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WO2010111353A1 - Dérivés de pipéridine n-substitués en tant qu'agents spécifiques des récepteurs de la sérotonine - Google Patents

Dérivés de pipéridine n-substitués en tant qu'agents spécifiques des récepteurs de la sérotonine Download PDF

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Publication number
WO2010111353A1
WO2010111353A1 PCT/US2010/028444 US2010028444W WO2010111353A1 WO 2010111353 A1 WO2010111353 A1 WO 2010111353A1 US 2010028444 W US2010028444 W US 2010028444W WO 2010111353 A1 WO2010111353 A1 WO 2010111353A1
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disorder
compound
mmol
sdi
attorney docket
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Inventor
Nathalie Schlienger
Mikkel Thygesen
Henriette Kold Uldam
Kara Schmelzer
Ali Tabatabaei
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Acadia Pharmaceuticals Inc
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Acadia Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present application relates to the fields of chemistry and medicine. More particularly, the present application relates to selective serotonin inverse agonists and/or antagonists and methods of treating diseases and/or conditions with the select selective serotonin inverse agonists and/or antagonists.
  • Serotonin or 5-hydroxytryptamine plays a significant role in the functioning of the mammalian body.
  • 5 -HT is an important neurotransmitter and neuromodulator that is implicated in such diverse behaviors and responses as sleeping, eating, locomotion, perceiving pain, learning and memory, sexual behavior, controlling body temperature and blood pressure.
  • serotonin plays an important role in the control systems of the afferent peripheral nociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)).
  • Peripheral functions in the cardiovascular, hematological and gastrointestinal systems have also been ascribed to 5 -HT.
  • 5 -HT has been found to mediate a variety of contractile, secretory, and electrophysiologic effects including vascular and nonvascular smooth muscle contraction, and platelet aggregation.
  • the 5 -HT2 A receptor subtype (also referred to as subclass) is widely yet discretely expressed in the human brain,
  • This receptor subtype is also expressed on mature platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis.
  • Serotonin receptors are members of a large human gene family of membrane-spanning proteins that function as transducers of intercellular communication.
  • GPCRs G-protein coupled receptors
  • G-proteins G-protein coupled receptors
  • second messenger molecules such as cyclic AMP, inositol phosphates, and diacylglycerol.
  • At least 15 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven families (5 -HT 1-7). Each subtype displays a unique distribution, preference for various ligands, and functional correlate(s).
  • Serotonin may be an important component in various types of pathological conditions such as certain psychiatric disorders (depression, aggressiveness, panic attacks, obsessive compulsive disorders, psychosis, schizophrenia, suicidal tendency), certain neurodegenerative disorders (Alzheimer-type dementia, Parkinsonism, Huntington's chorea), anorexia, bulimia, disorders associated with alcoholism, cerebral vascular accidents, and migraine (Meltzer, Neuropsychopharmacology, 21 :106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152 (1999); Glennon, Neurosci. Biobehavioral Rev., 14:35 (1990)). Recent evidence strongly implicates the 5-HT2 receptor subtype in the etiology
  • Schizophrenia is a particularly devastating neuropsychiatric disorder that affects approximately 1% of the human population. It has been estimated that the total financial cost for the diagnosis, treatment, and lost societal productivity of individuals affected by this disease exceeds 2% of the gross national product (GNP) of the United States. Current treatment primarily involves pharmacotherapy with a class of drugs known as antipsychotics.
  • Antipsychotics are effective in ameliorating positive symptoms (e.g., hallucinations and delusions), yet they frequently do not improve negative symptoms (e.g., social and emotional withdrawal, apathy, and poverty of speech).
  • positive symptoms e.g., hallucinations and delusions
  • negative symptoms e.g., social and emotional withdrawal, apathy, and poverty of speech.
  • nine major classes of antipsychotics are prescribed to treat psychotic symptoms. Use of these compounds is limited, however, by their side effect profiles. Nearly all of the "typical" or older generation compounds have significant adverse effects on human motor function.
  • Non- compliance can lead to increased hospitalization and health care costs.
  • Antipsychotic drugs have been shown to interact with a large number of central monoaminergic neurotransmitter receptors, including dopaminergic, serotonergic, adrenergic, muscarinic, and histaminergic receptors. It is likely that the therapeutic and adverse effects of these drugs are mediated by distinct receptor subtypes. The high degree of genetic and pharmacological homology between these receptor subtypes has hampered the development of subtype-selective compounds, as well as the determination of the normal physiologic or pathophysiologic role of any particular receptor subtype. Thus there is a need
  • Also provided are methods of inhibiting the activity of a serotonin receptor that can include contacting the monoamine receptor or a system containing a monoamine receptor with at least one substantially pure form of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) or a pharmaceutical composition described herein (e.g., a pharmaceutical composition that includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein).
  • a pharmaceutical composition described herein e.g., a pharmaceutical composition that includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein.
  • the methods comprise administering to a patient in need of such treatment or management a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof.
  • compositions, single unit dosage forms and dosing regiments which comprise a compound provided herein, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof.
  • a serotonin receptor in another embodiment, provided are methods of inhibiting the activity of a serotonin receptor that can include contacting the monoamine receptor or a system containing a monoamine receptor with at least one substantially pure form of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) or a pharmaceutical composition described herein (e.g., a pharmaceutical composition that includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein).
  • a pharmaceutical composition described herein e.g., a pharmaceutical composition that includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein.
  • kits for treating, managing and preventing various diseases and disorders which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound provided herein, or pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof.
  • a compound provided herein or pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof. Examples of dieases and disorders are described herein.
  • a compound provided herein, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof, is administered in combination with a second active agent.
  • Embodiments disclosed herein relate to a substantially pure form of a compound selected from Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V):
  • R is H. In another embodiment, R is CH 3 .
  • Ri is H.
  • Ri is an acyl .
  • Embodiments disclosed herein relate to a substantially pure form of a compound selected from Formula (I), Formula (II), Formula (III), Formula (IV) and Formula
  • Formulae (I), (II), (III), (IV) and (V) can include at least 75% of the compound.
  • (III), (IV) and (V) can include at least 80% of the compound.
  • the substantially pure form of a compound selected from Formulae (I), (II), (III), (IV) and (V) can include at least 85% of the compound. In yet still another embodiment, the substantially pure form of a compound selected from Formulae (I), (II), (III), (IV) and (V) can include at least 90% of the compound.
  • the substantially pure form of a compound selected from Formulae (I), (II), (III), (IV) and (V) can include at least 95% of the compound.
  • N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide for example, in mice, rats, monkeys and humans.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be “enatiomerically pure” or “stereomerically pure” or be stereoisomeric mixtures.
  • stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, greater than about 98% by weight of one stereoisomer of the compound and less than about 2% by weight of the other stereoisomers of the compound or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
  • stereomerically enriched means a composition that comprises greater than about 55% by weight of one stereoisomer of a compound, greater than about 60% by weight of one stereoisomer of a compound, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.
  • the term “enantiomerically pure” means a steromerically pure composition of a compound having one chiral center.
  • the term “enantiomerically enriched” means a stereomerically enriched composition of a compound having one chiral center.
  • the term “stereoisomer” encompasses all entiomerically/stereomerically pure and enantiomerically/stereomerically enriched compounds provided herein.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • acyl refers to a -CO-R 2 , wherein R 2 is C 1 -C 12 - alkyl. In one embodiment R 2 is branched Ci-Ci 2 alkyl. In one embodiment R 2 is methyl or ethyl.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids
  • Suitable non-toxic acids include inorganic and organic acids such as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucuronic, galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, p- toluenesulfonic and the like.
  • solvate means a compound that further includes a stoichiometric or non-shoichiometric amound of solvent bound by non- covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • prodrug refers to a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound.
  • prodrugs include, but are not limited to, compounds that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include compounds that comprise -NO, -NO , -ONO, or -ONO2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described in Burger 's Medicinal Chemistry and Drug Discovery, 172- 178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985).
  • biohydrolyzable carbamate refers to a carbamate, carbonate, ureide and phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable carbamates include, but are not limited to, carbamates that include lower alkylamine, substituted ethylenediamine, aminoacid, hydroxyalkylamine, heterocyclic and heteroaromatic amine, and polyether amine moieties.
  • carbamates that include lower alkylamine, substituted ethylenediamine, aminoacid, hydroxyalkylamine, heterocyclic and heteroaromatic amine, and polyether amine moieties.
  • the compound may comprise at least 75%, 80%, 85%, 90%, 95%, 99% of the mass, by weight, of a given sample.
  • esters and salts may be prepared from certain compounds of this invention. All of such stereoisomers, esters and salts are included in this invention.
  • esters are metabolically cleaved in the body, and that the actual drug, which such form is administered, is the hydroxy compound itself. It is possible, as has long been known in pharmaceutical chemistry, to adjust the rate or duration of action of the compound by appropriate choices of ester groups.
  • the compounds provided herein are radiolabeled.
  • Typical radiolabels may include 3 H, 11 C, 18 F and 125 I.
  • the compound as provided herein have one or more hydrogen or carbon atom enriched for deuterium (" 2 H") or carbon- 13 (" 13 C").
  • 2 H deuterium
  • 13 C carbon- 13
  • enriched for 2 H or 13 C it is meant that the 2 H or 13 C isotopes present at one or more positions in the compound are present in amounts greater than that found naturally.
  • Embodiments disclosed herein relate to a methods of inhibiting the activity of a serotonin receptor, including contacting the monoamine receptor or a system containing a monoamine receptor with at least one substantially pure form of a compound
  • the activity can be a signaling activity.
  • the activity can be constitutive.
  • the activity can be associated with serotonin receptor activation.
  • One embodiment disclosed herein relates to a method of inhibiting an activation of a serotonin receptor that can include contacting the monoamine receptor or a system containing a monoamine receptor with at least one substantially pure form of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) or a pharmaceutical composition described herein (e.g., a pharmaceutical composition that includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein).
  • the activation can be by an agonist agent.
  • the agonist agent can be exogenous. In an embodiment, the agonist agent can be endogenous. In some embodiments, the activation can be constitutive.
  • the system containing the serotonin receptor may, for example, be a subject such as a mammal, non-human primate or a human.
  • the system may also be an in vivo or in vitro experimental model, such as a cell culture model system that expresses a monoamine receptor, a cell-free extract thereof that contains a monoamine receptor, or a purified receptor.
  • tissue culture cells expressing the receptor, or extracts or lysates thereof are tissue culture cells expressing the receptor, or extracts or lysates thereof.
  • Cells that may be used in the present method include any cells capable of mediating signal transduction via monoamine receptors, especially the Serotonin 5HT2A receptor, either via endogenous expression of this receptor (certain types of neuronal cells lines, for example, natively express the 5HT2A receptor), or such as following introduction of the an exogenous gene into the cell, for example, by transfection of cells with plasmids containing the receptor gene.
  • Such cells are typically mammalian cells (or other eukaryotic cells, such as insect cells or Xenopus oocytes), because cells of lower life forms generally lack the appropriate signal transduction pathways for the present purpose.
  • suitable cells include: the mouse fibroblast cell line NIH 3T3 (ATCC
  • CRL 1658 which responds to transfected Mi receptors by increased growth
  • RAT 1 cells Pace et al, Proc. Natl. Acad. Sci. USA 88:7031-35 (1991)
  • pituitary cells Vallar et al, Nature 330:556-58 (1987)
  • Other useful mammalian cells for the present method include but are not limited to HEK 293 cells, CHO cells and COS cells.
  • Embodiments disclosed herein relate to a method of alleviating or treating one or more disease condition associated with a serotonin receptor that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) or a pharmaceutical composition described herein, such as a pharmaceutical composition that includes a therapeutically effective amount of at least one substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V).
  • the use of the compounds of Formulae (I), (II), (III), (IV) and/or (V) for treating a disease condition are provided.
  • the disease condition can be a neuropsychiatric disorder.
  • neuropsychiatric disorders include, but are not limited to, schizophrenia, schizoaffective disorder, mania, depression, a cognitive disorder, aggressiveness, panic attacks, obsessive compulsive disorder, borderline personality disorder, borderline disorder, multiplex developmental disorder (MDD), a behavioral disorder, psychosis, suicidal tendency, bipolar disorder, sleep disorder, addiction, attention deficit hyperactivity disorder (ADHD), post traumatic stress disorder (PTSD), Tourette's syndrome, anxiety, autism, Down's syndrome, a learning disorder, a psychosomatic disorder, alcohol withdrawal, epilepsy, pain, a disorder associated with hypoglutamatergia, and/or serotonin syndrome.
  • the depression can be dysthymia, SSRI-resistant depression and/or depression associated with psychosis.
  • the aggressiveness can be impulsive aggression.
  • the behavioral disorder can be associated with age- related dementia.
  • the disease condition is psychosis
  • the psychosis can be caused or results from various different origins.
  • the psychosis can be the result of drugs, treatment, and/or disease.
  • Exemplary diseases that can cause psychosis include dementia, post traumatic stress disorder, Alzheimer's disease, and schizophrenia.
  • the psychosis can be Parkinson's disease psychosis.
  • the psychosis can be
  • the psychosis can be dementia- related psychosis.
  • the psychosis can be the result of schizophrenia.
  • the sleep disorder can be selected from sleep maintenance insomnia, chronic insomnia, transient insomnia and periodic limb movements during sleep (PLMS).
  • the addiction can be selected from drug addiction, alcohol addiction, opioid addiction and nicotine addiction.
  • the anxiety can be general anxiety disorder (GAD).
  • the pain can be selected from chronic pain, neuropathic pain, inflammatory pain, diabetic peripheral neuropathy, fibromyalgia, postherpetic neuralgia and reflex sympathetic dystrophy.
  • the disease condition can be a cognitive disorder.
  • the disease condition can be a neurodegenerative disorder.
  • neurodegenerative disorders are Alzheimer's disease, Parkinson's disease, Huntington's chorea, sphinocerebellar atrophy, frontotemporal dementia, supranuclear palsy and Lewy body dementia.
  • the disease condition can be chemotherapy-induced emesis, frailty, on/off phenomena, non-insulin-dependent diabetes mellitus, metabolic syndrome, an autoimmune disorder, sepsis, increased intraocular pressure, glaucoma, a retinal disease, Charles Bonnet syndrome, substance abuse, sleep apnea, pancreatis, anorexia, bulimia, a disorder associated with alcoholism, a cerebral vascular accident, amyotrophic lateral sclerosis, AIDS related dementia, traumatic brain, traumatic spinal injury, tinnitus, a menopausal symptom, sexual dysfunction, low male fertility, low sperm motility, hair loss, hair thinning, incontinence, hemorrhoids, migraine, hypertension, thrombosis, abnormal hormonal activity, a hormonal disorder, a pituitary tumor, a side effect associated with a pituitary tumor, vasospasm, ischemia, cardiac arrhythmia
  • the autoimmune disorders can be lupus or multiple sclerosis.
  • the retinal disease can be age related macular degeneration.
  • the menopausal symptom can be hot flashes.
  • the sexual dysfunction can be selected from female sexual dysfunction, female sexual arousal dysfunction, hypoactive sexual desire disorder, decreased libido, pain,
  • the thrombosis can be associated with myocardial infarction, stroke, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and/or peripheral vascular disease.
  • the abnormal hormonal activity can be abnormal levels of ACTH, corticosterone, rennin, and/or prolactin.
  • the hormonal disorder can be Cushing's disease, Addison's disease, and/or hyperprolactinemia.
  • the side effect associated with a pituitary tumor can be selected from hyperprolactinemia, infertility, changes in menstruation, amenorrhea, galactorrhea, loss of libido, vaginal dryness, osteoporosis, impotence, headache, blindness and double vision.
  • the disease condition can be associated with dysfunction of the serotonin receptor, activation of the serotonin receptor and/or increased activity of the serotonin receptor.
  • the serotonin receptor can be a 5-HT2A subclass serotonin receptor.
  • the serotonin receptor can be a 5-HT2C subclass serotonin receptor.
  • the location of the serotonin receptor can vary.
  • the serotonin receptor can be in the central nervous system, the peripheral nervous system and/or in blood cells or platelets.
  • the serotonin receptor can be mutated or modified.
  • Embodiments disclosed herein relate to a method of alleviating or treating one or more disease condition associated with a serotonin receptor that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein with the administration of one or more additional therapeutic agents.
  • exemplary additional therapeutic agents include, but are not limited to, dopaminergic agents, anti-dyskensia agents, anti-dystonia agents, anti-myoclonus agents, anti-tremor agents, anti-psychotic agents, antidepressants, anti-dementia agents and sleep- inducing agents.
  • the dopaminergic agent can be selected from levodopa (such as SINEMETTM, SINEMET-CRTM, bromocriptine (such as PARLODELTM), pergolide (such as PERMAXTM), ephenedrine sulfate (such as EPHEDRINETM), pemoline such as
  • CYLERTTM mazindol
  • mazindol such as SANOREXTM
  • d,l- ⁇ -methylphenethylamine such as ADDERALLTM
  • methylphenydate such as RITALINTM
  • pramipexole such as MIRAPEXTM
  • modafmil such as PRO VIGILTM
  • ropinirole such as REQUIPTM
  • the anti-dyskensia agent, anti-dystonia, anti- myoclonus, or anti-tremor agent can be selected from baclofen (such as LIORESALTM), botulinum toxin (such as BOTOXTM), clonazepam (such as KLONOPINTM), and diazepam (such as VALIUMTM).
  • baclofen such as LIORESALTM
  • botulinum toxin such as BOTOXTM
  • clonazepam such as KLONOPINTM
  • diazepam such as VALIUMTM
  • the anti-psychotic agent can be selected from chlorpromazine (such as THORAZINETM), haloperidol (such as HALDOLTM), molindone (such as MOBANTM), thioridazine (such as MELLARILTM), a phenothiazine, a butyrophenome, a phenylbutylpiperadine, thioxanthine (such as fluphenthixol), a substituted benzamide (such as sulpiride), sertindole, amisulpride, risperidone, clozapine, olanzapine, ziprasidone, a debenzapine, a benzisoxidil, a salt of lithium, Aripiprazole (such as ABILIFY®), ETRAFON®, Droperidol (such as INAPSINE®), Thioridazine (such as MELLARIL®), Thiothixene (such as NAV
  • phenothiazines include chlorpromazine (such as Thorazine®), mesoridazine (such as SERENTIL®), prochlorperazine (such as COMPAZINE®), thioridazine (such as Mellaril), Fluphenazine (such as PROLIXIN®), Perpehnazine (such as TRILAFON®), and Trifluoperazine (such as STELAZINE®).
  • chlorpromazine such as Thorazine®
  • mesoridazine such as SERENTIL®
  • prochlorperazine such as COMPAZINE®
  • thioridazine such as Mellaril
  • Fluphenazine such as PROLIXIN®
  • Perpehnazine such as TRILAFON®
  • Trifluoperazine such as STELAZINE®
  • An example of a suitable phenylbutylpiperadine is pimozide (such as ORAP®).
  • debenzapines include clozapine (such as CLOZARIL®), loxapine (such as LOXITANE®), olanzapine (such as ZYPREXA®), and quetiapine (such as SEROQUEL®).
  • clozapine such as CLOZARIL®
  • loxapine such as LOXITANE®
  • olanzapine such as ZYPREXA®
  • quetiapine such as SEROQUEL®
  • a representative benzisoxidil is ziprasidone (such as GEODON®).
  • An example of a lithium salt is lithium carbonate.
  • the antidepressant can be selected from citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, and dapoxetine.
  • the anti-dementia agent can be a cholinesterase inhibitor such as donepezil (such as Aricept), galantamine (such as Razadyne) rivastigmine (such as
  • tacrine metrifonate
  • physostigmine neostigmine
  • pyridostigmine ambenonium, demarcarium, aldicarb, bendiocarb, bufencarb, carbaryl, carbendazim, carbetamide, carbofuran, chlorbufam, chloropropham, ethiofencarb, formetanate, methiocarb, methomyl, oxamyl, phenmedipham, pinmicarb, pirimicarb, propamocarb, propham, propoxur, edrophonium, phenothiazines, echothiophate, diisopropyl fluorophosphate, dimebon, Huperzine A, T-82 ((2-[2-(l-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-lH- pyrrolo[3,4-b]quinolin
  • the sleep-inducing agent can be selected from
  • Zolpidem, eszopiclone, a benzodiazepine, a melatonin agonist, and an antihistamine are included in a non- limiting list of benzodiazepines.
  • benzodiazepines include temazepam, diazepam, lorazepam, nitrazepam, and midazolam.
  • An exemplary melatonin agonist is ramelteon.
  • An example of a suitable antihistamine is diphenhydramine.
  • Some embodiments disclosed herein relate to a method of alleviating or treating a condition induced by the administration of an anti-psychotic compound that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject being administered the anti-psychotic compound.
  • the antipsychotic compound can have broad activity at multiple monoamine receptors subtypes.
  • the antipsychotic compound is a typical antipsychotic.
  • the antipsychotic compound can be an atypical antipsychotic.
  • the antipsychotic compound can be a D2 antagonist.
  • condition induced by the anti-psychotic compound can be a side effect selected from an extrapyramidal side effect, a histaminic side effect, an alpha adrenergic side effect, and an anticholinergic side effect.
  • Additional conditionals that can be induced by the anti-psychotic compound include stroke, tremors, sedation, gastrointestinal problems, neurological problems, increased risk of death, a cerebrovascular event, a movement disorder, dystonia,
  • akathisia a parkinsoniam movement disorder, dyskinesia, tardive dyskinesia, a cognitive disorder, prolactinemia, catalepsy, psychosis, neuroleptic malignant syndrome, a heart problem, a pulmonary problem, diabetes, liver failure, suicidality, sedation, orthostatic hypotension, choking, dizziness, tachycardia, blood abnormalities, an abnormal triglyceride level, an increased cholesterol level, dyslipidemia, hyperglycemia, syncope, a seizure, dysphagia, priapism, thrombotic thrombocytopenic purpura, disruption of body temperature regulation, insomnia, agitation, anxiety, somnolence, aggressive reaction, headache, constipation, nausea, dyspepsia, vomiting, abdominal pain, saliva increase, toothache, rhinitis, coughing, sinusitis, pharyngitis, dyspnea, back pain, chest pain, fever, rash, dry skin, seborr
  • hyperphosphatemia hypertrigylceridemia, hyperuricemia, hypoglycemia, polyuria, polydipsia, hemturia, dysuria, urinary retention, cystitis, renal insufficiency, arthrosis, synostosis, bursitis, arthritis, menorrhagia, dry vagina, nonpeurperal lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual bleeding, vaginal hemorrhage, increased SGOT, increased SGPT, cholestatic hepatitis, cholecystitis, choleithiasis, hepatitis, hepatocellular damage, epistaxis, superficial phlebitis, thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, decreased hearing, anemia, hypochromic anemia, normocytic anemia
  • the dyskinesia can be induced by treatment of Parkinson's disease.
  • the akathisia can be induced by administration of a neuroleptic agent or selective serotonin reuptake inhibitor.
  • the subject who is being administered the anti-psychotic compound is being treated for a disease or disorder selected from schizophrenia, bipolar disorder, agitation, psychosis, behavioral disturbances in Alzheimer's disease, depression with psychotic features or bipolar manifestations, obsessive compulsive disorder, post traumatic stress syndrome, anxiety, personality disorders (borderline and schizotypal), dementia, dementia with agitation, dementia in the elderly, Tourette's syndrome, restless leg syndrome, insomnia, social anxiety disorder, dysthymia, ADHD, and autism.
  • a disease or disorder selected from schizophrenia, bipolar disorder, agitation, psychosis, behavioral disturbances in Alzheimer's disease, depression with psychotic features or bipolar manifestations, obsessive compulsive disorder, post traumatic stress syndrome, anxiety, personality disorders (borderline and schizo
  • An embodiment disclosed herein relates to a method for alleviating or treating a condition associated with dopaminergic therapy that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject receiving dopaminergic therapy.
  • the subject can have a neurodegenerative disease such as Alzheimer disease, Parkinson's disease, Huntington's chorea, sphinocerebellar atrophy, frontotemporal dementia, supranuclear palsy, and/or Lewy body dementia.
  • the dopaminergic therapy can include the administration of a neurodegenerative disease such as Alzheimer disease, Parkinson's disease, Huntington's chorea, sphinocerebellar atrophy, frontotemporal dementia, supranuclear palsy, and/or Lewy body dementia.
  • the dopaminergic therapy can include the administration of a
  • levodopa such as SINAMETTM, SINAMETCRTM
  • bromocriptine such as PARLODELTM
  • pergolide such as PERMAXTM
  • ephenedrine sulfate such as EPHEDRINETM
  • pemoline such as CYLERTTM
  • mazindol such as SANOREXTM
  • d,l- ⁇ - methylphenethylamine such as ADDERALLTM
  • methylphenydate such as RITALINTM
  • pramipexole such as MIRAPEXTM
  • modafinil such as PRO VIGILTM
  • ropinirole such as REQUIPTM
  • the method further can include administering an anti- dyskensia agent and/or anti-psychotic agent.
  • Suitable anti-dyskenia agents include baclofen (such as LIORESALTM), botulinum toxin (such as BOTOXTM), clonazepam (such as KLONOPINTM), and diazepam (such as VALIUMTM). Exemplary antipsychotic agents are described herein.
  • Embodiments disclosed herein relate to a method of alleviating or treating schizophrenia that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject suffering from schizophrenia.
  • An embodiment disclosed herein relates to a method of alleviating or treating migraine that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject who suffers from a migraine.
  • Some embodiments disclosed herein relate to a method of alleviating or treating psychosis that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject suffering from psychosis.
  • the psychosis can be caused or results from various different origins.
  • the psychosis can be selected from drug-induced psychosis, treatment-induced psychosis and psychosis associated with a disease. Examples of diseases which are associated with psychosis include dementia, post traumatic stress disorder, Alzheimer's disease, Parkinson's disease and schizophrenia.
  • Embodiments disclosed herein relate to a method of alleviating or treating a condition amenable for treatment with an antipsychotic that can include administering a first amount of at least one substantially pure form of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as
  • a pharmaceutical composition described herein e.g., a pharmaceutical composition that includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein), and a second amount of an antipsychotic compound to a subject, wherein the second amount of the anti-psychotic compound is less than the amount of the anti-psychotic compound needed to produce a comparable efficacious effect when the anti-psychotic compound is administered alone.
  • the first amount and the second amount can be co-administered.
  • the co-administration can result in decreased severity or slower onset of a side effect associated with the antipsychotic agent as compared to the administration of the amount of the anti-psychotic agent alone.
  • Exemplary antipsychotic compounds are described herein.
  • Some embodiments disclosed herein relate to a method of alleviating or treating a pituitary tumor that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) or a pharmaceutical composition described herein (e.g., a pharmaceutical composition that includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) to a subject with a pituitary tumor.
  • the tumor can be a prolactinoma.
  • An embodiment disclosed herein relates to a method of inhibiting the formation of a pituitary tumor that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject at risk for forming a pituitary tumor.
  • Embodiments disclosed herein relate to a method of reducing the level of prolactin in a subject that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject with elevated levels of prolactin.
  • An embodiment disclosed herein relates to a method of reducing or inhibiting weight gain that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) or a pharmaceutical composition described herein (e.g., a pharmaceutical composition that
  • the subject includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) to a subject at risk of gaining weight.
  • the subject can be at risk to gain weight due to being administered a drug (e.g., an antipsychotic) that causes weight gain.
  • a drug e.g., an antipsychotic
  • Embodiments disclosed herein relate to a method of alleviating or treating a sleep disorder that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) or a pharmaceutical composition described herein (e.g., a pharmaceutical composition that includes an effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) to a subject suffering from a sleep disorder.
  • the sleep disorder can be insomnia such as sleep maintenance insomnia.
  • Some embodiments disclosed herein relate to a method of increasing slow- wave sleep that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject.
  • An embodiments disclosed herein relates to a method of alleviating or treating insomnia that can include administering a sleep-inducing agent adapted to induce onset of sleep in a subject; and administering to the subject a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to maintain the sleep induced by the sleep-inducing agent.
  • Embodiments disclosed herein relate to a method of alleviating or treating sleep maintenance insomnia that can include administering a therapeutically effective amount of at least one substantially pure form of a compound described herein or a pharmaceutical composition described herein to a subject suffering from sleep maintenance insomnia at a frequency of every other day or greater.
  • An embodiment disclosed herein relates to a method for identifying a compound which binds to a serotonin receptor that can include labeling a substantially pure form of a compound described herein; with a detectable label; contacting the serotonin receptor with the labeled compound; and determining whether the labeled compound binds to the serotonin receptor.
  • the detectable label can be a radiolabel such as [ 3 H], [ 18 F], [ 11 C] and [ 125 I].
  • the compounds disclosed herein are potent inverse agonist and/or antagonists of a serotonin receptor.
  • the serotonin receptor is a 5-HT2A receptor.
  • the serotonin receptor is a 5-HT2C receptor.
  • the compounds described herein are found not to interact with other serotonin receptors (5 -HT IA, IB, ID, IE, IF, 2B, 4 A, 6, and 7) at concentrations where the signaling of the 5-HT2A and/or 5-HT2C receptors is inhibited.
  • the compound is also selective to 5-HT2A and/or 5-HT2C receptors with respect to other monoamine-binding receptors, such as the dopaminergic, histaminergic, adrenergic and muscarinic receptors.
  • An "agonist" is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
  • partial agonist refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
  • an "inverse agonist” is defined as a compound that decreases the basal activity of a receptor (i.e., signaling mediated by the receptor). Such compounds are also known as negative antagonists.
  • an inverse agonist can be a ligand for a receptor that causes the receptor to adopt an inactive state relative to a basal state occurring in the absence of any ligand.
  • an antagonist can inhibit the activity of an agonist
  • an inverse agonist is a ligand that can alter the conformation of the receptor in the absence of an agonist.
  • Bond et al. in Nature 374:272 (1995). More specifically, Bond et al.
  • ligand free ⁇ 2 - adrenoceptor exists in equilibrium between an inactive conformation and a spontaneously active conformation. Agonists are proposed to stabilize the receptor in an active conformation. Conversely, inverse agonists are believed to stabilize an inactive receptor conformation. Thus, while an antagonist manifests its activity by virtue of inhibiting an agonist, an inverse agonist can additionally manifest its activity in the absence of an agonist by inhibiting the spontaneous conversion of an unliganded receptor to an active conformation.
  • antagonist refers to a compound that competes with an agonist or inverse agonist for binding to a receptor, thereby blocking the action of an agonist
  • An antagonist attenuates the action of an agonist on a receptor.
  • an antagonist also known as a "neutral agonist”
  • An antagonist may bind reversibly or irreversibly, and may reduce the activity of the receptor until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
  • IC 50 refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response.
  • the IC50 can be determined using by an assay.
  • the assay may be an R-SAT ® assay as described herein but is not limited to an RSAT assay.
  • EC 50 refers to an amount, concentration or dosage of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response such as but not limited to R-SAT ® assay described herein.
  • a "subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • a "patient” refers to a subject that is being treated in order to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
  • treating do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.
  • a therapeutically effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated.
  • a therapeutically effective amount of compound can be the amount need to prevent, alleviate or ameliorate symptoms of disease or prolong the survival
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • An embodiment disclosed herein relates to a pharmaceutical composition, comprising a therapeutically effective amount of a compound described herein (e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • a compound described herein e.g., a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) as described herein
  • a pharmaceutically acceptable carrier diluent, excipient or combination thereof.
  • the pharmaceutical composition that includes a therapeutically effective amount of a substantially pure form of a compound of Formulae (I), (II), (III), (IV) and/or (V) can also include one or more additional therapeutic agents.
  • additional therapeutic agents include, but are not limited to, dopaminergic agents, anti-dyskensia agents, anti-dystonia agents, anti-myoclonus agents, anti-tremor agents, anti-psychotic agents, antidepressants, anti-dementia agents and sleep- inducing agents.
  • the dopaminergic agent can be selected from levodopa (such as SINEMETTM, SINEMET-CRTM), bromocriptine (such as PARLODELTM), pergolide (such as PERMAXTM), ephenedrine sulfate (such as EPHEDRINETM), pemoline such as CYLERTTM), mazindol (such as SANOREXTM), d,l- ⁇ -methylphenethylamine (such as ADDERALLTM), methylphenydate (such as RITALINTM), pramipexole (such as MIRAPEXTM), modafmil (such as PRO VIGILTM), and ropinirole (such as REQUIPTM).
  • levodopa such as SINEMETTM, SINEMET-CRTM
  • bromocriptine such as PARLODELTM
  • pergolide such as PERMAXTM
  • ephenedrine sulfate such as EPHEDRINETM
  • pemoline such
  • the anti-dyskensia agent, anti-dystonia, anti- myoclonus, or anti-tremor agent can be selected from baclofen (such as LIORESALTM), botulinum toxin (such as BOTOXTM), clonazepam (such as KLONOPINTM), and diazepam (such as VALIUMTM).
  • baclofen such as LIORESALTM
  • botulinum toxin such as BOTOXTM
  • clonazepam such as KLONOPINTM
  • diazepam such as VALIUMTM
  • the anti-psychotic agent can be selected from chlorpromazine (such as THORAZINETM), haloperidol (such as HALDOLTM), molindone (such as MOBANTM), thioridazine (such as MELLARILTM), a phenothiazine, a butyrophenome, a phenylbutylpiperadine, thioxanthine (such as fluphenthixol), a substituted benzamide (such as sulpiride), sertindole, amisulpride, risperidone, clozapine, olanzapine, ziprasidone, a debenzapine, a benzisoxidil, a salt of lithium, Aripiprazole (such as ABILIFY®), Etrafon®, Droperidol (such as INAPSINE®), Thioridazine (such as MELLARIL®), Thiothixene (such as NAV
  • phenothiazines include chlorpromazine (such as THORAZINE®), mesoridazine (such as SERENTIL®), prochlorperazine (such as COMPAZINE®), thioridazine (such as Mellaril), Fluphenazine (such as PROLIXIN®), Perpehnazine (such as TRILAFON®), and Trifluoperazine (such as
  • STELAZINE® An example of a suitable phenylbutylpiperadine is pimozide (such as ORAP®).
  • debenzapines include clozapine (such as CLOZARIL®), loxapine (such as LOXITANE®), olanzapine (such as ZYPREXA®), and quetiapine (such as SEROQUEL®).
  • a representative benzisoxidil is ziprasidone (such as GEODON®).
  • An example of a lithium salt is lithium carbonate.
  • the antidepressant can be selected from citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, and dapoxetine.
  • the anti-dementia agent can be a cholinesterase inhibitor such as donepezil (such as Aricept), galantamine (such as Razadyne) rivastigmine (such as Exelon), tacrine, metrifonate, physostigmine, neostigmine, pyridostigmine, ambenonium, demarcarium, aldicarb, bendiocarb, bufencarb, carbaryl, carbendazim, carbetamide, carbofuran, chlorbufam, chloropropham, ethiofencarb, formetanate, methiocarb, methomyl, oxamyl, phenmedipham, pinmic
  • donepezil such as Aricept
  • the sleep-inducing agent can be selected from
  • Zolpidem, eszopiclone, a benzodiazepine, a melatonin agonist, and an antihistamine are included in a non- limiting list of benzodiazepines.
  • benzodiazepines include temazepam, diazepam, lorazepam, nitrazepam, and midazolam.
  • An exemplary melatonin agonist is ramelteon.
  • An example of a suitable antihistamine is diphenhydramine.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, intramuscular, intraocular, intranasal, intravenous, injection, aerosol, parenteral, and
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
  • parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
  • parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
  • one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the area of pain or inflammation, often in a depot or sustained release
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques,
  • carriers, and excipients may be used as suitable and as understood in the art; e.g., as disclosed in Remington's Pharmaceutical Sciences, cited above.
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • a suitable vehicle e.g., sterile pyrogen- free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An exemplary pharmaceutical carrier for the hydrophobic compounds disclosed herein is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • VPD co-solvent system is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-to xicity nonpolar surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Chapter 1, which is hereby incorporated by reference in its entirety).
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Where no human dosage is established, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may contain one or more unit dosage forms containing the active ingredient.
  • compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Reagents a) K 2 CO 3 , (CHs) 2 CHCH 2 Br; b) K 2 CO 3 , HONH 2 HCI; c) LiAIH 4 ; d) COCI 2 ; e) Pd-C, H 2
  • Scheme A shows a general reaction scheme for forming the compound of
  • the hydroxy group can be converted to an alkoxy or an acyl group using methods known to those skilled in the art, for example, reacting the alcohol with an alkyl halide in the presence of base (e.g. potassium carbonate) in a classical Williamson ether synthesis and variations thereof.
  • base e.g. potassium carbonate
  • Another method known in the art is to react the alcohol with second alcohol in a Mitsunobu-type reaction using a dialkyl azodicarboxylate and a phosphine, wherein the alcohol may be converted to an ester by reacting the alcohol with a suitable acyl halide or an acid anhydride.
  • Esters may also be generated in a Mitsunobu-type reaction between an alcohol and a carboxylic acid to form a compound of Formula (I).
  • Reagents a) K 2 CO 3 , 3-bromo-2-methylpropene; b) LiOH; c) DPPA
  • Reagents a) BoC 2 O; b) NaOH, methyl 3-bromo-2-(bromonnethyl)butanoate; c) Pd-C, H 2 ; d) TFA; e) COCI 2 ; f) Et 3 N, Chloroethyl chloroformate; g) LiOH
  • Reagents a) K 2 CO 3 , benzylbromide; b) LiAIH 4 ; c) (COCI) 2 , Et 3 N; d) NaCNBH 3 ; e) COCI 2 ; f) Pd-C, H 2
  • Scheme D shows a general reaction scheme for forming the compound of
  • Reagents a) K 2 CO 3 , benzylbromide; b) t-butylcarbamate, Et 3 SiH, TFA; c) Na 2 CO 3 , COCI 2 ; d) Pd-C, H 2
  • H-Cube hydrogenation reactor is used.
  • H-Cube reactors are available from ThalesNano Nanotechnology Inc.
  • HPLC/LCMS Method Samples were run on a Waters/Micromass
  • HPLC/MS using a diode array detector (190-450 nm) UV detector and Micromass ZMD- mass-spectrometer with electrospray ionization.
  • the mobile phase was 10 mM ammonium acetate in water/acetonitrile with a gradient starting at 30% acetonitrile, going to 95% acetonitrile over 12 min.
  • the flow rate was 1.0 mL/min.
  • the aqueous phase was made alkaline with 2M NaOH and extracted with dichloromethane (2x100 mL). The combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated to give 4-isobutoxy-3-benzyloxybenzylamine (130 mg, 43%) as a white solid.
  • aReagents a) K2CO3, 3-bromo-2-methylpropene; b) LiOH; c) Diphenylphosphoryl azide
  • K2CO3 (4.6 g, 33 mmol) and 3-bromo-2-methylpropene (3.3 rnL, 33 mmol) were added to a mixture of methyl 2-(4-hydroxyphenyl)acetate (5.0 g, 30 mmol) in acetone (50 mL). The resulting mixture was stirred at 60 0 C for 4 h, then allowed to cool to room temperature. The mixture was diluted with diethyl ether, washed with water and brine, dried
  • Acetic acid was added to 3-benzyloxy-4-fluorobenzaldehyde (150 mg, 0.65 mmol) and 4-amino-l-methylpiperidine (75 mg, 0.65 mmol) in methanol (10 mL), and the mixture stirred for 2 h at room temperature.
  • NaCNBH 3 (82 mg, 1.3 mmol) was added under N 2 atmosphere. The mixture was stirred for 2 h, quenched with aqueous NaOH and concentrated. Water was added and the aqueous solution extracted with CH 2 Cl 2 .
  • tert-bvXy ⁇ 4-hydroxy-3-methoxybenzylcarbamate (0.39 g, 1.53 mmol) was dissolved in 20 niL MeCN. Benzylbromide (0.20 ml, 1.68 mmol) and Cs 2 CO 3 (0.93 g, 2.85 mmol) were added. The reaction mixture was heated to 75 0 C and stirred for 2 h. The reaction was quenched with water and the product was extracted into CH 2 Cl 2 . The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated. The resulting product was dissolved in 20 mL CH 2 Cl 2 and 5 mL TFA was added. The mixture was stirred at room temperature for 1.5 h.
  • tert-EvXy ⁇ 3-hydroxy-4-methoxybenzylcarbamate (0.36 g, 1.41 mmol) was dissolved in 20 niL MeCN. Benzylbromide (0.18 ml, 1.52 mmol) and Cs 2 CO 3 (1.03 g, 3.16 mmol) were added. The reaction mixture was heated to 75 0 C and stirred for 2 h. The reaction was quenched with water and the resulting product was extracted into CH 2 Cl 2 . The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated. The product was re-dissolved in 20 mL CH 2 Cl 2 and 5 mL TFA was added.
  • the organic layer was separated and the aqueous layer extracted with CH 2 Cl 2 .
  • the combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated.
  • the flask containing the resulting product was equipped for magnetic stirring, and CH 2 Cl 2 (15 mL) and tert-butyi 4- (4-fluorobenzylamino)-piperidine-l-carboxylate (0.41 g, 1.32 mmol) were added.
  • the resulting mixture was stirred at room temperature over night.
  • the reaction was quenched with 2 M HCl and the resulting mixture was extracted with CH 2 Cl 2 .
  • the combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated.
  • tert-Butyl 4-(3-(3-benzyloxy-4-methoxybenzyl)-l-(4- fluorobenzyl)ureido)piperidine-l-carboxylate (0.35 g, 0.61 mmol) was dissolved in 20 mL CH 2 Cl 2 and 5 mL TFA was added. The reaction mixture was stirred at room temperature for 2 h before 2M NaOH and additional CH 2 Cl 2 were added. The product was extracted with CH 2 Cl 2 , and the combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated.
  • Benzyl 4-(4-fluorobenzylamino)piperidine-l-carboxylate (222 mg, 0.65 mmol) was added and the resulting mixture was stirred overnight at room temperature and then concentrated.
  • the crude product was purified by flash chromatography (SiO 2 , heptane:EtOAc, 2:1, 0.3 % 7 N NH 3 in MeOH) to give 280 mg of crude benzyl 4-(3- (4-(3 -(benzyloxy)-2-methylpropoxy)benzyl)- 1 -(4-fluorobenzyl)ureido)piperidine- 1 - carboxylate_containing approx 10% byproducts.
  • the crude material was used in the next step without any further purification.
  • R-SAT Receptor Selection and Amplification Assays.
  • R-SAT's were generally performed with 50 ng/well of receptor and 20 ng/well of ⁇ -galactosidase plasmid DNA. All receptor and G-protein constructs used were in the pSI mammalian expression vector (Promega Inc) as described previously.
  • the 5-HT 2 A or 5-HT 2 c receptor gene was amplified by nested PCR from brain
  • cDNA using the oligodeoxynucleotides based on the published sequence (Saltzman et. al, Biochem. Biophys. Res. Comm. 1991, 181, 1469).
  • cells were transfected for 12-16 h, then trypsinized and frozen in DMSO. Frozen cells were later thawed, plated at 10,000-40,000 cells per well of a 96 well plate that contained drug. With both methods, cells were then grown in a humidified atmosphere with 5% ambient CO 2 for five days.
  • Efficacy is the percent maximal repression compared to repression by a control compound (ritanserin in the case of 5-HT 2 A)- pICso is the negative of the log(ICso), where IC 50 is the calculated concentration in Molar that produces 50% maximal repression.

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Abstract

L'invention porte sur des formes sensiblement pures des composés des Formules (I), (II), (III), (IV) et (V), ou sur un sel, promédicament, hydrate, solvate, polymorphe, stéréo-isomère ou ester pharmaceutiquement acceptable de ces composés. L'invention porte également sur des méthodes d'inhibition de l'activité d'un récepteur de la sérotonine, sur des méthodes inhibant l'activité d'un récepteur de la sérotonine et sur des méthodes permettant de soulager ou de traiter diverses états pathologiques et effets secondaires de maladies.
PCT/US2010/028444 2009-03-25 2010-03-24 Dérivés de pipéridine n-substitués en tant qu'agents spécifiques des récepteurs de la sérotonine Ceased WO2010111353A1 (fr)

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CN109111385A (zh) * 2017-06-23 2019-01-01 上海翰森生物医药科技有限公司 5-ht2a受体抑制剂及其制备方法和应用
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CN109734652A (zh) * 2019-03-07 2019-05-10 夸克侠医药科技(辽宁)有限公司 一种高纯度匹莫范色林的制备方法
CN113214141A (zh) * 2020-01-21 2021-08-06 瀚远医药有限公司 5ht2a受体拮抗剂及其制备和应用
CN113214289B (zh) * 2020-01-21 2022-10-28 瀚远医药有限公司 5-ht2a受体拮抗剂及其治疗中枢神经系统疾病的应用
CN113214141B (zh) * 2020-01-21 2022-04-08 瀚远医药有限公司 5ht2a受体拮抗剂及其制备和应用
CN113214289A (zh) * 2020-01-21 2021-08-06 瀚远医药有限公司 5-ht2a受体拮抗剂及其治疗中枢神经系统疾病的应用
WO2021147909A1 (fr) * 2020-01-21 2021-07-29 行远医药科技有限公司 Antagoniste du récepteur 5ht2a et son application médicale
WO2021147818A1 (fr) * 2020-01-21 2021-07-29 瀚远医药有限公司 Antagoniste du récepteur 5-ht2a et son application dans le traitement de maladies du système nerveux central
WO2022017440A1 (fr) * 2020-07-22 2022-01-27 山东绿叶制药有限公司 Inhibiteur du récepteur 5-ht2a ou agoniste inverse, procédé de préparation associé, et application associée
CN116730981A (zh) * 2020-07-22 2023-09-12 山东绿叶制药有限公司 5-ht2a受体抑制剂或反向激动剂及其制备方法和应用
CN116730981B (zh) * 2020-07-22 2024-07-02 山东绿叶制药有限公司 5-ht2a受体抑制剂或反向激动剂及其制备方法和应用
EP4186893A4 (fr) * 2020-07-22 2025-02-05 Geneora Pharma (Shijiazhuang) Co., Ltd. Inhibiteur du récepteur 5-ht2a ou agoniste inverse, procédé de préparation associé, et application associée
CN113354621A (zh) * 2021-06-04 2021-09-07 沈阳药科大学 含有吡啶基团的1-取代苄基-3-芳基脲类化合物及其制备方法和应用
CN113292484A (zh) * 2021-06-04 2021-08-24 沈阳药科大学 3-(4-甲基哌啶-1-基)-3-苄基脲类化合物及其类似物、制备方法及应用

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