1.1-1.51, wherein the patient has or has been diagnosed with opiate dependence, cocaine dependence, amphetamine dependence, and / or alcohol dependence, or is suffering from withdrawal from a drug or alcohol dependence (e.g., opiate, cocaine or amphetamine dependence). 1.53 Any of Methods 1 or 1.1-1.52, wherein the patient has previously suffered an opiate or opioid overdose. 1.54 The patient does not respond to or is unable to tolerate the side effects of non-narcotic analgesics and / or opiate and opioid drugs, or the use of opiate or opioid drugs is contraindicated in said patient, e.g., because of previous substance abuse or high potential for substance abuse, e.g., opiate and opioid drugs are not suitable for use with, e.g., morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, Any of Methods 1 or 1.1-1.53 ​​comprising benzodiazepine, fentanyl, alpha-methylfentanyl, alfentanil, trefantinil, brifentanil, remifentanil, ocfentanil, sufentanil, carfentanil, meperidine, prozine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol and anileridine or any combination thereof. 1.55 Method 1 or any of Methods 1.1-1.54, wherein the patient is unable to tolerate the side effects of conventional antipsychotics, such as chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. 1.56 The patient is unable to tolerate the side effects of non-narcotic analgesics and / or opioids and opioid drugs or the use of opioid drugs is contraindicated in the patient, e.g., due to previous substance abuse or high potential for substance abuse, e.g., opioids and opioid drugs are, e.g., morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl , alpha-methylfentanyl, alfentanil, trefantinil, brifentanil, remifentanil, ocfentanil, sufentanil, carfentanil, meperidine, prozine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol and anileridine or any combination thereof. 1.57 Method 1 or any of Methods 1.1-1.56, wherein said patient does not respond to or cannot tolerate side effects from treatment with a selective serotonin reuptake inhibitor (SSRI), such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. 1.58 Method 1 or any of Methods 1.1-1.57, wherein the patient does not respond to or cannot tolerate side effects from treatment with a serotonin-norepinephrine reuptake inhibitor (SNRI), such as venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran. 1.59 Method 1 or any of Methods 1.1-1.58, wherein said patient does not respond to or cannot tolerate side effects from treatment with antipsychotic agents, such as clomipramine, risperidone, quetiapine, and olanzapine. 1.60 Method 1 or any of Methods 1.1-1.59, wherein the patient has previously been treated with another pain-relieving medication and the patient did not respond adequately to the medication, e.g., the patient's pain did not subside sufficiently or the patient suffered from a side effect that prevented continued treatment. 1.61 Method 1.60, wherein the patient has developed or is at risk for developing an addiction to said other pain relief medication. 1.62 The other pain relieving agent is a non-opiate analgesic (e.g., a non-steroidal anti-inflammatory drug, such as ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, oxaprozin, meclofenamate, mefenamic acid, phenylbutazone, indomethacin, ketorolac, diclofenac, sulindac, etodolac, tolmetin, nabumetone, piroxicam, acetaminophen, aspirin, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib), an opiate analgesic (e.g., morphine, codeine, methadone, oxycodone, hydrocodone, hydromorphone, oxymorphone, buprenorphine, fentanyl, levorphanol, meperidine, nalbuphine, pentazocine, tramadol, methadone) and local anesthetics (e.g., benzocaine, lidocaine, procaine, bupivacaine, tetracaine), or other drugs (e.g., tricyclic antidepressants or anticonvulsants, e.g., amitriptyline, desipramine, duloxetine, pregabalin, gabapentin, valproate, carbamazepine, phenytoin). 1.63 Any of the preceding methods, wherein the effective amount is from 1 mg to 1000 mg, preferably from 2.5 mg to 50 mg, or for long acting formulations from 25 mg to 1500 mg, e.g., from 50 mg to 500 mg, or from 250 mg to 1000 mg, or from 250 mg to 750 mg, or from 75 mg to 300 mg, measured as the equivalent amount of the free base of the compound. 1.64 Any of the preceding methods, wherein the effective amount, measured as the equivalent amount of the free base of the compound, is from 1 mg to 100 mg per day, preferably from 2.5 mg to 50 mg per day. 1.65 Any of the preceding methods, wherein the effective amount of a compound of the invention, measured as the equivalent amount of the free base of the compound, is from 1 mg to 1000 mg, for example, from 2.5 mg to 50 mg, or for long acting formulations, from 25 mg to 1500 mg, for example, from 50 mg to 500 mg, or from 250 mg to 1000 mg, or from 250 mg to 750 mg, or from 75 mg to 300 mg. 1.66 Any of the preceding methods, wherein the effective amount of a compound of the invention, measured as the equivalent amount of the free base of the compound, is from 1 mg to 100 mg per day, for example from 2.5 mg to 50 mg per day. 1.67 Any of the preceding methods, wherein the effective amount of the compound of the invention is from 1 mg to 5 mg, preferably from 2.5 to 5 mg, per day, measured as the equivalent amount of the free base of the compound. 1.68 Any of the preceding methods, wherein the effective amount of a compound of the invention is 2.5 mg or 5 mg per day, measured as the equivalent amount of the free base of the compound. 1.69 Any of Methods 1 or 1.1-1.68, wherein the compound of Formula I is administered in the form of a pharmaceutical composition comprising the compound of Formula I in admixture with a pharma- ceutically acceptable diluent or carrier. 1.70 Method 1.69, wherein the compound of Formula I is in the form of a pharma- ceutically acceptable salt in admixture with a pharma- ceutically acceptable diluent or carrier. 1.71 Method 1.69 or 1.70, wherein the pharmaceutical composition is a sustained or delayed release formulation, e.g., according to Pharmaceutical Composition 1-A described herein. 1.72 Method 1.69, 1.70 or 1.71, wherein the pharmaceutical composition comprises a compound of formula I in a polymer matrix, for example according to Pharmaceutical Composition 1-B described herein. 1.73 Any of Methods 1.69-1.72, wherein the pharmaceutical composition is formulated as an osmotic controlled release oral delivery system, e.g., according to any of Pharmaceutical Compositions 1-C or P.1 through P.7 described herein. 1.74 Any of methods 1.69-1.72, wherein the pharmaceutical composition is in the form of a tablet or capsule. 1.75 Any of methods 1.69-1.72, wherein the pharmaceutical composition is formulated for oral, sublingual, or buccal administration. 1.76 Any of methods 1.69-1.72, wherein the pharmaceutical composition is a fast dissolving oral tablet (e.g., a fast dissolving sublingual tablet). 1.77 Any of methods 1.69-1.72, wherein the pharmaceutical composition is formulated for intranasal or pulmonary administration (e.g., as an aerosol, mist, or powder for inhalation). 1.78 Any of methods 1.69-1.72, wherein the pharmaceutical composition is formulated for administration by injection, e.g., as a sterile aqueous solution. 1.79 Method 1.78, wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection. 1.80 Any of Methods 1 or 1.1-1.79, wherein the method further comprises concurrent administration of one or more other therapeutic agents, e.g., administered simultaneously, separately or sequentially. 1.81 Method 1.80, wherein the one or more additional therapeutic agents include an opiate or opioid agent, such as an opioid agonist or partial opioid agonist, e.g., a mu-agonist or partial agonist, including a mixed agonist / antagonist (e.g., an agent having partial mu-agonist activity and kappa-antagonist activity), or a kappa-agonist or partial agonist. 1.82 Method 1.80, wherein the additional opiate or opioid agent is selected from the group consisting of morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentanyl, alfentanil, trefantinil, brifentanil, remifentanil, ocfentanil, sufentanil, carfentanil, meperidine, prodine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and anileridine, or any combination thereof. 1.83 Method 1.80, wherein the additional opiate or opioid agent is buprenorphine, and said method may not include concomitant treatment with an anxiolytic, e.g., a GABA compound or a benzodiazepine. 1.84 Method 1.80, wherein the additional opiate or opioid agent is an opioid receptor antagonist or inverse agonist, e.g., a full opioid antagonist selected from naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodim, or nor-binaltorphimine. 1.85 Any of methods 1.80-1.84, wherein the additional therapeutic agent is an NMDA receptor antagonist, e.g., administered simultaneously, separately or sequentially. 1.86 Method 1.85, wherein the NMDA receptor antagonist is selected from the group consisting of ketamine (e.g., S-ketamine and / or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine and agmatine, or any combination thereof. 1.87 The additional therapeutic agent is a compound that modulates GABA receptor activity, a GABA-B receptor agonist, a 5-HT receptor modulator, a 5-HT 1AReceptor agonist, 5-HT 2A Receptor antagonist, 5-HT 2A Receptor inverse agonists, melatonin receptor agonists, ion channel modulators, ion channel blockers, SARIs (serotonin-2 receptor antagonists / reuptake inhibitors), orexin receptor antagonists, H3 receptor agonists, H3 receptor antagonists, noradrenergic receptor agonists, noradrenergic receptor antagonists, galanin receptor agonists, CRH receptor antagonists, human growth hormone, growth hormone receptor agonists, estrogen, estrogen receptor agonists, neurokinin-1 drugs, antidepressants, opioid receptor agonists, partial opioid receptor agonists agonists, opioid receptor antagonists, opioid receptor inverse agonists, nociception / orphanin receptor agonists, typical antipsychotics, atypical antipsychotics, serotonin HT6 receptor antagonists and mGluR-2, -3 or -5 receptor agonists or antagonists, any of methods 1.80 to 1.86. 1.88 Any of methods 1.80-1.87, wherein the additional therapeutic agent is a compound that modulates GABA activity (e.g., enhances activity and promotes GABA transmission). 1.89 Method 1.88, wherein the additional therapeutic agent is a GABA compound selected from the group consisting of doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), and estazolam. 1.90 The additional therapeutic agent may be selected from pimavanserin, ketanserin, risperidone, eplivanserin, vorinanserin, pulvanserin, MDL 100907 (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego, CA), and AVE8488 (Sanofi-Aventis, France). 2A Any of methods 1.80 to 1.89, which is a receptor antagonist. 1.91 Any of methods 1.80-1.90, wherein the additional therapeutic agent is a melatonin receptor agonist, optionally selected from the group consisting of one or more of melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), PD-6735 (Phase II Discovery), and agomelatine. 1.92 Any of methods 1.80-1.91, wherein the additional therapeutic agent is an ion channel blocker, which may be selected from lamotrigine, gabapentin, and pregabalin. 1.93 Any of methods 1.80-1.92, wherein the additional therapeutic agent is an orexin receptor antagonist optionally selected from the group consisting of orexin, SB-334867-a (GlaxoSmithKline, UK) and GW649868 (GlaxoSmithKline). 1.94 Any of methods 1.80-1.93, wherein the additional therapeutic agent is a serotonin-2 receptor antagonist / reuptake inhibitor (SARI) which may be selected from the group consisting of one or more of Org 50081 (Organon-Netherlands), ritanserin, nefazodone, cerzone and trazodone. 1.95 The additional therapeutic agent may be selected from the group consisting of one or more of repinotan, sarizotan, eptapirone, buspirone, and MN-305 (MediciNova, San Diego, CA).1A Agonist, methods 1.80-1.94. 1.96 Any of methods 1.80-1.95, wherein the additional therapeutic agent is a neurokinin-1 drug, and the drug can be casopitant. 1.97 Any of methods 1.80-1.96, wherein the additional therapeutic agent is an antipsychotic agent, and the antipsychotic agent may be selected from the group consisting of chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone. 1.98 Any of methods 1.80-1.97, wherein the additional therapeutic agent is an antidepressant, and the antidepressant may be selected from amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine. 1.99 Any of methods 1.80-1.98, wherein the additional therapeutic agent is an atypical antipsychotic, and the agent may be selected from the group consisting of brexpiprazole, cariprazine, asenapine, lurasidone, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone. 1.100 Any of methods 1.80-1.99, wherein the additional therapeutic agent is an atypical stimulant and may be selected from modafinil, adrafinil, and armodafinil. 1.101 Any of methods 1.80 to 1.100, wherein the additional therapeutic agent is an anti-Parkinson's agent which may be selected from L-dopa, co-careldopa, duodopa, stalevo, symmetrel, benztropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline and tolcapone. 1.102 Any of methods 1.80-1.101, wherein any one or more additional therapeutic agents are administered to the patient as a single pharmaceutical composition, e.g., a depot composition as described above. 1.103 Any of methods 1.80-1.102, wherein any one or more additional therapeutic agents are administered to the patient as separate pharmaceutical compositions, e.g., one is a depot composition as described above and the other is not (e.g., an oral dosage form).

[0046] As mentioned above, the compounds of the present invention can be particularly useful due to their ability as biased mu-opioid receptor ligands.Depending on cell type, or even within the same cell type, the intracellular domain of activated mu-opioid receptor can interact with inhibitory G protein or beta-arrestin.The binding of unbiased agonists to mu-opioid receptor results in approximately equal activation of both G protein signaling and beta-arrestin signaling.

[0047] In contrast, when biased agonist binds to mu-opioid receptor, the intracellular domain of the receptor is biased to bind and interact with G protein instead of beta-arrestin.Thus, the compounds of the present invention can act as partial or full agonists of G protein-coupled signaling of mu-opioid receptor, but not as antagonists of beta-arrestin signaling of the receptor.This is in contrast to traditional opioid agonists, such as morphine and fentanyl, which tend to strongly activate both G protein signaling and beta-arrestin signaling pathways.The activation of beta-arrestin signaling by such drugs is believed to mediate the gastrointestinal dysfunction, addictive and respiratory depressant effects typically mediated by opioid drugs, whereas the analgesic and anesthetic effects of mu-opioid receptor agonists are mediated by G protein signaling pathway.

[0048] Moreover, it is known that biased agonists are generally useful for the treatment of opioid overdoses, because they antagonize the beta-arrestin pathway, thus counteracting the respiratory depression caused by opioids.But, beneficially, while they do so, they also provide pain relief.Biased beta-arrestin antagonists are expected to be useful for the treatment of opioid overdoses, because they inhibit the most severe adverse effects of opioids, but also provide pain relief.

[0049] The United States is currently in the midst of a widespread opioid abuse epidemic that began in the late 1990s and has been fueled by a combination of overprescribed prescription opioids (e.g., oxycodone, sold as OxyContin by Purdue Pharma), cheap imported illegal heroin, and a combination of legal and illegal fentanyl. Heroin and oxycodone (along with codeine, hydrocodone, hydromorphone, oxymorphone, and several other drugs) are natural or semisynthetic analogs of morphine, while fentanyl is the leading and most prominent new class of synthetic opioid. Unlike natural and semisynthetic opioids, fentanyl and fentanyl analogs do not possess the complete classical pentacyclic nucleus of morphine. Instead, fentanyl and fentanyl analogs share a common 4-aminophenyl (piperidine) nucleus. The most common fentanyl analogues are sufentanil, alfentanil, remifentanil and carfentanil.

[0050] Fentanyl and its analogs are substantially more potent than both morphine and heroin due to strong mu-opioid receptor binding, high lipid solubility, or both. Compared to morphine and heroin, these drugs cross the blood-brain barrier much more quickly due to their higher lipid solubility, resulting in greater potency for comparable receptor binding. Fentanyl is generally considered to be about 50 times more potent than heroin and 100 times more potent than morphine (some sources indicate it is 150 times more potent than morphine). Sufentanil is considered to be 5 to 10 times more potent than fentanyl and carfentanil, and about 100 times more potent than fentanyl (and thus 10,000 times more potent than morphine).

[0051] Due to its extremely high potency and widespread, inexpensive availability, adulteration of amphetamines, heroin, and other street drugs with variable and unpredictable amounts of fentanyl is becoming increasingly common. As a result of this and other trends, fentanyl is becoming the leading cause of opioid overdoses and, in particular, opioid-related deaths in the United States. By 2016, fentanyl was responsible for at least 50% of opioid deaths, rising to over 70% of deaths in 2017 and 2018. See Torralva & Janowsky, J. Pharmacol. Exp. Ther. 371:453-475 (2019). In fact, rates of amphetamine overdoses have increased substantially in recent years, driven primarily by fentanyl adulteration of amphetamines. In just a five-year period, amphetamine deaths have increased fourfold, primarily driven by fentanyl adulteration.

[0052] Only three fentanyl analogues have been approved for human use (sufentanil, alfentanil, and remifentanil), while only one (carfentanil) has been approved for veterinary use. Nevertheless, these and many other novel synthetic fentanyl analogues are found as adulterants in street drugs, including amphetamines, heroin, cocaine, alprazolam (Xanax), and hydrocodone / paracetamol (Norco). See Armenian et al., Neuropharmacology (2017). Until 2013, there were only sporadic occurrences of fentanyl or fentanyl analogues adulterating the US heroin supply, but since then, such compounds have made widespread inroads in North America and are adulterating both heroin and cocaine. Deaths from fentanyl-laced heroin and cocaine doubled from 2012 to 2014. Counterfeit Xanax and Norco purchased on the street caused two major outbreaks in California in 2015-2016. Adulteration of non-opioid drugs with fentanyl and fentanyl analogues is particularly troublesome because users of such drugs are often opioid naive (and therefore have little or no established drug tolerance) and thus exhibit significantly worse clinical outcomes. As standard fentanyl analogues became more widespread (in both medical and forensic settings), illicit manufacturers began to switch to novel synthetic fentanyl derivatives to evade detection, and today a large number of such illicit compounds are known and available on the black market from Chinese and other manufacturers. At least 21 synthetic opioid compounds are today cataloged by the US Drug Enforcement Administration.

[0053] Due to its high potency and high lipid solubility, fentanyl-induced overdoses are much more difficult to treat than morphine, heroin, or oxycodone overdoses. Fentanyl exhibits an exceptionally rapid onset of action, which makes reversal with treatment with mu-receptor antagonists (e.g., naloxone or naltrexone) difficult in outpatient settings (where EMS response times, or police surveillance, are often longer than the time to develop severe respiratory depression). Larger doses of mu-receptor antagonists are also required to reverse a fentanyl overdose, and there are limitations to the rate and dose of mu-opioid antagonists that can be safely administered. Morphine takes an average of 19 minutes to reach 80% of its peak effect, whereas fentanyl produces severe respiratory depression much more rapidly.

[0054] However, it is even more disturbing that fentanyl and its analogs have an additional mechanism of action that is becoming crucial in the ongoing opioid epidemic. Although all opioids cause respiratory depression by activating the mu-opioid receptor of the beta-arrestin signaling pathway in the brain for reasons that are not yet entirely clear, fentanyl and its analogs can also cause a combination of rapid vocal cord closure (laryngospasm) and severe muscle rigidity in the chest wall and diaphragm. This can be caused by intravenous, transdermal or inhalation administration of fentanyl and fentanyl analogs. Neither morphine, heroin, nor any other opioid with the classical morphine skeleton has this property. This severe chest wall rigidity is referred to as fentanyl-induced respiratory muscle rigidity (FIRMR) (or simply fentanyl-induced muscle rigidity, FIMR), and the combination of FIRMR and laryngospasm is clinically known as wooden chest syndrome (WCS). WCS can develop within just 1 to 2 minutes of injection of fentanyl, fentanyl analogs or heroin, or other drugs that contain fentanyl or its analogs. WCS has been demonstrated after as little as 50 micrograms of intravenous fentanyl.

[0055] The main cause of mortality in WCS appears to be mechanical obstruction of ventilation caused by closure of the glottic structures and upper airway. Laryngospasm is defined as the involuntary closure or obstruction of the glottic opening, which is controlled by the intrinsic muscles of the larynx. These muscles are innervated by both sympathetic (adrenergic) and parasympathetic (cholinergic) nerve fibers, and the ultimate activity of these muscles is therefore determined by the balance of sympathetic and parasympathetic input.

[0056] Although FIRMR and WCS have long been known in the surgical anesthesia community (as they commonly occur in the therapeutic dose range in surgical anesthesia), these conditions are not well known in the first responder or emergency medical community. This is because these effects of fentanyl are not recognized by those treating the drug abuser, who often die suddenly (often complicated by the lack of knowledge of the patient who has taken something that has fentanyl in it). Numerous witness and survivor accounts of overdose report extremely rapid onset of cyanosis, loss of consciousness, severe muscular rigidity, and seizure-like behavior immediately after injection of the drug. The rapidity of death is quite different from the respiratory depression usually associated with morphine, heroin, and oxycodone overdoses. Indeed, mechanical failure of breathing in fentanyl or fentanyl analogue overdose typically develops less than 2 minutes after drug administration and precedes centrally-mediated respiratory depression (a 50% decline in respiratory mechanics takes 7-9 minutes to develop).

[0057] Even more disturbing, the standard first-line treatments for opioid overdoses, naloxone, naltrexone, and nalmefene, are ineffective at reversing these fentanyl-induced effects. Severe chest wall rigidity also impairs the effectiveness of chest compressions in cardiopulmonary resuscitation. As a result, the ratio of emergency room visits to death in heroin-related overdoses has been reported to be approximately 10:1, whereas the ratio in fentanyl-related overdoses is only 1:1.

[0058] The standard dose of intravenous naloxone administered in opioid overdoses is 0.4 to 2 mg, with additional doses up to 10 mg at 2- to 3-minute intervals. However, intranasal naloxone, widely used by first responders, only has a maximum recommended total dose of 4 mg. See, for example, Williams et al., Prehospital Emergency Care 23(6):749-63 (2019). However, one study found that the upper airway effects of morphine could be completely blocked by a dose of 0.1 mg / kg (e.g., 7 mg in a 70-kg human) of naloxone, whereas 0.8 to 1.6 mg / kg (56 to 112 mg in a 70-kg human) of naloxone was required to completely block the upper airway effects of fentanyl. A study investigating the occurrence of fentanyl overdoses in 2006 reported that patients were given 0.4 to 12 mg of naloxone in hospital emergency rooms, with only 15% of patients responding to the 0.4 mg dose, and 6 of 26 patients requiring at least 6 mg to reverse respiratory depression. Another study investigating 18 patients who overdosed on counterfeit hydrocodone / paracetamol contaminated with fentanyl required an intravenous bolus of 0.4 to 8 mg of naloxone, with 4 of the patients requiring a naloxone injection lasting 26 to 40 hours.

[0059] Unfortunately, high doses of naloxone are not practical for therapeutic use because rapid infusion of as little as 0.4 mg of naloxone (0.0057 mg / kg in a 70 kg adult) in active opioid users commonly leads to laryngospasm, pulmonary edema, hemodynamic instability, and cardiac arrhythmias (all due to catecholamine release). High-dose naloxone treatment is therefore specifically contraindicated in this field. Thus, in this field, it is usually very difficult, if not impossible, to use naloxone to reverse a fentanyl-induced overdose before it becomes fatal, without further medical and pharmacological support.

[0060] That WCS is not simply the result of mu-opioid receptor agonism is evident because other potent mu-opioid agonists (e.g., morphine) do not cause WCS, and potent mu-opioid antagonists (e.g., naloxone) do not reverse WCS in the usual dose range. Thus, fentanyl and its analogs must cause WCS by some other mechanism involving other neurotransmitter systems.

[0061] Evidence from both in vitro studies and various animal models indicates that fentanyl exerts these effects via stimulation of noradrenergic and possibly cholinergic activity in the locus coeruleus (LC) region of the brain. Without being bound by theory, it is believed that in the LC, fentanyl acts as an agonist of mu-opioid receptors, and the resulting hyperpolarization of LC neurons produces activity of efferent noradrenergic neurons, specifically in the locus coeruleus-spinal fibers that connect to motor neurons in the spinal cord that terminate in the chest wall and abdomen, and in laryngeal nerve fibers that contribute to the vagus nerve via the upper and middle cervical ganglia. These laryngeal nerve fibers directly innervate the intrinsic muscles of the larynx.

[0062] The role of alpha1-adrenergic receptors is particularly pointed to by animal studies, which demonstrate that prazosin, a selective alpha1-adrenergic antagonist, administered intravenously 10 minutes before fentanyl, inhibits the expression of FIMR, and the same result occurs with ablation of the LC region of the brain. Other studies show that intrathecal administration of prazosin at the spinal cord at level L3 also inhibits FIMR, whereas administration of yohimbine, an alpha2-adrenergic antagonist, does not. Fentanyl itself is an antagonist of alpha1-adrenergic receptors, but there is some evidence in animals that it is weak and selective for alpha1B and alpha1A receptors (but not alpha1D receptors). Unfortunately, these studies do not directly predict the beneficial use of alpha 1-adrenergic antagonists in the treatment of opioid overdose, since the corresponding human doses used in animal studies produce lethal hypotension in humans.

[0063] There is also growing evidence for an intermediate role for GABA interneurons in the pathogenesis of WCS. GABA interneurons are part of an inhibitory network throughout the brain, and they are particularly abundant in the LC. The LC responds to the maintenance of basal skeletal muscle tone in the trunk via noradrenergic activity of spinal motor neurons, but norepinephrine release from presynaptic terminals in the LC is inhibited by GABA efferent signaling. Inhibition of GABA interneurons thus results in increased skeletal muscle tone due to increased LC noradrenergic activity. Without being bound by theory, it is believed that fentanyl binds to mu-opioid receptors on GABA interneurons, and this results in inhibition of GABA interneuron afferents, resulting in the release of inhibition on LC sympathetic neurons.

[0064] There is also evidence that LC neurons are rich in muscarinic and nicotinic acetylcholine receptors.LC receives cholinergic input from other brain regions, such as the pontine reticular formation, and it is believed that fentanyl-induced mu-receptor agonism in these adjacent regions can stimulate acetylcholine release, which leads to further stimulation of norepinephrine release by LC.There is also some evidence that fentanyl acts directly as an M3 muscarinic receptor antagonist, which can cause inhibition of parasympathetic tone in the intrinsic muscles of the larynx, further increasing the spasms that result from sympathetic activation of these muscles.

[0065] NMDA and non-NMDA glutamate receptor activity has also been implicated in the pathogenesis of WCS.

[0066] Because of the intermediate role of these other neurotransmitters (e.g., norepinephrine, acetylcholine, GABA) in the pathogenesis of WCS, a further reason for the failure of WCS to respond to mu-opioid antagonist treatment may be that once these indirect fentanyl-stimulatory effects are initiated (by mu-receptor agonism), only mu-receptor antagonism can reverse the effects already in motion.

[0067] Finally, there is also evidence that fentanyl, but not morphine, has some activity as a norepinephrine reuptake inhibitor. This effect has been shown in various neuronal cell lines to be not antagonized by naloxone, indicating that it is not an indirect effect of mu-receptor agonism. It is therefore possible that fentanyl exerts a direct effect on neurons in the LC to stimulate hyperactivity of muscles involved in the FIMR and WCS.

[0068] Thus, there remains a need for therapeutic agents that are specifically adapted to reverse the effects of acute fentanyl overdose or fentanyl analog overdose. Fentanyl analogs include, but are not limited to, the compounds sufentanil, alfentanil, remifentanil, carfentanil, and derivatives of these compounds, which are further described herein. Fentanyl and fentanyl analogs are collectively referred to herein as "F / FA."

[0069] Without being bound by theory, the compounds of the present invention are believed to inhibit 5-HT 2A It is believed that due to their D1 and mu opioid modulating activity, and especially due to their biased mu-opioid receptor activity, they may be unexpectedly effective in reversing the symptoms of F / FA overdose, especially respiratory depression, chest wall rigidity and laryngospasm. This is believed to be via beta-arrestin signaling, especially due to the activity of these compounds as mu-receptor antagonists. It is also believed that their activity as alpha1-adrenergic antagonists, as indirect NMDA and AMPA antagonists, and potentially due to their indirect effects on GABA expressing neurons. These properties are very unique and are not shared with older mu-opioid receptor antagonists, such as naloxone, used both for opioid overdose treatment and surgical reversal of opioid agonism.

[0070] The compounds disclosed herein are also highly beneficial in treating acute overdoses and chronic opioid addiction, as they do not induce opioid withdrawal symptoms, as can be the case with opioid withdrawal or opioid antagonist treatment. Opioid withdrawal syndrome can be extremely severe for addicted patients, and can include symptoms such as tachycardia, nausea, vomiting, diarrhea, extreme anxiety, restless legs, muscle pain, and excessive sweating. These withdrawal symptoms are the result of the body adapting to the presence of opioids, which has led to tolerance and physical dependence. In severe cases, abrupt cessation of opioid abuse or treatment with opioid antagonists can result in withdrawal symptoms that last for weeks or months. Administration of opioid antagonists, such as naloxone or naltrexone, especially in high doses, can induce acute withdrawal effects, especially in patients suffering from acute overdoses of F / FA. In patients suffering from overdoses of weaker opioid agonists, e.g., heroin, antagonists, treatment may be performed using small repeated doses to avoid or minimize such withdrawal syndromes. However, in acute F / FA overdoses, it is often impossible to avoid severe withdrawal with traditional antagonist treatments, since such small doses of antagonists are ineffective and thus there is no chance of reversing the overdose.

[0071] In a further embodiment of the third aspect, the present disclosure provides a further embodiment of Method 1, the method being a method for one or more of the following (Method 1-A): (a) Treating or reversing F / FA overdosage; (b) treating or reversing F / FA-induced respiratory depression; (c) treating or reversing F / FA-induced muscle rigidity; (d) treating or reversing F / A-induced laryngospasm; (e) abolishing or inhibiting the binding of F / FA to mu-opioid receptors in the central nervous system (e.g., in the locus coeruleus); (f) inhibiting F / FA-induced beta-arrestin signaling in the central nervous system (e.g., in the locus coeruleus); (g) Preventing deaths due to F / FA overdose; and (h) Anesthesia recovery (e.g., after surgery) The method comprises administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutical composition comprising a compound of the invention.

[0072] Further exemplary embodiments of this aspect of Method 1 include: 1.104 Any of Method 1 or 1.1 to 1.103, wherein the method is Method 1-A. 1.105 Patient unconscious, method 1-A or 1.104. 1.106 The patient is suspected of having an acute F / FA overdose, Method 1-A or 1.104 or 1.105. 1.107 The patient demonstrates chest wall rigidity, either Method 1-A or Methods 1.104-1.106. 1.108 The patient demonstrates laryngospasm, either Method 1-A or Methods 1.104-1.107. 1.109 Any of Method 1-A or Methods 1.104-1.08, wherein the patient is diagnosed with, suspected of, or has Wooden Chest Syndrome (WCS). 1.110 Method 1-A or any of Methods 1.104-1.08, wherein the patient is diagnosed with, suspected of, or has fentanyl-induced muscular rigidity (FIMR) or fentanyl-induced respiratory muscular rigidity (FIRMR), wherein said FIMR or FIRMR is caused by fentanyl or a fentanyl analogue. 1.111 The patient is in a setting other than a hospital or other than an emergency clinic, either Method 1-A or Methods 1.104 through 1.110. 1.112 The patient is suspected of having an opioid use disorder or has a history of an opioid use disorder, either Method 1-A or Methods 1.104 through 1.111. 1.113 The patient is suspected of being an opioid naive user, either Method 1-A or Methods 1.104 through 1.112. 1.114 The patient has been or is suspected of having been overdosed on a legal or illegal drug contaminated or adulterated with F / FA (e.g., morphine, heroin, codeine, hydrocodone, oxycodone, hydromorphone, marijuana or cannabis products, tetrahydrocannabinol, cocaine, amphetamine, methamphetamine, methylenedioxymethamphetamine, alprazolam, or other illegal or legal drugs), either Method 1-A or Methods 1.104-1.113. 1.115 Any of Method 1-A or Methods 1.104-1.114, wherein the F / FA is or is administered as a general anesthesia (e.g., surgical anesthesia). 1.116 Method 1.115, wherein the general anesthesia further comprises or comprises one or more of an inhaled anesthetic (e.g., isoflurane, sevoflurane, desflurane, nitrous oxide, halothane, methoxyflurane), another opioid agonist (e.g., morphine, oxycodone), a sedative or hypnotic (e.g., propofol, midazolam, ketamine, etomidate) or a muscle relaxant (e.g., atracurium, mivacurium, pancuronium, rocuronium, vecuronium, cistracurium, succinylcholine). 1.117 Method 1.115 or 1.116, wherein the patient has difficulties resulting from anesthesia, for example due to persistent respiratory depression. 1.118 Method 1-A or any of Methods 1.104-1.117, where the patient has not responded or has not responded adequately (e.g., with respect to signs or symptoms of respiratory depression) to a single dose of a mu-opioid antagonist (e.g., naloxone or naltrexone, e.g., 0.1 to 4 mg) administered by any route (e.g., intranasally, intravenously, subcutaneously or intramuscularly). 1.119 Method 1-A or any of Methods 1.104-1.117, where the patient has not responded or has not responded adequately (e.g., with respect to signs or symptoms of respiratory depression) to multiple doses of a mu-opioid antagonist (e.g., naloxone or naltrexone, e.g., 0.4 to 20 mg total) administered by any route (e.g., intranasally, intravenously, subcutaneously or intramuscularly). 1.120 Method 1-A or any of Methods 1.104-1.119, wherein the patient suffers from a recurrence of respiratory depression following a single or multiple dose of a mu-opioid antagonist (e.g., naloxone or naltrexone, e.g., intranasal, intravenous, subcutaneous or intramuscular) administered by any route. 1.121 Method 1-A or any of Methods 1.104-1.120, wherein the patient suffered one or more opioid withdrawal symptoms or other adverse events (e.g., agitation, combativeness, laryngospasm, pulmonary edema, hemodynamic instability or cardiac arrhythmias) following single or multiple doses of a mu-opioid antagonist (e.g., naloxone or naltrexone, e.g., intranasal, intravenous, subcutaneous or intramuscular) administered by any route. 1.122 Any of methods 1.118-1.121, wherein said mu-opioid antagonist is naloxone, naltrexone, or nalmefene. 1.123 Any of methods 1.118 to 1.121, wherein the mu-opioid antagonist is naloxone. 1.124 Any of Methods 1-A or 1.104-1.123, wherein the patient has received at least one dose of naloxone and is experiencing one or more opioid withdrawal symptoms or adverse events such that further administration of naloxone is contraindicated. 1.125 Where the use of naloxone is contraindicated for any reason, either method 1-A or 1.104-1.124. 1.126 Any of Methods 1-A or 1.104-1.125, wherein the patient has previously suffered an opioid overdose. 1.127 Method 1-A or any of 1.104-1.126, wherein the patient is identified as suffering from F / FA overdose by toxicological or forensic methods (e.g., by identifying the presence of F / FA in the patient's blood or in the patient's drug or drug paraphernalia). 1.128 Any of Methods 1-A or 1.104-1.127, wherein the effective amount of the compound of Formula I is an amount effective to reverse one or more of: respiratory arrest, respiratory depression, skeletal muscle spasms, chest wall rigidity, laryngospasm, miosis, cardiac arrest, bradycardia, or loss of consciousness. 1.129 Any of Methods 1-A or 1.104-1.128, wherein the effective amount of a compound of the invention is from 0.1 mg to 200 mg, for example 1 to 200 mg, or 10 to 150 mg, or 25 to 100 mg, or 50 to 100 mg, or 75 to 100 mg, or 25 to 75 mg, or 25 to 50 mg, or 1 to 50 mg, or 1 to 25 mg, 0.1 to 50 mg, 2.5 mg to 50 mg, or for long acting formulations, 25 mg to 1500 mg, for example 50 mg to 500 mg, or 250 mg to 1000 mg, or 250 mg to 750 mg, or 75 mg to 300 mg. 1.130 Method 1.129, wherein the effective amount is administered as a single dose. 1.131 Method 1.129, wherein the effective amount is administered in two or more doses over less than 30 minutes (e.g., less than 20 minutes, or less than 15 minutes, or less than 10 minutes). 1.132 Any of Methods 1-A or 1.104-1.131, wherein an effective amount of a compound of the invention is administered by intranasal administration (eg, as an aerosol, mist or powder for inhalation). 1.133 Any of Methods 1-A or 1.104-1.131, wherein an effective amount of a compound of the invention is administered across the oral mucosa, for example, by a fast dissolving oral tablet (eg, a fast dissolving sublingual tablet). 1.134 Any of Methods 1-A or 1.104-1.131, wherein an effective amount of a compound of the invention is administered by injection (e.g., intravenous, intramuscular, intrathecal, intraperitoneal or subcutaneous injection). 1.135 Any of Methods 1-A or 1.104-1.134, wherein the method does not include concurrent administration of any other opioid antagonist (e.g., naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodein, cyprodim, or nor-binaltorphimine). 1.136 The method is 1 Compounds of formula I, where R 1 As described above, -C(O)-OC(R a )(R b )(R c ), -C(O)-O-CH2-OC(R a )(R b )(R c ) or -C(R 6 )(R 7 )-OC(O)-R 8 Any of methods 1-A or 1.104 to 1.135, comprising administering a pharmaceutical composition comprising both of 1.137 Method 1-A or any of 1.104-1.136, wherein a compound of the invention is the only pharmacological treatment for overdose (e.g., excluding supportive interventions such as administration of oxygen, cardiopulmonary resuscitation, chest compressions, and administration of fluids). 1.138. Method 1-A or any of 1.104 to 1.137, wherein the method is for treating or reversing F / FA overdosage. 1.139 Any of Method 1-A or 1.104 to 1.138, wherein the method is for treating or reversing F / FA-induced respiratory depression. 1.140 Any of Methods 1-A or 1.104 to 1.139, wherein the method is for treating or reversing F / FA-induced muscle rigidity. 1.141 Any of Method 1-A or 1.104 to 1.140, wherein the method is for treating or reversing F / A-induced laryngospasm. 1.142 Any of Methods 1-A or 1.104 to 1.141, wherein the method is for abolishing or inhibiting binding of F / FA to mu-opioid receptors in the central nervous system (e.g., in the locus coeruleus). 1.143 Any of Methods 1-A or 1.104 to 1.142, wherein the method is for inhibiting F / FA-induced beta-arrestin signaling in the central nervous system (e.g., in the locus coeruleus). 1.144 Any of Method 1-A or 1.104 to 1.143, wherein the method is for preventing death due to F / FA overdose. 1.145 Any of Method 1-A or 1.104 to 1.144, wherein the method is a method for anesthesia recovery (e.g., post-operative, e.g., anesthesia recovery). 1.146 Method 1-A or any of 1.104-1.145, wherein the F / FA is any F / FA disclosed throughout this specification. 1.147 Method 1-A or any of 1.104-1.146, wherein F / FA is selected from fentanyl, sufentanil, alfentanil, remifentanil, carfentanil, thiafentanil, lofentanil, ocfentanil, trefantinil and brifentanil. 1.148 Method 1-A or any of 1.104-1.147, wherein F / FA is selected from fentanyl, sufentanil, alfentanil and carfentanil. 1.149 F / FA is fentanyl, method 1-A or any of 1.104-1.148. 1.150 Any of Methods 1-A or 1.104-1.149, wherein the method does not cause induced withdrawal in the patient, e.g., withdrawal symptoms selected from tachycardia, nausea, vomiting, diarrhea, extreme anxiety, restless legs, muscle pain, and profuse sweating. 1.151 Method 1-A or any of 1.104 through 1.150, where the source of the F / FA is another illicit drug that is to be adulterated with the F / FA, such as cocaine, heroin, oxycodone, amphetamine, methamphetamine, or marijuana. 1.152 The method is (a) Treating or reversing a drug overdose; (b) treating or reversing drug-induced respiratory depression; (c) treating or reversing drug-induced muscular rigidity; (d) Treating or reversing drug-induced laryngospasm; or (e) Prevent deaths from drug overdoses The method of any of Methods 1-A or 1.104 to 1.150, wherein the drug is an illicit drug adulterated with F / FA. 1.153 Method 1.152, wherein the illegal drug is heroin, cocaine, amphetamine, methamphetamine, oxycodone, or marijuana. 1.154 Method 1.152 or 1.153, wherein the risk of overdose, respiratory depression, muscular rigidity, laryngospasm and / or death is due primarily or exclusively to the adulteration of F / FA in the illicit drug (e.g., in the absence of the adulteration of F / FA, the illicit drug would not pose said risk of overdose, respiratory depression, muscular rigidity, laryngospasm and / or death).

[0073] The compounds of the present disclosure (i.e., compounds of the present invention) and pharmaceutical compositions of the present disclosure can be used in combination with a second therapeutic agent, particularly at lower doses than when the individual agents are used as monotherapy, to improve the therapeutic activity of the combined agents without causing the undesirable side effects that typically occur with conventional monotherapy.Thus, the compounds of the present disclosure can be administered simultaneously, sequentially or simultaneously with other therapeutic agents described herein above, such as opiates, opioids, analgesics, antidepressants, anti-psychotics, other sleep aids, and / or agents used to treat Parkinson's disease or mood disorders.

[0074] In any of the embodiments of Method 1 below in which a compound of the present disclosure is administered with one or more second therapeutic agents, the one or more second therapeutic agents may be administered as part of a pharmaceutical composition comprising the compound of the present disclosure. Alternatively, the one or more second therapeutic agents may be administered in a separate pharmaceutical composition (e.g., pills, tablets, capsules, and injections) that is administered simultaneously, sequentially, or separately from the administration of the compound of the present disclosure.

[0075] In some further embodiments of the present disclosure, the pharmaceutical compositions of the present disclosure can be used in combination with a second therapeutic agent, particularly at lower doses than when the individual agents are used as monotherapy, to improve the therapeutic activity of the combined agents without causing undesirable side effects, and the second therapeutic agent is an opioid antagonist or inverse agonist (e.g., naloxone). The compounds of the present disclosure can be administered simultaneously, sequentially, or simultaneously with such opioid antagonist or opioid inverse agonist.

[0076] In a fourth aspect, the disclosure provides for the use of a compound of the invention in the manufacture of a medicament for use according to Method 1 or any of Methods 1.1-1.154. In another embodiment, the disclosure provides a compound of the invention for use in treating a disease or disorder according to Method 1 or any of Methods 1.1-1.154.

[0077] Detailed Description Compounds of formula A and related compounds have been shown to have a variety of useful pharmaceutical properties, each of which is expected to be common to many of the compounds of the present disclosure. Such properties, and data supporting the efficacy of such therapeutic agents, are disclosed, for example, in U.S. Pat. No. 10,245,260, U.S. Pat. No. 11,376,249, U.S. Patent Application Publication No. 2021 / 0093634, WO 2021 / 154519, U.S. Patent Application Publication No. 2022 / 0088014, WO 2020 / 206391, U.S. Patent Application Publication No. 2022 / 0184072, U.S. Provisional Application No. 63 / 262,732, and PCT / US2022 / 078177, the contents of each of which are hereby incorporated by reference in their entirety.

[0078] For example, compounds of formula A exhibit potent 5-HT agonism along with moderate D2 receptor and SERT antagonism. 2A, D1 and mu opioid receptor antagonism. Moreover, it has been unexpectedly found that such compounds can operate as "biased" mu opioid receptor ligands. This means that when a compound binds to the mu opioid receptor, it may operate as a partial mu agonist via G-protein coupled signaling, but act as a mu antagonist via beta-arrestin signaling. This is in contrast to the traditional opioid agonists morphine and fentanyl, which tend to strongly activate both G-protein and beta-arrestin signaling. Activation of beta-arrestin signaling by such drugs is believed to mediate the gastrointestinal dysfunction and respiratory depression typically mediated by opioid drugs. The compounds of the present invention are therefore expected to produce pain relief with less severe gastrointestinal and respiratory side effects than existing opioid analgesics. This effect has been shown in preclinical studies of the biased mu agonist oliceridine, as well as in phase II and III clinical trials. Oliceridine has been shown to reduce beta-arresting signaling compared to morphine and produce biased mu agonism via G-protein coupled signaling, leading to its ability to produce analgesia with reduced respiratory side effects compared to morphine. Furthermore, because these compounds antagonize the beta-arrestin pathway, they are expected to be useful in treating opioid overdoses, as they inhibit the most severe opioid adverse effects while also providing pain relief. Furthermore, these compounds have sleep-promoting effects due to serotonergic activity. Since many people suffering from chronic pain have difficulty sleeping due to pain, these compounds can help such patients sleep through the night due to the synergistic effects of serotonergic and opioid receptor activity.

[0079] Thus, in certain embodiments, the compounds of the present disclosure may be used alone or together with opioid antagonists or inverse agonists (e.g., naloxone or naltrexone) in methods for treating opioid use disorder (OUD), opioid overdose, or opioid withdrawal. The compounds of the present disclosure are expected to show a strong ability to alleviate the dysphoria and psychiatric comorbidities associated with drug withdrawal (e.g., mood and anxiety disorders, sleep disorders), which also provide strong analgesia, but without the adverse effects (e.g., GI effects and pulmonary depression) and abuse potential seen with other opioid treatments (e.g., oxycodone, methadone, or buprenorphine). The unique pharmacological profile of these compounds should also alleviate the risk of adverse drug-interactions (e.g., alcohol). These compounds are therefore particularly suited for treating symptoms associated with opioid use disorder and opioid withdrawal. In addition to the direct effects of the compounds on mu receptor activity, the effects of the compounds on serotonergic pathways result in antidepressant, sleep-promoting, and anxiolytic effects. Because depression and anxiety are important factors that lead patients to become susceptible to opioid use in the first place, the compounds of the present disclosure reduce both the psychiatric comorbidities that drive opioid use while at the same time reducing the symptoms of opioid withdrawal, a dual-pronged strategy that reduces the risk of remission. The sleep maintenance afforded by these compounds further improves the quality of life of patients undergoing OUD treatment.

[0080] Unless otherwise specified or apparent from context, the following terms used herein have the following meanings:

[0081] The terms "opiate" and "opioid" are distinct, with "opiate" referring to natural products derived from opium poppy, such as morphine, codeine, and heroin, while "opioid" is understood to refer to these natural compounds, as well as their semi-synthetic and synthetic derivatives, such as fentanyl and its analogues.

[0082] As used herein, unless otherwise indicated, "alkyl" refers to a saturated or unsaturated hydrocarbon moiety, e.g., from 1 to 21 carbon atoms in length, and any such alkyl may be straight-chained or branched (e.g., n-butyl or tert-butyl), and is preferably straight-chained, unless otherwise specified. For example, "C1 to 21 "Alkyl" refers to an alkyl having 1 to 21 carbon atoms. In one embodiment, the alkyl is selected from the group consisting of one or more hydroxy or C 1~22 and optionally substituted with an alkoxy (e.g., ethoxy) group. In another embodiment, the alkyl contains 1 to 21 carbon atoms, is preferably straight chained, and may be saturated or unsaturated, e.g., in some embodiments where R1 is an alkyl chain containing 1 to 21 carbon atoms, preferably 6 to 15 carbon atoms, 16 to 21 carbon atoms, e.g., so that, together with the -C(O)- to which it is attached, e.g., when cleaved from the compound of formula I, it forms the residue of a natural or unnatural, saturated or unsaturated fatty acid.

[0083] The term "pharmaceutical acceptable diluents or carriers" is intended to mean diluents and carriers that are useful in pharmaceutical preparations and that do not contain substances known to be allergenic, pyrogenic or pathogenic, or that potentially cause or promote disease. Pharmaceutically acceptable diluents or carriers therefore exclude bodily fluids, such as for example blood, urine, spinal fluid, saliva, and components thereof, such as blood cells and circulating proteins. Suitable pharma- ceutically acceptable diluents and carriers can be found in a number of well-known treatises on pharmaceutical formulations, such as Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated by reference herein in their entireties.

[0084] The terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound refer to the physical state of said compound after it has been isolated from a synthetic process (e.g., from a reaction mixture), or from a natural source, or a combination thereof. Thus, the terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound refer to the physical state of said compound after it has been obtained from a purification process described herein or known to one of skill in the art (e.g., chromatography, recrystallization, LC-MS and LC-MS / MS techniques) with sufficient purity to permit characterization by standard analytical techniques described herein or known to one of skill in the art.

[0085] Unless otherwise indicated, the compounds of the present disclosure, e.g., compounds I or 1.1-1.20 (collectively, the compounds of the present invention), may be present in free base form or in salt form, e.g., pharma- ceutical acceptable salt form, e.g., as acid addition salts. Acid-addition salts of compounds of the present invention that are sufficiently basic, e.g., acid-addition salts with inorganic or organic acids, e.g., hydrochloric acid or toluenesulfonic acid. Additionally, salts of compounds of the present invention that are sufficiently acidic are alkali metal salts, e.g., sodium or potassium salts, or salts with organic bases that provide a physiologically acceptable cation. In certain embodiments, the salts of compounds of the present invention are toluenesulfonic acid addition salts.

[0086] The compounds of the present invention are intended for use as pharmaceuticals, and therefore pharma- ceutically acceptable salts are preferred. Salts that are not suitable for pharmaceutical use may be useful, for example, in isolating or purifying the free compounds of the present invention, and thus are still included within the scope of the compounds of the present disclosure.

[0087] The compounds of the present invention may be in pure or substantially pure enantiomeric form, e.g., greater than 70% enantiomeric excess ("ee"), preferably greater than 80% ee, more preferably greater than 90% ee, and most preferably greater than 95% ee. The compounds of the present disclosure should be understood to include mixtures containing an amount of an enantiomer of a compound of formula I, as well as diastereomeric mixtures thereof. Purification of said isomers and separation of said isomeric mixtures can be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed).

[0088] It is also intended that the compounds of the present disclosure encompass their stable and unstable isotopes. Stable isotopes are non-radioactive isotopes that contain one additional neutron compared to the same abundant nuclide (i.e., element). The activity of compounds containing such isotopes is preserved, and such compounds are also expected to have utility for measuring the pharmacokinetics of non-isotopic analogs. For example, a hydrogen atom at a position on a compound of the present disclosure can be replaced with deuterium (a stable isotope that is non-radioactive). An example of a known stable isotope is deuterium ( 2 H or D), 13 C. 15 N, 18 Alternatively, unstable isotopes, which are radioactive isotopes that contain additional neutrons compared to the homogeneous abundant nuclide (i.e., element), e.g. 123 I, 131 I, 125 I, 11 C. 18 F may be replaced by the corresponding abundant species of I, C, and F. Another example of a useful isotope of the compounds of the invention is: 11 C isotopes. These radioisotopes are useful for radioimaging and / or pharmacokinetic studies of the compounds of the present invention. In addition, substitution of atoms with distributed natural isotopes with heavier isotopes can result in desirable changes in pharmacokinetic rates when these substitutions are made at metabolically liable sites. For example, deuterium ( 2Incorporation of H) can slow metabolic degradation if the hydrogen position is a site of enzymatic or metabolic activity.

[0089] The compounds of the present disclosure may be included as depot formulations, for example by dispersing, dissolving or encapsulating the compounds of the present invention in a polymer matrix as previously described herein, so that the compounds are released continuously as the polymer degrades over time. Release of the compounds of the present invention from the polymer matrix provides, for example, a controlled and / or delayed and / or sustained release of the compounds from the pharmaceutical depot composition to the subject to whom the pharmaceutical depot is administered, for example, a warm-blooded animal, e.g., a human. Thus, the pharmaceutical depot delivers the compounds of the present invention to the subject at a concentration effective to treat a particular disease or medical condition for a sustained period of time, for example, 14 to 180 days, preferably about 30, about 60 or about 90 days.

[0090] Polymers useful for the polymer matrix in the compositions of the invention (e.g., depot compositions of the invention) include polyesters of hydroxy fatty acids and their derivatives, or other agents such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-beta-hydroxybutyric acid, epsilon-capro-lactone ring-opening polymers, lactic acid-glycolic acid copolymers, 2-hydroxybutyric acid-glycolic acid copolymers, polylactic acid-polyethylene glycol copolymers or polyglycolic acid-polyethylene glycol copolymers), alkyl alpha-cyanoacrylates (e.g., The polymer may include polymers such as poly(butyl 2-cyanoacrylate), polyalkylene oxalates (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoesters, polycarbonates (e.g., polyethylene carbonate or polyethylene-propylene carbonate), polyortho-carbonates, polyamino acids (e.g., poly-gamma-L-alanine, poly-.gamma-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), hyaluronic acid esters, one or more of which may be used.

[0091] When the polymers are copolymers, they can be either random, block and / or graft copolymers. When the above alpha-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in the molecule, any one of D-isomers, L-isomers and / or DL-isomers can be used. In particular, alpha-hydroxycarboxylic acid polymers (preferably lactic acid-glycolic acid polymers), their esters, poly-alpha-cyanoacrylic acid esters, etc. can be used, with lactic acid-glycolic acid copolymers (also called poly(lactide-alpha-glycolide) or poly(lactic acid-co-glycolic acid), hereinafter referred to as PLGA) being preferred. Thus, in one embodiment, the polymer useful for the polymer matrix is ​​PLGA. The term PLGA as used herein includes polymers of lactic acid (also called polylactide, poly(lactic acid) or PLA). Most preferably, the polymer is a biodegradable poly(d,l-lactide-co-glycolide) polymer.

[0092] In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymeric material. The term "biocompatible" is defined as a polymeric material that is not toxic, carcinogenic, and does not significantly induce inflammation in body tissues. The matrix material should be biodegradable, that is, the polymeric material should degrade by body processes into products that can be easily excreted from the body and should not accumulate in the body. In that the polymeric matrix is ​​biocompatible with the body, the products of biodegradation should also be biocompatible with the body. Particular useful examples of polymeric matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(orthocarbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, and natural polymers including albumin, casein, and waxes, such as glycerol mono- and distearate. A preferred polymer for use in the practice of the present invention is dl (polylactide-co-glycolide). The molar ratio of lactide to glycolide in such copolymers preferably ranges from about 75:25 to 50:50.

[0093] Useful PLGA polymers may have a weight-average molecular weight of about 5,000 to 500,000 Daltons, preferably about 150,000 Daltons. Depending on the rate of degradation to be achieved, polymers of different molecular weights may be used. For a diffusion mechanism of drug release, the polymer should remain intact until all of the drug is released from the polymer matrix and then degrade. Drugs may also be released from the polymer matrix as the polymer excipient bioerodes.

[0094] PLGA may be prepared by any conventional method or may be commercially available. For example, PLGA may be produced from cyclic lactide, glycolide, etc. by ring-opening polymerization using a suitable catalyst (see EP 0058481 B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0095] PLGA is believed to be biodegradable under biological conditions (e.g., in the presence of water and biological enzymes found in the tissues of warm-blooded animals, e.g., humans), by the breakdown of the entire solid polymer composition, with the hydrolytically and enzymatically cleavable ester bonds breaking down to form lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble, non-toxic products of normal metabolism, which can further biodegrade to form carbon dioxide and water. In other words, PLGA is believed to degrade by hydrolysis of its ester groups in the presence of water, e.g., in the body of warm-blooded animals, e.g., humans, to produce lactic acid and glycolic acid, creating an acidic microclimate. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body of warm-blooded animals, e.g., humans, under normal physiological conditions, and thus are well tolerated and produce minimal systemic toxicity.

[0096] In another embodiment, the polymer matrix useful in the present invention may include star polymers, in which the structure of the polyester is star-shaped. These polyesters have a single polyol residue as the central moiety surrounded by a chain of acid residues. The polyol moiety may be, for example, glucose, or, for example, mannitol. These esters are known and are described in British Patent No. 2,145,422 and U.S. Patent No. 5,538,739, the contents of which are incorporated by reference.

[0097] Star polymers can be prepared using polyhydroxy compounds, such as polyols, such as glucose or mannitol, as initiators. The polyols contain at least three hydroxy groups and have a molecular weight of up to about 20,000 Daltons, and at least one, preferably at least two, for example an average of three, of the hydroxy groups of the polyols containing polylactide or co-polylactide chains are in the form of ester groups. Branched polyesters, such as poly(d,l-lactide-co-glycolide), have a central glucose moiety with rays of linear polylactide chains.

[0098] The above-described depot composition of the present invention (long-acting injectable composition having the compound of the present invention in a polymer matrix) may contain a polymer in the form of microparticles or nanoparticles in which the compound of the present invention is dispersed or encapsulated, or in liquid form. "Microparticle" refers to a solid particle containing the compound of the present invention in solution or solid form, such compound being dispersed or dissolved within a polymer that serves as the matrix of the particle. By appropriate selection of polymer material, microparticle formulations can be made in which the resulting microparticles exhibit both diffusional and biodegradable release properties.

[0099] When the polymer is in the form of microparticles, the microparticles can be prepared using any suitable method, for example, by solvent evaporation or solvent extraction. For example, in the solvent evaporation method, the compound of the present invention and the polymer can be dissolved in a volatile organic solvent (for example, a ketone, for example, acetone; a halogenated hydrocarbon, for example, chloroform or methylene chloride; a halogenated aromatic hydrocarbon; a cyclic ether, for example, dioxane; an ester, for example, ethyl acetate; a nitrile, for example, acetonitrile; or an alcohol, for example, ethanol) and dispersed in an aqueous phase containing a suitable emulsion stabilizer (for example, polyvinyl alcohol, PVA). The organic solvent is then evaporated to obtain microparticles with the compound of the present invention encapsulated. In the solvent extraction method, the compound of the present invention and the polymer can be dissolved in a polar solvent (for example, acetonitrile, dichloromethane, methanol, ethyl acetate or methyl formate) and then dispersed in an aqueous phase (for example, a water / PVA solution). An emulsion is produced to obtain microparticles with the compound of the present invention encapsulated. Spray drying is an alternative manufacturing technique for preparing microparticles.

[0100] Alternative methods for preparing the microparticles of the present invention are described in both US Pat. No. 4,389,330 and US Pat. No. 4,530,840.

[0101] The microparticles of the present invention can be prepared by any method that can produce microparticles in a size range that is acceptable for use in injection compositions. One preferred method of preparation is described in U.S. Pat. No. 4,389,330. In this method, the active agent is dissolved or dispersed in a suitable solvent. To the medium containing the agent, a polymer matrix material is added in an amount relative to the active ingredient that will yield a product with the desired active agent loading. All of the ingredients of the microparticle product may be blended together in the solvent medium.

[0102] Solvents for making such compositions containing the compounds of the present invention and polymer matrix materials that can be used in the practice of the present invention include organic solvents such as acetone; halogenated hydrocarbons such as chloroform, methylene chloride, etc.; aromatic hydrocarbon compounds; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols such as benzyl alcohol; ethyl acetate.In one embodiment, the solvent for use in the practice of the present invention can be a mixture of benzyl alcohol and ethyl acetate.More information on the preparation of microparticles useful in the present invention can be found in U.S. Patent Application Publication No. 2008 / 0069885, the contents of which are incorporated herein by reference in their entirety.

[0103] The amount of the compound of the present disclosure incorporated into the microparticles typically ranges from about 1 wt.% to about 90 wt.%, preferably 30 to 50 wt.%, and more preferably 35 to 40 wt.%, where wt.% refers to the portion of the compound of the present disclosure relative to the total weight of the microparticle.

[0104] The pharmaceutical depot composition may comprise a pharma- ceutically acceptable diluent or carrier, such as a water-miscible diluent or carrier.

[0105] Details of osmotic-controlled release oral delivery system compositions can be found in EP1 539 115 [US Pub. No. 2009 / 0202631] and WO2000 / 35419 (US2001 / 0036472), the contents of each of which are incorporated by reference in their entirety.

[0106] A "therapeutically effective amount" is an amount of a compound of the invention (e.g., contained in a pharmaceutical depot) that, when administered to a subject suffering from a disease or disorder, is effective to cause a decrease, alleviation or regression of the disease or disorder over the time period for which treatment is intended.

[0107] Dosages used in the practice of the present invention will, of course, vary depending, for example, on the particular disease or condition being treated, the particular compound of the present invention being used, the mode of administration, and the therapy desired.Unless otherwise indicated, the amount of a compound of the present invention (whether administered as a free base or as a salt form) for administration refers to or is based on the amount of the compound of the present invention in free base form (i.e., calculations of the amount are based on the amount of free base).

[0108] The compounds of the invention can be administered by any satisfactory route, including orally, parenterally (intravenously, intramuscularly or subcutaneously) or transdermally. In certain embodiments, the compounds of the invention, for example in a depot formulation, are preferably administered parenterally, for example by injection, for example intramuscularly or subcutaneously.

[0109] In general, it is indicated that satisfactory results for the methods of treatment disclosed herein or the use of the compounds of the invention described above can be obtained by oral administration of about 1 mg to about 100 mg once daily, as specified above, preferably at a dose of 2.5 mg to 50 mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg once daily, preferably by oral administration.

[0110] For the treatment of some diseases, particularly for the treatment of sleep disorders, lower doses, for example about 2.5 mg to 5 mg, e.g. 2.5 mg, 3 mg, 4 mg or 5 mg, of the compounds of the invention in free or pharma- ceutically acceptable salt form, administered once daily, preferably orally, are satisfactory.

[0111] For methods of treatment involving the simultaneous administration of a second therapeutic agent, satisfactory results are obtained with doses of less than 100 mg, preferably less than 50 mg, for example less than 40 mg, less than 30 mg, less than 20 mg, less than 10 mg, less than 5 mg, less than 2.5 mg once daily.

[0112] For the treatment of disorders disclosed herein, where a depot composition is used to achieve a longer duration of action, the dosage will be higher compared to shorter acting compositions, e.g., higher than 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or more than 1000 mg. The duration of action of the compounds of the present disclosure can be controlled by manipulation of the polymer composition, i.e., the polymer:drug ratio and the size of the microparticles. When the composition of the present invention is a depot composition, administration by injection is preferred.

[0113] The pharmaceutical acceptable salt of the compound of the present disclosure can be synthesized by conventional chemical methods from parent compound containing basic or acidic moiety.Generally, such salt can be prepared by reacting the free base form of these compounds with stoichiometric amount of suitable acid in water or in organic solvent or in the mixture of the two, and generally non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.Further details for preparing these salts, such as toluenesulfonate salt in amorphous or crystalline form, can be found in US8,309,722, 8.648,077, 9,199,995 and 9,586,960.

[0114] Pharmaceutical compositions containing the compounds of the present disclosure can be prepared using conventional diluents or excipients (examples include, but are not limited to, sesame oil) and techniques known in the galenic art.Accordingly, oral dosage forms can include tablets, capsules, liquids, suspensions, etc.

[0115] The term "concurrently," when referring to therapeutic applications, means the administration of two or more active ingredients to a patient as part of a regimen to treat a disease or disorder, whether the two or more active agents are given at the same time or at different times, or whether they are given by the same route of administration or by different routes. Concurrent administration of two or more active ingredients can be at different times on the same day, or on different dates, or at different times.

[0116] The term "concurrently," when referring to therapeutic applications, refers to the administration of two or more active ingredients by the same route of administration or at about the same time.

[0117] The term "separately", when referring to therapeutic applications, refers to the simultaneous or near simultaneous administration of two or more active ingredients by different routes of administration.

[0118] Methods of Making the Compounds of the Invention Compounds of formula A and methods for their synthesis, including the synthesis of intermediates used in the synthetic schemes described below, are disclosed, for example, in US 10,245,260 and US 2022 / 0041600 and US 2022 / 0064166, the contents of which are hereby incorporated by reference in their entireties. Compounds of the present disclosure may be prepared using similar procedures, in which the opposite enantiomer of a compound of formula I, or a synthetic intermediate thereof, is isolated and purified.

[0119] The synthesis of similar fused gamma-carbolines is disclosed, for example, in US 8,309,722, US 8,993,572, US 2017 / 0183350, WO 2018 / 126140 and WO 2018 / 126143, the contents of each of which are incorporated by reference in their entirety. Compounds of the present disclosure may be prepared using similar procedures.

[0120] Isolation or purification of diastereoisomers of compounds of the present invention can be achieved by conventional methods known in the art, such as column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, simulated moving bed.

[0121] Salts of the compounds of the present disclosure may be prepared similarly as described in U.S. Pat. Nos. 6,548,493, 7,238,690, 6,552,017, 6,713,471, 7,183,282, 8,648,077, 9,199,995, 9,586,860, U.S. Reissue Patent No. 39680, and U.S. Reissue Patent No. 39679, the contents of each of which are incorporated by reference in their entirety. EXAMPLES

[0122] Example 1 Synthesis of trans-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (racemic mixture)

[0123] [ka]

[0124] The compound of Example 1 may be prepared according to the following scheme.

[0125] [ka]

[0126] Step A: (4aR,9bR)-2-benzyl-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (2). To a suspension of 2-benzyl-6-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (5.50 g, 16 mmol) in THF (10 mL) is slowly added borane (1.0 M in THF, 150 mL) at room temperature. The resulting solution is heated to 40° C. and stirred over the weekend. After cooling to room temperature, the reaction mixture is concentrated and HCl (6N, 37 mL) is added. The mixture is heated to 100° C. and stirred for 0.5 h, then cooled to room temperature. Water (45 mL) is added and the precipitate is collected by filtration. The filtrate is basified and concentrated. The residue is purified by column chromatography using a gradient of 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v / v)] in ethyl acetate to obtain the racemic title compound (compound 2) as a white foam (1.56 g, 28% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.34 (d, J = 5.8 Hz, 4H), 7.28 (dt, J = 5.9, 2.2 Hz, 1H), 7.16 (dd, J = 8.2, 1.1 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.56 (dd, J = 8.1, 7.2 Hz, 1H), 5.77 (d, J = 3.0 Hz, 1H), 3.65 (s, 2H), 3.49 - 3.37 (m, 2H), 3.01 - 2.89 (m, 1H), 2.85 - 2.69 (m, 1H), 2.20 (m, 1H), 2.16 - 2.05 (m, 1H), 2.05 - 1.98 (m, 1H), 1.86 - 1.66 (m, 1H). HRMS (ESI) m / z C 18 H 20 BrN2[M+H] + Calculated value: 343.0804; Measured value: 343.0828.

[0127] Step B: 2-((4aR,9bR)-2-benzyl-6-bromo-1,2,3,4,4a,9b-hexahydro-5H-pyrido[4,3-b]indol-5-yl)acetamide (3). To a degassed suspension of compound 2 (0.420 g, 1.22 mmol) in toluene (4 mL) is added lithium bis(trimethylsilyl)amide (1.0 M in toluene, 4 mL) at 0° C. and the mixture is stirred for 0.5 h. Chloroacetamide (0.112 g, 1.22 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is quenched with methanol (5 mL) and concentrated. The residue is suspended in dichloromethane (100 mL), washed with water (20 mL) and then dried over MgSO4. The dichloromethane phase is separated and evaporated to dryness. The residue is purified by column chromatography using a gradient of 0-50% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v / v)] in ethyl acetate to obtain the racemic title compound (compound 3) as a white solid (0.340 g, 69% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.49 (s, 2H), 7.32 (m, 4H), 7.29 - 7.22 (m, 1H), 6.99 - 6.93 (m, 2H), 6.58 (m, 1H), 4.18 - 3.86 (m, 2H), 3.73 - 3.52 (m, 2H), 3.46 (m, 1H), 3.42 (m, 1H), 3.04 - 2.92 (m, 1H), 2.75 (m, 1H), 2.15 (t, J = 10.5 Hz, 1H), 2.11 - 2.00 (m, 1H), 1.95 (m, 1H), 1.66 (dd, J = 11.7, 4.0 Hz, 1H). HRMS (ESI) m / z C 20 H 23 BrNO [M+H] + Calculated value: 400.1019; Measured value: 400.1041.

[0128] Step C: (6bR,10aR)-8-benzyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (4). A mixture of racemic compound 3 (0.92 g, 2.3 mmol), K2CO3 (0.69 g, 5.1 mmol) and CuI (0.11 g, 0.58 mmol) in dioxane (10 mL) is bubbled with argon for 5 min. To this mixture is added N,N,N',N'-tetramethylethylenediamine (0.20 mL) and the resulting suspension is stirred at 100 °C for 48 h. The mixture is cooled to room temperature and poured onto a pad of silica gel and filtered. The filter cake is rinsed with ethyl acetate / methanol / 7N NH3 (20:1:0.1 v / v / v) (200 mL). The filtrate is concentrated to dryness to give the title compound (compound 4) as a white solid (0.157 g, 21% yield). The crude product was used directly in the next reaction without further purification. 1 H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.35 (d, J = 5.5 Hz, 4H), 7.27 (m, 1H), 6.86 - 6.64 (m, 2H), 6.60 (dt, J = 7.6, 1.1 Hz, 1H), 3.78 (d, J = 14.4 Hz, 1H), 3.70 - 3.54 (m, 2H), 3.51 - 3.41 (m, 1H), 2.98 (dt, J = 11.8, 3.3 Hz, 1H), 2.84 (m, 1H), 2.51 (m, 2H), 2.30 - 2.09 (m, 2H), 2.04 (dd, J = 11.8, 3.1 Hz, 1H), 1.80 - 1.61 (m, 1H). HRMS (ESI) m / z C 20 H 22 NO [M+H] + Calculated value: 320.1757; Measured value: 320.1745.

[0129] Step D: (6bR,10aR)-6b,7,8,9,10,10a-Hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (5). Pd / C (0.011 g) is added to a solution (45 mL) of racemic compound 4 (0.050 g, 0.16 mmol) in methanol (45 mL). The mixture is degassed with hydrogen and stirred overnight under hydrogen atmosphere. The solvent is removed and the residue is purified by column chromatography using a gradient of 0-100% mixed solvent [methanol / 7N NH3 (10:1:0.1 v / v)] in ethyl acetate. The title compound (compound 5) is obtained as a white solid (0.021 g, 57% yield). MS (ESI) m / z 230.1 [M+H] + .

[0130] Step E: (6bR,10aR)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (6). A mixture of racemic compound 5 (0.021 g, 0.09 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (25 μL, 0.14 mmol) and KI (0.023 g, 0.14 mmol) in DMF (3.0 mL) is bubbled with argon for 3 min, then DIPEA (25 μL, 0.14 mmol) is added. The resulting mixture is heated to 76 °C and stirred at this temperature for 2 h. The solvent is removed and the residue is purified by silica gel column chromatography using a gradient of 0-100% mixed solvent [ethyl acetate / methanol / 7N NH3 (10:1:0.1 v / v / v)] in ethyl acetate to obtain the title product as a white solid (0.0035 g, 10% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.11 (t, J = 8.8 Hz, 2H), 7.00-6.91 (m, 2H), 6.79 (d, J = 7.4 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 4.00 (t, J = 6.4 Hz, 2H), 3.79 (d, J = 14.4 Hz, 1H), 3.53 (dd, J = 10.6, 3.4 Hz, 1H), 3.05 (d, J = 11.3 Hz, 1H), 2.86-2.71 (m, 1H), 2.58 (t, J = 6.6 Hz, 2H), 2.18 - 2.00 (m, 3H), 1.92 (p, J = 6.7 Hz, 2H), 1.69 (dd, J = 11.6, 4.0 Hz, 1H). HRMS (ESI) m / z C 22 H 25 FN3O2[M+H] + Calculated value: 382.1925; Measured value: 382.1942.

[0131] Example 2 Receptor Binding Profile Receptor binding is determined for the compounds of Example 1 and Formulae A and B. The following literature procedures were used, each of which is incorporated herein by reference in its entirety: 5-HT 2A : Bryant, HU et al. (1996), Life Sci., 15:1259-1268; D2: Hall, DA and Strange, PG (1997), Brit. J. Pharmacol., 121:731-736; D1: Zhou, QY et al. (1990), Nature, 347:76-80; SERT: Park, YM et al. (1999), Anal. Biochem., 269:94-104; Mu opiate receptor: Wang, JB et al. (1994), FEBS Lett., 338:217-222.

[0132] Generally, the percent of control specific binding obtained in the presence of a test compound;

[0133]

number

[0134]

number

[0135] I C 50 The value (the concentration that causes half-maximal inhibition of specific binding of the control) and the Hill coefficient (nH) were calculated using the Hill equation

[0136]

number

[0137]

number

[0138] The following receptor affinity results are obtained:

[0139] [Table 1]

[0140] These receptor binding studies demonstrate an unexpectedly different pharmacological profile of the compound of Example 1 (compound of formula I) compared to its diastereoisomers, compounds of formulas A and B.

[0141] The preceding examples are exemplary only and are not meant to limit the scope of the disclosure in any way.

Claims

1. A compound of formula I, in free or salt form (e.g., a pharma- ceutically acceptable salt form), e.g., isolated or purified, free or salt form (e.g., a pharma- ceutically acceptable salt form), 【Chemistry 1】 Compounds having trans-stereochemistry across the 6b-10a ring fusion.

2. Compound I is a compound of formula IA and IB, in free or salt form (e.g., a pharma- ceutically acceptable salt form): 【Chemistry 2】 2. The compound of claim 1, which is a mixture of compounds of the formula:

3. 2. The compound of claim 1, wherein compound I is racemic, e.g., a 50:50 molar ratio of compound of formula IA to compound of formula 1B.

4. 2. The compound of claim 1, wherein compound I has a molar excess of the compound of formula 1A, e.g., at least 55 mol%, or at least 60 mol%, or at least 65 mol%, or at least 70 mol%, or at least 75 mol%, or at least 80 mol%, or at least 85 mol%, or at least 90 mol%, or at least 95 mol% of the compound of formula 1A, measured from the total amount of compounds of formula I (i.e., not taking into account any compounds other than the compounds of formulae 1A and 1B).

5. 2. The compound of claim 1, wherein compound I has a molar excess of the compound of formula 1B, e.g., at least 55 mol%, or at least 60 mol%, or at least 65 mol%, or at least 70 mol%, or at least 75 mol%, or at least 80 mol%, or at least 85 mol%, or at least 90 mol%, or at least 95 mol% of the compound of formula 1B, measured from the total amount of compounds of formula I (i.e., not taking into account any compounds other than the compounds of formulae 1A and 1B).

6. The compound is substantially free of any compound of formula A, e.g., having 5 wt. % or less of compounds of formula A, measured relative to the total weight of the compound, e.g., 4 wt. % or less, or 3 wt. % or less, or 2 wt. % or less, or 1 wt. % or less, or 0.5 wt. % or less, or 0.25 wt. % or less, or 0.15 wt. % or less, or 0.1 wt. % or less, or 0.05 wt. % or less, or 0.01 wt. % or less of compounds of formula A, and / or the compound is substantially free of any compound of formula B, e.g., having 5 wt. % or less of compounds of formula B, measured relative to the total weight of the compound, e.g., 4 wt. % or less, or 3 wt. % or less, or 2 wt. % or less, or 1 wt. % or less, or 0.5 wt. % or less, or 0.25 wt. % or less.

6. The compound of claim 1 having no more than 0.15 wt.%, or no more than 0.1 wt.%, or no more than 0.05 wt.%, or no more than 0.01 wt.% of a compound of formula B.

7. 7. The compound according to any one of claims 1 to 6, wherein the compound is in substantially pure form, e.g. at least 90%, or at least 95%, or at least 98%, or at least 99% pure relative to all compounds or impurities present other than any compound of formula I.

8. 8. A compound according to any one of claims 1 to 7 in the form of a salt, for example a pharma- ceutically acceptable salt.

9. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, in free or pharma- ceutically acceptable salt form (e.g. a pharma- ceutical acceptable salt form), in admixture with a pharma- ceutical acceptable diluent or carrier.

10. A method for treating or preventing a central nervous system disorder, comprising administering to a patient in need thereof a compound according to any one of claims 1 to 8, in free or pharma- ceutical acceptable salt form, or a pharmaceutical composition according to claim 9.

11. The disorder is serotonin 5-HT ２Ａ 11. The method of claim 10, wherein the central nervous system disorder is a disorder involving the opioid receptor, the dopamine D1 receptor and / or D2 receptor system, and / or the serotonin reuptake transporter (SERT) pathway, and / or the mu-opioid receptor pathway.

12. 10. Use of a compound according to any one of claims 1 to 8, in free or pharma- ceutically acceptable salt form, or a pharmaceutical composition according to claim 9, in the manufacture of a medicament for treating or preventing a central nervous system disorder.

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