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WO2010111353A1 - N-substituted piperidine derivatives as serotonin receptor agents - Google Patents

N-substituted piperidine derivatives as serotonin receptor agents 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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PCT/US2010/028444
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French (fr)
Inventor
Nathalie Schlienger
Mikkel Thygesen
Henriette Kold Uldam
Kara Schmelzer
Ali Tabatabaei
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Acadia Pharmaceuticals, Inc.
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Publication of WO2010111353A1 publication Critical patent/WO2010111353A1/en

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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

Disclosed herein are substantially pure forms of the compounds of Formula (I), (II), (III), (IV) and (V), or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, polymorph, stereoisomer or ester thereof. Also disclosed are methods of inhibiting an activity of a serotonin receptor, methods inhibiting an activation of a serotonin receptor, and methods of alleviating or treating various disease conditions and side effects.

Description

Attorney Docket No. 12560-046-228
ACADIA.142 VPC
N-SUBSTITUTED PIPERIDINE DERIVATIVES AS SEROTONIN RECEPTOR
AGENTS
CLAIM OF PRIORITY
[0001] Priority is claimed herein to U.S. Provisional Patent Application No.
61/163,439, entitled "N-Substituted Piperidine Derivatives as Serotonin Receptor Agents," filed March 25, 2009. The above-referenced application is incorporated by reference herein in its entirety.
BACKGROUND
Field
[0002] 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.
Description of the Related Art
[0003] Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in the functioning of the mammalian body. In the central nervous system, 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. In the spinal column, 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. (Fuller, Biology of Serotonergic Transmission, 1982; Boullin, Serotonin In Mental Abnormalities 1 :316 (1978); Barchas, et al, Serotonin and Behavior, (1973)). The 5 -HT2 A receptor subtype (also referred to as subclass) is widely yet discretely expressed in the human brain,
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including many cortical, limbic, and forebrain regions postulated to be involved in the modulation of higher cognitive and affective functions. 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.
[0004] Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists (Gershon, et al., The Peripheral Actions of 5 -Hydroxy tryptamine, 246 (1989); Saxena, et al., J. Cardiovascular Pharmacol. 15: Supp. 7 (1990)). Serotonin receptors are members of a large human gene family of membrane-spanning proteins that function as transducers of intercellular communication. They exist on the surface of various cell types, including neurons and platelets, where, upon their activation by either their endogenous ligand serotonin or exogenously administered drugs, they change their conformational structure and subsequently interact with downstream mediators of cellular signaling. Many of these receptors, including the 5-HT2A subclass, are G-protein coupled receptors (GPCRs) that signal by activating guanine nucleotide binding proteins (G-proteins), resulting in the generation, or inhibition of, second messenger molecules such as cyclic AMP, inositol phosphates, and diacylglycerol. These second messengers then modulate the function of a variety of intracellular enzymes, including kinases and ion channels, which ultimately affect cellular excitability and function.
[0005] 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). [0006] 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 of
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such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorders and appetite disorders. [0007] 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). [0008] Currently, 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. These "extrapyramidal" side effects, so termed due to their effects on modulatory human motor systems, can be both acute (e.g., dystonic reactions, a potentially life threatening but rare neuroleptic malignant syndrome) and chronic (e.g., akathisias, tremors, and tardive dyskinesia). Drug development efforts have, therefore, focused on newer "atypical" agents free of some of these adverse effects. However, atypical agents also have the potential for serious side effects including increased risk of stroke, abnormal shifts in sleep patterns, extreme tiredness and weakness, metabolic disorders (including hyperglycemia and diabetes), and weight gain. One of the most common reasons for noncompliance and discontinued use of antipsychotic medication is weight gain. Non- compliance can lead to increased hospitalization and health care costs. [0009] 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
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to develop drugs that are selective for individual receptor classes and subclasses amongst monoaminergic neurotransmitter receptors.
[0010] The prevailing theory for the mechanism of action of antipsychotic drugs involves antagonism of dopamine D2 receptors. Unfortunately, it is likely that antagonism of dopamine D2 receptors also mediates the extrapyramidal side effects. Antagonism of 5-HT2A is an alternate molecular mechanism for drugs with antipsychotic efficacy, possibly through antagonism of heightened or exaggerated signal transduction through serotonergic systems. 5-HT2A antagonists are therefore good candidates for treating psychosis without extrapyramidal side effects. Compounds that are selective for 5-HT2A and/or 5-HT2C receptors have beneficial effects in the treatment of psychosis, schizophrenia or similar neuropsychiatric disorders, while avoiding adverse effects associated with drugs hitherto suggested for this purpose.
[0011] Traditionally, these receptors have been assumed to exist in a quiescent state unless activated by the binding of an agonist (a drug that activates a receptor). It is now appreciated that many, if not most, of the GPCR monoamine receptors, including serotonin receptors, can exist in a partially activated state in the absence of their endogenous agonists. This increased basal activity (constitutive activity) can be inhibited by compounds called inverse agonists. Both agonists and inverse agonists possess intrinsic activity at a receptor, in that they alone can activate or inactivate these molecules, respectively. In contrast, classic or neutral antagonists compete against agonists and inverse agonists for access to the receptor, but do not possess the intrinsic ability to inhibit elevated basal or constitutive receptor responses.
SUMMARY
[0012] Provided herein are substantially pure compounds selected from Formula (I),
Formula (II), Formula (III), Formula (IV) and Formula (V):
Figure imgf000005_0001
(I)
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Figure imgf000006_0001
(H)
Figure imgf000006_0002
(HI)
Figure imgf000006_0003
(V) or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof.
[0013] 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).
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[0014] Further provided are methods of treating and alleviating various neurological disorders or diseases and side effects. 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.
[0015] Also provided herein are pharmaceutical 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.
DETAILED DESCRIPTION
[0016] In one embodiment, provided are compounds of Formula (I), Formula (II),
Formula (III), Formula (IV) and Formula (V), and pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof.
[0017] 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). [0018] In another embodiment, provided are methods of 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. Examples of dieases and disorders are described herein.
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[0019] In other embodiments, 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.
COMPOUNDS
[0020] 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):
Figure imgf000008_0001
(I)
Figure imgf000008_0002
(H)
Figure imgf000008_0003
(HI)
Figure imgf000008_0004
(IV)
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Figure imgf000009_0001
(V) or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof, wherein: R is H or CH3 and Ri is H or acyl.
In one embodiment, R is H. In another embodiment, R is CH3.
In certain embodiments, Ri is H.
In one embodiment, Ri is an acyl . [0021] Provided herein are compounds selected from the following group:
Figure imgf000009_0002
or a pharmaceutically acceptable salt, solvate (e.g. hydrate), prodrug, clathrate, polymorph, stereoisomer or ester thereof.
[0022] Embodiments disclosed herein relate to a substantially pure form of a compound selected from Formula (I), Formula (II), Formula (III), Formula (IV) and Formula
SDI-10975vl Attorney Docket No. 12560-046-228
(V), or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, polymorph, or ester thereof.
[0023] In an embodiment, the substantially pure form of a compound selected from
Formulae (I), (II), (III), (IV) and (V) can include at least 75% of the compound. In another embodiment, the substantially pure form of a compound selected from Formulae (I), (II),
(III), (IV) and (V) can include at least 80% of the compound.
[0024] In yet another embodiment, 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.
[0025] In another embodiment, the substantially pure form of a compound selected from Formulae (I), (II), (III), (IV) and (V) can include at least 95% of the compound. In another embodiment, the substantially pure form of a compound selected Formulae (I), (II),
(III), (IV) and (V) can include at least 99% of the compound. Compounds of Formulae (I),
(II), (III), (IV) and (V) can be produced synthetically. Compounds of Formulae (I) and (II) have been shown to be metabolites of N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-
N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide, for example, in mice, rats, monkeys and humans.
[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0027] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be "enatiomerically pure" or "stereomerically pure" or be stereoisomeric mixtures. As used herein the term "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
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compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
[0028] 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.
[0029] As used herein and unless otherwise indicated, the term "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.
[0030] As used herein, and unless otherwise indicated, the term "enantiomerically pure" means a steromerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" means a stereomerically enriched composition of a compound having one chiral center. [0031] As used herein, the term "stereoisomer" encompasses all entiomerically/stereomerically pure and enantiomerically/stereomerically enriched compounds provided herein.
[0032] In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z each double bond may independently be E or Z a mixture thereof. Likewise, all tautomeric forms are also intended to be included.
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[0033] As used herein, the term "acyl" refers to a -CO-R2, wherein R2 is C1-C12- alkyl. In one embodiment R2 is branched Ci-Ci2 alkyl. In one embodiment R2 is methyl or ethyl.
[0034] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature
(See, Biochem. 11 :942-944 (1972)).
[0035] As employed herein, the following terms have their accepted meaning in the chemical literature.
AcOH acetic acid anhyd anhydrous
Bn benzyl
Boc tert-butyloxycarbonyl
CDI 1 , 1 '-carbonyldiimidazole
DCM dichloromethane
DIAD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminium hydride
DMF Λ/,Λ/-dimethylformamide
DMSO dimethyl sulfoxide
DPPA diphenylphosphoryl azide
Et2O diethyl ether
EtOAc ethyl acetate
EtOH Ethanol
MeOH Methanol
NH4OAc ammonium acetate
Pd/C palladium on activated carbon
TFA trifluoracetic acid
THF Tetrahydrofuran
[0036] As used herein, and unless otherwise specified, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids,
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including inorganic acids and organic 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. As used herein, the term "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. [0037] As used herein, the term "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. Examples of 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).
[0038] As used herein, the terms "biohydrolyzable carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide" and "biohydrolyzable phosphate " 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. Examples of 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. [0039] The terms "pure," "purified," "substantially pure," and "isolated" as used herein refer to the compound of the embodiment being free of other, dissimilar compounds with which the compound, if found in its natural state, would be associated in its natural
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state. In some embodiments described as "pure," "purified," "substantially purified," or "isolated" herein, the compound may comprise at least 75%, 80%, 85%, 90%, 95%, 99% of the mass, by weight, of a given sample.
[0040] One of ordinary skill in this field will recognize that certain compounds of this invention will contain atoms which may be in a particular optical or geometric configuration. Likewise, one will recognize that various pharmaceutically acceptable esters and salts may be prepared from certain compounds of this invention. All of such stereoisomers, esters and salts are included in this invention.
[0041] Pharmaceutical chemists will easily recognize that physiologically active compounds which have accessible hydroxy groups are frequently administered in the form of pharmaceutically acceptable esters. The literature concerning such compounds, such as estradiol, provides a great number of instances of such esters. The compounds of this invention are no exception in this respect, and can be effectively administered as an ester, formed on the hydroxy groups, just as one skilled in pharmaceutical chemistry would expect. It is believed that 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.
[0042] In some embodiments the compounds provided herein are radiolabeled.
Typical radiolabels may include 3H, 11C, 18F and 125I. In certain embodiments, the compound as provided herein have one or more hydrogen or carbon atom enriched for deuterium ("2H") or carbon- 13 ("13C"). By "enriched for 2H or 13C" it is meant that the 2H or 13C isotopes present at one or more positions in the compound are present in amounts greater than that found naturally.
METHODS OF USE
[0043] Provided herein are methods of using a compound provided herein or pharmaceutically acceptable salt, prodrug, hydrate, solvate, clathrate, polymorph, stereoisomer or ester thereof. 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
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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). In an embodiment the activity can be a signaling activity. In some embodiments, the activity can be constitutive. In one embodiment, the activity can be associated with serotonin receptor activation.
[0044] 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). In some embodiments, the activation can be by an agonist agent. In an embodiment, the agonist agent can be exogenous. In an embodiment, the agonist agent can be endogenous. In some embodiments, the activation can be constitutive. [0045] 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. Non-limiting examples of such systems 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. Examples of suitable cells include: the mouse fibroblast cell line NIH 3T3 (ATCC
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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)); and 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.
[0046] 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). In certain embodiments, the use of the compounds of Formulae (I), (II), (III), (IV) and/or (V) for treating a disease condition are provided.
[0047] In an embodiment, the disease condition can be a neuropsychiatric disorder.
Exemplary 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. In an embodiment, the depression can be dysthymia, SSRI-resistant depression and/or depression associated with psychosis. In an embodiment, the aggressiveness can be impulsive aggression.
[0048] In one embodiment, the behavioral disorder can be associated with age- related dementia. When the disease condition is psychosis, the psychosis can be caused or results from various different origins. For example, 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. In an embodiment, the psychosis can be Parkinson's disease psychosis. In an embodiment, the psychosis can be
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Alzheimer's disease-induced psychosis. In an embodiment, the psychosis can be dementia- related psychosis. In an embodiment, the psychosis can be the result of schizophrenia. [0049] In some embodiments, the sleep disorder can be selected from sleep maintenance insomnia, chronic insomnia, transient insomnia and periodic limb movements during sleep (PLMS).
[0050] In an embodiment, the addiction can be selected from drug addiction, alcohol addiction, opioid addiction and nicotine addiction. In one embodiment, the anxiety can be general anxiety disorder (GAD).
[0051] In some embodiments, the pain can be selected from chronic pain, neuropathic pain, inflammatory pain, diabetic peripheral neuropathy, fibromyalgia, postherpetic neuralgia and reflex sympathetic dystrophy.
[0052] In an embodiment, the disease condition can be a cognitive disorder.
[0053] In another embodiment, the disease condition can be a neurodegenerative disorder. Examples of neurodegenerative disorders are Alzheimer's disease, Parkinson's disease, Huntington's chorea, sphinocerebellar atrophy, frontotemporal dementia, supranuclear palsy and Lewy body dementia.
[0054] In some embodiments, 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, cardiac insufficiency, asthma, emphysema, and/or an appetite disorder. In one embodiment, the autoimmune disorders can be lupus or multiple sclerosis. In an embodiment, the retinal disease can be age related macular degeneration. In some embodiments, the menopausal symptom can be hot flashes. In an embodiment, the sexual dysfunction can be selected from female sexual dysfunction, female sexual arousal dysfunction, hypoactive sexual desire disorder, decreased libido, pain,
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aversion, female orgasmic disorder and an ejaculatory problem. In an embodiment, the thrombosis can be associated with myocardial infarction, stroke, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and/or peripheral vascular disease. In some embodiments, the abnormal hormonal activity can be abnormal levels of ACTH, corticosterone, rennin, and/or prolactin. In one embodiment, the hormonal disorder can be Cushing's disease, Addison's disease, and/or hyperprolactinemia. In some embodiments, 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. [0055] In some embodiments, 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. With respect to the serotonin receptor, in some embodiments, the serotonin receptor can be a 5-HT2A subclass serotonin receptor. In an embodiment, the serotonin receptor can be a 5-HT2C subclass serotonin receptor. The location of the serotonin receptor can vary. For example, the serotonin receptor can be in the central nervous system, the peripheral nervous system and/or in blood cells or platelets. In an embodiment, the serotonin receptor can be mutated or modified.
[0056] 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.
[0057] Further embodiments relate to the use of compounds, as described herein, in the manufacture or preparation of a medicament for the treatment of a disease condition as described herein.
[0058] 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. In an embodiment, the dopaminergic agent can be selected from levodopa (such as SINEMET™, SINEMET-CR™, bromocriptine (such as PARLODEL™), pergolide (such as PERMAX™), ephenedrine sulfate (such as EPHEDRINE™), pemoline such as
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CYLERT™), mazindol (such as SANOREX™), d,l-α-methylphenethylamine (such as ADDERALL™), methylphenydate (such as RITALIN™), pramipexole (such as MIRAPEX™), modafmil (such as PRO VIGIL™), and ropinirole (such as REQUIP™). [0059] In some embodiments, the anti-dyskensia agent, anti-dystonia, anti- myoclonus, or anti-tremor agent can be selected from baclofen (such as LIORESAL™), botulinum toxin (such as BOTOX™), clonazepam (such as KLONOPIN™), and diazepam (such as VALIUM™).
[0060] In an embodiment, the anti-psychotic agent can be selected from chlorpromazine (such as THORAZINE™), haloperidol (such as HALDOL™), molindone (such as MOBAN™), thioridazine (such as MELLARIL™), 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 ANE®), Promethazine (such as PHENERGAN®), Metoclopramide (such as REGLAN®), Chlorprothixene (such as TARACT AN®), TRIA VIL®, Molindone (such as MOBAN®), Sertindole (such as SERLECT®), Amisulpride (such as SOLIAN®), Melperone, Paliperidone (such as INVEGA®), Tetrabenazine and their active metabolites. Exemplary 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®). A non-limiting list of 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.
[0061] In an embodiment, the antidepressant can be selected from citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, and dapoxetine. [0062] In one embodiment, the anti-dementia agent can be a cholinesterase inhibitor such as donepezil (such as Aricept), galantamine ( such as Razadyne) rivastigmine (such as
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Exelon), 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-l-one hemifumarate)), TAK-147 (zanapezil), phenserine, quilostigmine, ganstigmine, butyrophenones, imipramines, tropates, phencyclidines, curariforms, ethephon, ethopropazine, iso-OMPA, tetrahydrofurobenzofuran cymserine, N^henethyl-norcymserine, N8-benzylnorcymserine, N1,N8-bisnorcymserine, N^N8- bisbenzylnorphysostigmine, N1,N8-bisbenzylnorphenserine and N^N8- bisbenzylnorcymserine.
[0063] In some embodiments, the sleep-inducing agent can be selected from
Zolpidem, eszopiclone, a benzodiazepine, a melatonin agonist, and an antihistamine. A non- limiting list of benzodiazepines include temazepam, diazepam, lorazepam, nitrazepam, and midazolam. An exemplary melatonin agonist is ramelteon. An example of a suitable antihistamine is diphenhydramine.
[0064] 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. In some embodiments, the antipsychotic compound can have broad activity at multiple monoamine receptors subtypes. In an embodiment, the antipsychotic compound is a typical antipsychotic. In other embodiments, the antipsychotic compound can be an atypical antipsychotic. In an embodiment, the antipsychotic compound can be a D2 antagonist. In some embodiments, the 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,
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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, seborrhea, increased upper respiratory infection, abnormal vision, arthralgia, hypoaesthesia, manic reaction, concentration impairment, dry mouth, pain, fatigue, acne, pruritus, myalgia, skeletal pain, hypertension, diarrhea, confusion, asthenia, urinary incontinence, sleepiness, increased duration of sleep, accommodation disturbance, palpitations, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, lassitude, increased pigmentation, increased appetite, automatism, increased dream activity, diminished sexual desire, nervousness, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia, emotional liability, a nightmare, delirium, yawning, dysarthria, vertigo, stupor, paraesthesia, aphasia, hypoesthesia, tongue paralysis, a leg cramp, torticollis, hypotonia, coma, migrain, hyperreflexia, choreoathetosis, anorexia, flatulence, stomatitis, melena, hemorrhoids, gastritis, fecal incontinence, erutation, gastroeophageal reflux, gastroenteritis, esophagitis, tongue discoloration, choleithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, gastrointestinal hemorrhage, hematemesis, edema, rigors, malaise, pallor, enlarged abdomen, ascites, sarcoidosis, flushing, hyperventilation, bronchospasm, pneumonia, tridor, asthma, increased sputum, aspiration, photosensitivity, increased sweating, acne, decreased sweating, alopecia, hyperkeratosis, skin exfoliation, bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria, ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversion, a ventricular extrasystole, ST depression, AV block, myocarditis, abnormal accommodation, xerophthalmia, diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation, hyponatremia, creatine phosphokinase increase, thirst, weight decrease, decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia,
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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, granulocytopenia, leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, male breast pain, antiduretic hormone disorder, bitter taste, micturition disturbances, oculogyric crisis, abnormal gait, involuntary muscle contraction, increased injury, a pituitary tumor, galactorrhea, bradykinesia, myoclonus, hiccups, uncontrolled gambling, a drug craving, rigidity, psychomotor slowing, tics, Friedrich's ataxia, Machado-Joseph's disease, restless legs syndrome, and a hallucinogenic effect. In an embodiment, the dyskinesia can be induced by treatment of Parkinson's disease. In an embodiment, the akathisia can be induced by administration of a neuroleptic agent or selective serotonin reuptake inhibitor. In some embodiments, 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.
[0065] 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. In some embodiments, 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. In an embodiment, the dopaminergic therapy can include the administration of a
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compound selected from levodopa, (such as SINAMET™, SINAMETCR™), bromocriptine (such as PARLODEL™), pergolide (such as PERMAX™), ephenedrine sulfate (such as EPHEDRINE™), pemoline such as CYLERT™), mazindol (such as SANOREX™), d,l-α- methylphenethylamine (such as ADDERALL™), methylphenydate (such as RITALIN™), pramipexole (such as MIRAPEX™), modafinil (such as PRO VIGIL™), and ropinirole (such as REQUIP™). In some embodiments, the method further can include administering an anti- dyskensia agent and/or anti-psychotic agent. Suitable anti-dyskenia agents include baclofen (such as LIORESAL™), botulinum toxin (such as BOTOX™), clonazepam (such as KLONOPIN™), and diazepam (such as VALIUM™). Exemplary antipsychotic agents are described herein.
[0066] 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.
[0067] 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.
[0068] 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. As stated previously, the psychosis can be caused or results from various different origins. In an embodiment, 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.
[0069] 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
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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), 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. In some embodiments, the first amount and the second amount can be co-administered. In an embodiment, 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.
[0070] 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. In an embodiment, 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. [0071] 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
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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. In an embodiment, the subject can be at risk to gain weight due to being administered a drug (e.g., an antipsychotic) that causes weight gain.
[0072] 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. In some embodiments, 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.
[0073] 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. In an embodiment, the detectable label can be a radiolabel such as [3H], [18F], [11C] and [125I].
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[0074] In some embodiments, the compounds disclosed herein are potent inverse agonist and/or antagonists of a serotonin receptor. In an embodiment, the serotonin receptor is a 5-HT2A receptor. In an embodiment, the serotonin receptor is a 5-HT2C receptor. In an embodiment, 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. In one embodiment, 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. [0075] An "agonist" is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
[0076] As used herein, "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.
[0077] 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. For example, 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. Thus, while 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. The concept of an inverse agonist has been explored by Bond et al. in Nature 374:272 (1995). More specifically, Bond et al. have proposed that ligand free β2- 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.
[0078] As used herein, "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
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or inverse agonist on the receptor. An antagonist attenuates the action of an agonist on a receptor. However, an antagonist (also known as a "neutral agonist") has no effect on constitutive receptor activity. 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.
[0079] As used herein, "IC50" 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.
[0080] As used herein, "EC50" 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.
[0081] As used 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. [0082] As used herein, 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.
[0083] As used herein, the terms "treating," "treatment," "therapeutic," or "therapy" 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.
[0084] The term "therapeutically effective amount" is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount need to prevent, alleviate or ameliorate symptoms of disease or prolong the survival
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of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the symptoms of the disease being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. [0085] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
[0086] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, 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. [0087] As used herein, 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.
PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS [0088] 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.
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[0089] In some embodiments, 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. [0090] Suitable 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. In an embodiment, the dopaminergic agent can be selected from levodopa (such as SINEMET™, SINEMET-CR™), bromocriptine (such as PARLODEL™), pergolide (such as PERMAX™), ephenedrine sulfate (such as EPHEDRINE™), pemoline such as CYLERT™), mazindol (such as SANOREX™), d,l-α-methylphenethylamine (such as ADDERALL™), methylphenydate (such as RITALIN™), pramipexole (such as MIRAPEX™), modafmil (such as PRO VIGIL™), and ropinirole (such as REQUIP™). [0091] In some embodiments, the anti-dyskensia agent, anti-dystonia, anti- myoclonus, or anti-tremor agent can be selected from baclofen (such as LIORESAL™), botulinum toxin (such as BOTOX™), clonazepam (such as KLONOPIN™), and diazepam (such as VALIUM™).
[0092] In an embodiment, the anti-psychotic agent can be selected from chlorpromazine (such as THORAZINE™), haloperidol (such as HALDOL™), molindone (such as MOBAN™), thioridazine (such as MELLARIL™), 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 ANE®), Promethazine (such as PHENERGAN®), Metoclopramide (such as REGLAN®), Chlorprothixene (such as TARACT AN®), TRIA VIL®, Molindone (such as MOBAN®), Sertindole (such as SERLECT®), Droperidol, Amisulpride (such as SOLIAN®), Melperone, Paliperidone (such as INVEGA®), Tetrabenazine and their active metabolites. Exemplary 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
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STELAZINE®). An example of a suitable phenylbutylpiperadine is pimozide (such as ORAP®). A non-limiting list of 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.
[0093] In an embodiment, the antidepressant can be selected from citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, and dapoxetine. [0094] In one embodiment, 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, 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-l-one hemifumarate)), TAK-147 (zanapezil), phenserine, quilostigmine, ganstigmine, butyrophenones, imipramines, tropates, phencyclidines, curariforms, ethephon, ethopropazine, iso-OMPA, tetrahydrofurobenzofuran cymserine, N^henethyl-norcymserine, N8-benzylnorcymserine, N1,N8-bisnorcymserine, N^N8- bisbenzylnorphysostigmine, N1,N8-bisbenzylnorphenserine and N^N8- bisbenzylnorcymserine.
[0095] In some embodiments, the sleep-inducing agent can be selected from
Zolpidem, eszopiclone, a benzodiazepine, a melatonin agonist, and an antihistamine. A non- limiting list of benzodiazepines include temazepam, diazepam, lorazepam, nitrazepam, and midazolam. An exemplary melatonin agonist is ramelteon. An example of a suitable antihistamine is diphenhydramine.
[0096] The term "pharmaceutical 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
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topical administration. Pharmaceutical 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. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
[0097] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
[0098] The pharmaceutical 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). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is hereby incorporated by reference in its entirety.
[0099] 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. [00100] Alternatively, 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 formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.
[0100] The pharmaceutical 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. [0101] 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,
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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.
[0102] For injection, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0103] For oral administration, 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). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[0104] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions 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.
[0105] Pharmaceutical preparations, 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
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or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. [0106] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
[0107] For administration by inhalation, 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. In the case of a pressurized aerosol, 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. [0108] 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.
[0109] Pharmaceutical formulations 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.
[0110] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
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[0111] 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.
[0112] In addition to the formulations described previously, 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. Thus, for example, 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. [0113] 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. A common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-to xicity nonpolar surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone. Alternatively, other delivery systems for 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. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various 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. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
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[0114] Many of the compounds used in the pharmaceutical combinations disclosed herein 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.
[0115] 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). Typically, 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.
[0116] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. 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. Alternatively the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day. Thus, 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. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
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[0117] 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). 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.
[0118] 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%. [0119] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0120] The amount of 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.
[0121] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, 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. Alternatively, 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. Recognized in vitro models exist for nearly every class of condition, including but not limited to cancer, cardiovascular disease, and various immune dysfunction. Similarly, acceptable animal models may be used to establish efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and regime. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans. [0122] The 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
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may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. 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.
GENERAL SYNTHESIS
[0123] Compounds of Formulae (I), (II), (III), (IV) and (V) as described herein may be prepared in various ways. General synthetic routes to the compounds of Formulae (I), (II), (III), (IV) and (V) are shown in Schemes A-E. The routes shown are illustrative only and are not intended, nor are they to be construed, to limit the scope of this invention in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed synthesis and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of this application.
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Scheme A
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0003
Figure imgf000038_0004
Reagents: a) K2CO3, (CHs)2CHCH2Br; b) K2CO3, HONH2 HCI; c) LiAIH4; d) COCI2; e) Pd-C, H2
[0124] Scheme A shows a general reaction scheme for forming the compound of
Formula (I). 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. 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).
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Scheme B
Figure imgf000039_0001
Reagents: a) K2CO3, 3-bromo-2-methylpropene; b) LiOH; c) DPPA
[0125] An exemplary method for synthesizing the compound of Formula (II) is shown in Scheme B.
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Scheme C
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
Reagents: a) BoC2O; b) NaOH, methyl 3-bromo-2-(bromonnethyl)butanoate; c) Pd-C, H2; d) TFA; e) COCI2; f) Et3N, Chloroethyl chloroformate; g) LiOH
[0126] One method for synthesizing the compound of Formula (III) is shown in
Scheme C.
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Scheme D
Figure imgf000041_0001
Figure imgf000041_0002
Reagents: a) K2CO3, benzylbromide; b) LiAIH4; c) (COCI)2, Et3N; d) NaCNBH3; e) COCI2; f) Pd-C, H2
[0127] Scheme D shows a general reaction scheme for forming the compound of
Formula (IV). All the compounds described herein can be purified using methods known to those skilled in art.
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Scheme E
Figure imgf000042_0001
Reagents: a) K2CO3, benzylbromide; b) t-butylcarbamate, Et3SiH, TFA; c) Na2CO3, COCI2; d) Pd-C, H2
[0128] One example of a method for synthesizing a compound of Formula (V) is shown in Scheme E. All the compounds described herein can be purified using methods known to those skilled in art.
EXAMPLES
[0129] Certain embodiments of the claimed subject matter are illustrated by the following non-limiting examples.
[0130] Chemistry. 1H NMR spectra were recorded at 400 MHz on a Varian
Mercury- VX400MHz spectrometer and chemical shifts are given in δ-values [ppm] referenced to the residual solvent peak chloroform (CDCI3) at 7.26 and methanol (CD3OD) at 3.31 ppm. Coupling constants, J, are reported in Hertz. Unless otherwise stated, the NMR spectra of the compounds are described for their free amine form. Column chromatography was carried out using silica gel 60 (particle size 0.030-0.070 mm) from Merck. In certain embodiments, "CombiFlash" chromatography is used. CombiFlash chromatography systems are available from Teledyne Isco, Inc. Materials and solvents were of the highest grade available from commercial sources and used without further purification. Reversed phase Ci8 solid phase extraction cartridges (SPE) were DSC-18 2 g/12 mL columns from Discovery™ Solid Phase Extraction Products, Supelco. Preparative HPLC was run on a
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Waters/Micromass HPLC/MS using a diode array detector (190-450 nm) UV detector and Micromass ZMD-mass-spectrometer with electrospray ionization. A YMC J'sphere ODS H80 19x100 mm column was used. The mobile phase was 0.15% TFA in water/acetonitrile with a gradient starting at 30% acetonitrile, going to 100% acetonitrile over 13 min. The flow rate was 17 mL/min.
[0131] In some embodiments, an H-Cube hydrogenation reactor is used. H-Cube reactors are available from ThalesNano Nanotechnology Inc. [0132] 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. A Phenomenex Luna C18(2) 3 μm, 75 x 4.6 mm column was used. 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.
[0133] Preparation of hydrochloride salts. The tertiary amine products were dissolved in dichloromethane, treated with an excess of IM HCl in diethyl ether and precipitated from n-heptane. The solvents were removed in vacuo and after drying, the hydrochloride salts were obtained as colorless solids in quantitative yield.
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SDI-10975vl Attorney Docket No. 12560-046-228 l-f4-Fluorobenzyl)-3-f3-hvdroxy-4-isobutoxybenzyl)-l-fl-methylpiperidin-4-yl)urea
Figure imgf000044_0001
Scheme l.β
Figure imgf000044_0002
Figure imgf000044_0003
a Reagents: a) K2CO3, (CH3)2CHCH2Br; b) K2CO3, HONH2 HCl; c) LiAlH4; d) COCl2; e) Pd-C, H2
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l-(4-Fluorobenzyl)-3-(3-hydroxy-4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea (hydrochloride)
[0134] 4-Hydroxy-3-benzyloxybenzaldehyde was prepared according to the literature procedures: Santangelo, F.; Casagrande, C; Synth. Commun. 1996, 26, 2863-2873; Kessar, S.V.; Gupta, Y.P.; Mohammad, T.; Goyal, M.; Sawal, K.K.; J. Chem. Soc, Chem. Commun. 1983, 400-401.
[0135] 4-Hydroxy-3-benzyloxybenzaldehyde (700 mg, 3.07 mmol) was dissolved in DMF (10 mL). Potassium carbonate (1.27 g, 9.20 mmol) was added followed by isobutylbromide (1.00 mL, 9.20 mmol). The reaction mixture was heated to 60 0C for 20 h. The mixture was concentrated, water (50 mL) was added and the mixture extracted with dichloromethane (2x50 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated to give 4-isobutoxy-3-benzyloxybenzaldehyde (873 mg, 100%). [0136] 4-isobutoxy-3-benzyloxybenzaldehyde (300 mg, 1.06 mmol) was dissolved in ethanol (25 mL). Potassium carbonate (161 mg, 1.16 mmol) was added followed by hydroxylamine hydrochloride (74 mg, 1.06 mmol). The reaction mixture was heated to reflux for 2 h. Ethanol was evaporated and water (20 mL) was added. The water phase was extracted with dichloromethane (2x20 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated. The resulting material was dissolved in diethyl ether (5 mL) and added to a stirred suspension of lithium aluminum hydride (112 mg, 2.94 mmol) in diethyl ether (10 mL) at 0 0C. The reaction mixture was heated to reflux for 2 h. After cooling to room temperature, the mixture was stirred vigorously and water (1 mL) was added followed by 2M aqueous NaOH (2 mL) and water (2 mL). The resulting white slurry was filtered and the filtrate was diluted with water (50 mL). The aqueous phase was extracted with dichloromethane (2x100 mL), which was reextracted with 2M aqueous HCl (2x100 mL). The aqueous phase was made alkaline with 2M NaOH and extracted with dichloromethane (2x100 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated to give 4-isobutoxy-3-benzyloxybenzylamine (130 mg, 43%) as a white solid.
[0137] 4-isobutoxy-3-benzyloxybenzylamine (60 mg, 0.21 mmol) was dissolved in
THF (1 mL) and added dropwise to a phosgene solution (20% in toluene, 1 mL, 2.02 mmol)
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at 0 0C under argon. The mixture was stirred for 2 h after which argon was bubbled through the solution for 3 h into a KOH scrubbing bath to remove excess phosgene. Dichloromethane (5 mL) was added followed by a solution of 4-(4-fluorobenzyl)amino-l-methylpiperidine (47 mg, 0.21 mmol) and triethylamine (42 mg, 0.42 mmol) in dichloromethane (2 mL). The reaction mixture was stirred for 2h and concentrated. Purification by flash chromatography (5% methanol in dichloromethane) gave l-(4-Fluorobenzyl)-3-(3-benzyloxy-4- isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea (50 mg, 27%) as a colorless oil. [0138] 1 -(4-Fluorobenzyl)-3-(3-benzyloxy-4-isobutoxybenzyl)- 1 -(I - methylpiperidin-4-yl)urea (50 mg, 0.093 mmol) was dissolved in absolute ethanol (5 mL). 10% Palladium on charcoal (10 mg) was added under argon. Hydrogen pressure (1 atm.) was applied from a balloon and the reaction mixture was stirred for 3h. Filtration through Celite and evaporation gave 1 -(4-Fluorobenzyl)-3 -(3 -hydroxy-4-isobutoxybenzyl)- 1 -( 1 - methylpiperidin-4-yl)urea (41 mg, 100%) as a colorless oil: 1H-NMR (CDCl3, 400 MHz, Free base) δ 7.21-6.46 (m, 7H), 4.77-4.60 (m, 2H), 4.39 (s, 2H), 4.21 (d, J=5.5 Hz, 2H), 3.75 (d, J=7.0 Hz, 2H), 3.50-3.41 (m, 2H), 2.91-2.80 (m, 2H), 2.72 (s, 3H), 2.53-2.39 (m, 2H), 2.13-2.05 (m, IH), 1.91-1.83 (m, 2H), 1.02 (d, J=7.0 Hz, 6H); LC-MS showed [M+H]+ = 444. The collected compound was converted into its hydrochloride salt, which was obtained as a colorless solid.
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l-(4-Fluorobenzyl)-3-(4-(2-methylallyloxy)benzyl)-l-Q-methylpiperidin-4-yl)urea
Figure imgf000047_0001
Scheme 2.a
Figure imgf000047_0002
aReagents: a) K2CO3, 3-bromo-2-methylpropene; b) LiOH; c) Diphenylphosphoryl azide
Figure imgf000047_0003
Methyl 2-(4-(2-methylallyloxy)phenyl)acetate
[0139] 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 0C for 4 h, then allowed to cool to room temperature. The mixture was diluted with diethyl ether, washed with water and brine, dried
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(Na2SO4), concentrated and purified by flash chromatography (SiO2, heptane:EtOAc, 20:1 - 5:1) to give 6.2 g (99%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.19 (m, 2H), 6.88 (m, 2H), 5.05 (m, 2H), 4.41 (s, 2H), 3.69 (s, 3H), 3.56 (s, 2H), 1.81 (m, 3H).
Figure imgf000048_0001
2-(4-(2-Methylallyloxy)phenyl)acetic acid
[0140] 1 M aqueous LiOH-solution (5 mL) was added to a mixture of methyl 2-(4-
(2-methylallyloxy)phenyl)acetate (1.0 g, 4.5 mmol) in THF (20 mL), and the resulting mixture was stirred at 65 0C over night. The reaction mixture was diluted with water (20 mL) and 2 M NaOH (5 mL), and extracted with Et2O (2 x 20 mL). 2 M HCl was added to the aqueous phase until pH 2. The aqueous phase was extracted with Et2O (2 x 50 mL). The ethereal phases from the last extraction were combined, dried (Na2SO4), and concentrated to give 615 mg (66%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.19 (m, 2H), 6.88 (m, 2H), 5.05 (m, 2H), 4.43 (s, 2H), 3.59 (s, 2H), 1.83 (m, 3H).
Figure imgf000048_0002
l-f4-Fluorobenzyl)-3-f4-f2-methylallyloxy)benzyl)-l-fl-methylpiperidin-4-yl)urea [0141] Proton sponge (171 mg, 0.80 mmol) was added to a mixture of 2-(4-(2- methylallyloxy)phenyl)acetic acid (150 mg, 0.73 mmol) in THF and the resulting mixture was stirred for 15 min. Diphenylphosphoryl azide (0.17 mL, 0.80 mmol) was added to the resulting mixture, which was stirred over night at 62 0C and placed in a freezer for two weeks. Et2O was added to the resulting precipitate and the suspension was stirred for 10 min, after whichthe precipitate was filtered off. The filtrate was concentrated and the residue was taken up in CH2Cl2 (2 mL) and added to a solution of 4-(4-fluorobenzyl)amino-l- methylpiperidine (162 mg, 0.73 mmol) in CH2Cl2. The resulting mixture was stirred overnight at room temperature, then concentrated. Flash chromatography (SiO2,
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CH2Cl2:Me0H 0-20%) gave a crude product that was subjected to preparative TLC (SiO2, EtOAc:MeOH:NH4OH(aq), 20:1 :1) to give 40 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.15 (m, 2H), 6.98 (m, 4H), 6.80 (m, 2H), 5.05 (m, 2H), 4.49-4.26 (m, 8H), 2.86 (m, 2H), 2.26 (s, 3H), 2.05 (dt, J= 11.7, 0.9 Hz, 2H), 1.81 (m, 3H), 1.74-1.60 (m, 4H); LC-MS ([M+H] + = 426.
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Methyl 3-(4-(|3-(4-fluorobenzyl)-3-Q-methylpiperidin-4-yl)ureido)methyr)phenoxy)-2- methylpropanoate
Figure imgf000050_0001
Scheme 3.°
Figure imgf000050_0002
Figure imgf000050_0003
Figure imgf000050_0004
a Reagents: a) BoC2O; b) NaOH, methyl 3-bromo-2-(bromomethyl)butanoate; c) Pd-C, H2; d) TFA; e) COCl2; f) Et3N, Chloroethyl chloroformate; g) LiOH
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Figure imgf000051_0001
fert-Butyl 4-hvdroxybenzylcarbamate
[0142] 4-(Aminomethyl)phenol (4.9 mmol, Ig) was dissolved in methanol. Boc- anhydride (5.8 mmol, 1.3 g) and NaHCO3 (14.7 mmol, 1.2 g) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated and CH2Cl2 and water were added. The organic phase was separated and the aqueous phase was extracted 3 times with CH2Cl2. The combined organic phases were dried (Na2SO4) and evaporated. The crude product was purified by column chromatography using combiflash (Heptane: EtOAc 0-40%) to give 1.5 g (83%) of the title compound: LC-MS [M+H]+= 224.
Figure imgf000051_0002
Methyl 2-(ϊ4-(ϊferM)utoxycarbonylamino)methyl)phenoxy)methyl)acrylate
[0143] Powered sodium hydroxide (0.45 mmol, 18.0 mg) and methyl 3-bromo-2-
(bromomethyl)propanoate (0.45 mmol, 0.065 mL) were added to a solution of tert-butyl A- hydroxybenzylcarbamate (0.45 mmol, 0.1 g) in 4 mL of ethanol, and the reaction mixture was stirred over night at room temperature. The ethanol was evaporated, water was added, and the product was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4) and evaporated. The crude product was purified by column chromatography using combiflash (Heptane: EtOAc 0-40%; 4 g column) to give 80 mg (55%) of the title compound: LC-MS [M+H]+= 322.
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Figure imgf000052_0001
Methyl 3-f4-ffte^-butoxycarbonylamino)methyl)phenoxy)-2-methyl-propanoate
[0144] Methyl 2-((4-((fert-butoxycarbonylamino)methyl)phenoxy)methyl)acrylate
(180 mg 0.56 mmol) in methanol was hydrogenated using Pd-C 10% in an H-cube. The reaction mixture was filtered through Celite and the solvent was evaporated to afford methyl 3-(4-((fert-butoxycarbonylamino)methyl)phenoxy)-2-methylpropanoate (170 mg, 94%):
Figure imgf000052_0002
Methyl 3-(4-(aminomethyDphenoxy)-2-methylpropanoate
[0145] TFA (11.2 mmol, 0.877 mL) was added to a solution of methyl 3-(4-((tert- butoxycarbonylamino)methyl)phenoxy)-2-methylpropanoate (400 mg, 1.2 mmol) in CH2Cl2 at 0 0C, and the reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated and CH2Cl2 was added to the residue. The organic layer was washed with 2N NaOH and water, dried (Na2SO4) and evaporated to obtain methyl 3-(4- (aminomethyl)phenoxy)-2-methylpropanoate (200 mg, 100%): 1H NMR (400 MHz, CDCl3) δ 7.25 - 7.16 (m, 2H), 6.92 - 6.83 (m, 2H), 4.07 (ddd, J= 80.6, 9.1, 6.4, 2H), 3.79 (s, 2H), 3.71 (d, J= 2.0, 3H), 2.94 (dd, J= 13.3, 6.8, IH), 1.45 (d, J= 4.8, 2H), 1.28 (dd, J= 6.1, 2.4, 3H).
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Figure imgf000053_0001
Methyl 3-(4-(|3-(4-fluorobenzyl)-3-Q-methylpiperidin-4-yl)ureido)methyl)phenoxy)-2- methylpropanoate
[0146] Methyl 3-(4-(aminomethyl)phenoxy)-2-methylpropanoate (0.62 mmol, 200 mg), was dissolved in 10 mL Of CH2Cl2 and 10 rnL of 5% sodium carbonate was added and the mixture was stirred at 0 0C for 5 min. Stirring was stopped and a phosgene solution (20% in toluene, 0.62 mL, 1.24 mmol) was added directly to the organic layer by syringe. Stirring was continued for 45 min at 0 0C. More CH2Cl2 was added and the organic layer was separated, and the aqueous phase extracted with CH2Cl2 (20 mL). The combined organic phase was dried (Na2SO4) and evaporated. The crude product was re-dissolved in 15 mL of CH2Cl2 to which was added 4-(4-fluorobenzyl)amino-l-methylpiperidine (275 mg, 1.24 mmol) and the mixture stirred overnight at room temperature. Additional CH2Cl2 was added followed by 2N HCl. The mixture was extracted with CH2Cl2, and the combined organic phases washed with 5% NaHCO3, dried (Na2SO4) and evaporated. The crude product was purified by column chromatography (SiO2; EtOAc: MeOH: 7 N NH3 in MeOH, 9:1 :0.5) to afford the title compound (200 mg, 69%): LC-MS [M+H]+= 472.
Figure imgf000053_0002
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3-f4-ff3-f4-Fluorobenzyl)-3-fl-methylpiperidin-4-yl)ureido)methyl)phenoxy)-2- methylpropanoic acid
[0147] Methyl 3-(4-((3-(4-fluorobenzyl)-3-(l-methylpiperidin-4- yl)ureido)methyl)phenoxy)-2-methylpropanoate (5 mg, 0.01 mmol,), was dissolved in 500 μL of THF, LiOH was added, and the mixture stirred at room temperature for 3 h. The THF layer was separated, concentrated and evaporated to dryness to provide a crude product which was used directly in the next step without further purification. LC-MS [M+H]+ = 458.
Figure imgf000054_0001
Methyl 3-(4-(T3-(4-fluorobenzyl)-3-(piperidin-4-yl)ureido)methyl)phenoxy)-2- methylpropanoate
[0148] Methyl 3-(4-((3-(4-fluorobenzyl)-3-(l-methylpiperidin-4- yl)ureido)methyl)phenoxy)-2-methylpropanoate (52 mg, 0.11 mmol) was dissolved in 2 mL of 1,2-dichloroethane. Triethyl amine (19 μL, 0.132 mmol) and chloroethyl chloroformate (15 μL, 0.132 mmol) were added and the mixture was stirred at 50 0C for 4 h. The solvent was evaporated and the product was purified by column chromatography (SiO2, EtOAc). The resulting carbamate intermediate was re-dissolved in methanol and heated at 50 0C for 2 h. The solvent was evaporated and methyl 3-(4-((3-(4-fluorobenzyl)-3-(piperidin-4- yl)ureido)methyl)phenoxy)-2-methylpropanoate was isolated as the HCl salt (47.4 mg, 87%): LC-MS [M+H]+= 458.
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Figure imgf000055_0001
3-f4-ff3-f4-fluorobenzyl)-3-fpiperidin-4-yl)ureido)methyl)phenoxy)-2-methylpropanoic acid
[0149] 1 M LiOH-H2O (2 mL) was added to a solution of methyl 3-(4-((3-(4- fluorobenzyl)-3-(piperidin-4-yl)ureido)methyl)phenoxy)-2-methylpropanoate (50 mg, 0.11 mmol) in THF (2 mL). The reaction mixture was stirred for 2 h at room temperature, CH2Cl2 (10 mL) was added, and the organic phase was separated and discarded. THF was added to the aqueous solution and the organic phase was separated, dried (Na2SO4) and evaporated. The residue was purified by repeated reversed phase HPLC (Ci 8 column, MeOH- Water 20:80 containing 0.1% TFA) to afford 3-(4-((3-(4-fluorobenzyl)-3-(piperidin-4- yl)ureido)methyl)phenoxy)-2-methylpropanoic acid.(23.7 mg, 50%): 1H NMR (400 MHz, CD3OD) δ 7.24 (m, 2H), 7.00 (m, 4H), 6.83 (m 2H), 4.48 (s, 2H), 4.27 m, 3H), 4.12-4.00 (m, 2H), 3.47 (m, 2H), 3.07 (m, 2H), 2.81(m, 4H), 2.01-1.90 (m, 4H), 1.27(d,3H): LC-MS [M+H]+= 444.19.
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l-f4-Fluorobenzyl)-3-f2-hvdroxy-4-methoxybenzyl)-l-fl-methylpiperidin-4-yl)urea
Figure imgf000056_0001
Scheme 4.a
Figure imgf000056_0002
a Reagents: a) K2CO3, benzylbromide; b) t-butylcarbamate, Et3SiH, TFA; c) Na2CO3, COCl2; d) Pd-C, H2
Figure imgf000056_0003
2-(Benzyloxy)-4-methoxybenzaldehyde
[0150] K2CO3 and benzyl bromide were added to a solution of 2-hydroxy-4- methoxy benzaldehyde (1 g, 6.57 mmol) in ethanol (100 mL), and the mixture was then heated for two days at 50 0C. The solution was concentrated and the residue was dissolved in
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diethyl ether. The ether solution was washed with brine, 5% aqueous NaOH, water, dried (Na2SO4) and evaporated to give the 2-benzyloxy-4-methoxybenzaldehyde (1.5 g, 95%): LC-MS [M+H]+= 243.02.
Figure imgf000057_0001
fert-butyl 2-(benzyloxy)-4-methoxybenzylcarbamate
[0151] A solution of 2-benzyloxy-4-methoxybenzaldehyde (113 mg, 0.47 mmol), t- butyl carbamate (162 mg, 1.39 mmol), triethyl silane (1.38 mmol, 219 μL) and TFA (0.91 mmol, 70μL) in MeCN (3 mL) was stirred at 22 0C for 18 h. The reaction mixture was then diluted with diethyl ether, washed with saturated NaHCOs and brine, dried (Na2S(M) and evaporated to give a crude product (131 mg, 82%) which was used without further purification. The Boc group was removed by TFA in CH2Cl2 and using conventional procedure to afford (2-benzyloxy-4-methoxyphenyl)methanamine in quantitative yield: 1H NMR (400 MHz, CDCl3) δ 7.47 - 7.28 (m, 5H), 7.11 (d, J= 8.2, IH), 6.54 (d, J= 2.3, IH), 6.50 (dd, J= 8.2, 2.4, IH), 5.04 (s, 2H), 3.80 (s, 3H), 3.77 (s, 2H); LC-MS [M+H]+ = 244,13.
Figure imgf000057_0002
3-f2-fBenzyloxy)-4-methoxybenzyl)-l-f4-fluorobenzyl)-l-fl-methylpiperidin-4-yl)urea
[0152] 10 mL of 5% sodium carbonate was added to a solution of (2-benzyloxy-4- methoxypheny)methanamine (0.8 mmol, 200 mg) in CH2Cl2 (10 mL) , and the mixture was
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stirred at 0 0C for 5 min. The stirring was stopped and a phosgene solution (20% in toluene, 0.8 rnL, 1.6 mmol) was added directly to the organic layer by syringe. Stirring was continued for 45 min at 0 0C and additional CH2Cl2 (15 rnL) was added. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (20 mL). The combined organic phase was dried (Na2SO4) and evaporated. The resulting crude product was dissolved in CH2Cl2 (15 mL) and 4-(4-fluorobenzyl)amino-l-methylpiperidine (356 mg, 1.6 mmol) was added and the reaction mixture, which was stirred overnight at room temperature. Additional CH2Cl2 was added followed by 2N HCl. The reaction mixture was extracted with CH2Cl2, and the combined organic phase was washed with 5% NaHCO3 dried (Na2SO4) and evaporated. The crude product was purified by column chromatography (SiO2, EtOAc followed by EtOAc: MeOH: NH3, 8:1 :0.25) to afford 3-(2-(Benzyloxy)-4-methoxybenzyl)-l- (4-fiuorobenzyl)-l-(l-methylpiperidin-4-yl)urea.(100 mg, 25 %): LC-MS [M+H]+ = 492.
Figure imgf000058_0001
l-f4-Fluorobenzyl)-3-f2-hvdroxy-4-methoxybenzyl)-l-fl-methylpiperidin-4-yl)urea
[0153] 3-(2-(Benzyloxy)-4-methoxybenzyl)-l-(4-fluorobenzyl)-l-(l- methylpiperidin-4-yl)urea (100 mg, 0.2 mmol) was hydrogenated using an H-cube at 1 bar and 30 0C temperature using Pd-C 10% as catalyst to afford 356SB10 (58 mg): 1H NMR (400 MHz, CDCl3) δ 7.10 (m, 2H), 6.95 (m, 2H), 6.81 (m, IH), 6.46 (m, IH), 6.29 (m, IH), 5.02 (t, IH), 4.33 (m, 2H), 4.18 (m, 2H), 3.73 (m, 3H), 3.43 (m, IH), 2.92 (m, 2H), 2.28 (m, 3H), 2.14 (s, 3H), 2.09 (m, 2H), 1.74-1.67 (m, 3H); LC-MS [M+H]+ = 402.
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l-f4-Fluorobenzyl)-3-f4-hvdroxy-2-methoxybenzyl)-l-fl-methylpiperidin-4-yl)urea
Figure imgf000059_0001
Scheme 5.°
Figure imgf000059_0002
a Reagents: a) K2CO3, benzylbromide; b) t-butylcarbamate, Et3SiH, TFA; c) Na2CO3, COCl2; d) Pd-C, H2
Figure imgf000059_0003
fert-Butyl 4-(benzyloxy)-2-methoxybenzylcarbamate
[0154] A solution of 4-(benzyloxy)-2-methoxybenzaldehyde (113 mg, 0.47), t-butyl carbamate (162 mg, 1.39 mmol) triethyl silane (1.38 mmol, 219 μL), TFA (0.91 mmol, 70μL) in MeCN (3 mL) was stirred at 22 0C for 18 h. The reaction mixture was diluted with diethyl ether, washed with saturated NaHCO3 and brine, dried (Na2SO4) and evaporated. The
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resulting crude product (124 mg, 80%) was used directly in the next step without further purification. The Boc group was removed by CH2Cl2 and TFA using the conventional procedure to afford 4-(benzyloxy)-2-methoxyphenyl)methanamine in quantitative yield: LC- MS [M+H]+= 344.
Figure imgf000060_0001
3-f4-fBenzyloxy)-2-methoxybenzyl)-l-f4-fluorobenzyl)-l-fl-methylpiperidin-4-yl)urea
[0155] 10 rnL of 5% sodium carbonate was added to a solution of tert-butyi 4-
(benzyloxy)-2-methoxybenzylcarbamate (0.8 mmol, 200 mg) in CH2Cl2 (10 mL) , and the mixture was stirred at 0 0C for 5 min. The stirring was stopped and a phosgene solution (20% in toluene, 0.8 mL, 1.6 mmol) was added directly to the organic layer by syringe. Stirring was continued for 45 min at O0C and CH2Cl2 (15 mL) was added. The organic layer was separated and the aqueous phase extracted with CH2Cl2 (20 mL). The combined organic phase was dried (Na2SO4) and evaporated. The resulting crude product was dissolved in CH2Cl2 (15 mL), 4-(4-fluorobenzyl)amino-l-methylpiperidine (356 mg, 1.6 mmol) was added, and the mixture was stirred overnight at room temperature. Additional CH2Cl2 was added followed by 2N HCl. The reaction mixture was extracted with CH2Cl2, and the combined organic phase was washed with 5% NaHCO3, dried (Na2SO4) and evaporated. The crude product was purified column chromatography (SiO2, EtOAc followed by EtOAc: MeOH: NH3, 8:1 :0.25) to afford 3-(4-(benzyloxy)-2-methoxybenzyl)-l-(4-fluorobenzyl)-l- (l-methylpiperidin-4-yl)urea (150 mg, 37 %): LC- LC-MS [M+H]+= 492.
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Figure imgf000061_0001
l-f4-Fluorobenzyl)-3-f4-hvdroxy-2-methoxybenzyl)-l-fl-methylpiperidin-4-yl)urea
[0156] 3-(4-(Benzyloxy)-2-methoxybenzyl)-l-(4-fluorobenzyl)-l-(l- methylpiperidin-4-yl)urea (150 mg, 0.3 mmol) was dissolved in MeOH and hydrogenated using an H-cube at 1 bar and 30 0C and Pd-C 10% as catalyst. Filtration (Celite) and evaporation of the solvent afforded 1 -(4-Fluorobenzyl)-3 -(4-hydroxy-2-methoxybenzyl)- 1 ■ (l-methylpiperidin-4-yl)urea (148 mg, 97%): 1H NMR (400 MHz, CDCl3) δ 7.06 (m, 2H), 6.92 (m, 4H), 6.24 (m, 2H), 4.91 (m, IH), 4.31-4.18 (m, 5H), 3.43 (s, 3H), 3.40, (s, 3H), 2.88-2.85 (m,2H), 2.24 (s, 3H), 2.08 (m, 2H), 1.66 (m, 3H); LC-MS [M+H]+ = 402.
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SDI-10975vl Attorney Docket No. 12560-046-228 l-f4-Fluoro-3-hvdroxybenzyl)-3-(4-hvdroxybenzyl)-l-fl-methylpiperidin-4-yl)urea
Figure imgf000062_0001
a Reagents: a) K2CO3, benzylbromide; b) LiAlH4; c) (COCl)2, Et3N; d) NaCNBH3; e) COCl2; f) Pd-C, H2
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l-f4-Fluoro-3-hvdroxybenzyl)-3-f4-hvdroxybenzyl)-l-fl-methylpiperidin-4-yl)urea
[0157] Methyl 4-fluoro-3-hydroxybenzoate (0.3 g, 1.8 mmol), K2CO3 (0.15 g, 3.0 mmol) and benzylbromide (0.34 g, 2.0 mmol) were mixed in 2 mL dry DMF. The reaction mixture was heated overnight, concentrated and extracted with CH2Cl2 after addition of water. The combined organic phases were dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (SiO2, CH2Cl2) to afford 410 mg of pure (NMR) methyl 3-benzyloxy-4-fluorobenzoate.
[0158] Methyl 3-benzyloxy-4-fluorobenzoate (400 mg, 1.54 mmol) and LiAlH4 (290 mg, 7.7 mmol) in dry THF were stirred at room temperature for 48 h under N2 atmosphere. The reaction mixture was quenched with 4N NaOH and extracted with diethyl ether and ethyl acetate. The combined organic phases were dried (Na2SO4) and evaporated to give 0.3 g of 3- benzyloxy-4-fluorobenzyl alcohol, which was was used in the next step without further purification.
[0159] 3-Benzyloxy-4-fluorobenzyl alcohol was subjected to a Swern oxidation.
DMSO (0.31 mL) was added dropwise to a solution of oxalyl chloride (0.280 g, 0.19 mL) in dry CH2Cl2 at - 76 0C. The mixture was stirred for 30 min, and a solution of 3-benzyloxy-4- fluorobenzyl alcohol (297 mg, 1.28 mmol) in 7 mL of dry CH2Cl2 was added. The mixture was stirred at -76 0C for 1.5 h, 1.5 mL triethylamine was added, and the mixture was stirred for 30 min and allowed to reach room temperature. Additional CH2Cl2 was added. The organic phase was then washed with 0.5 M HCl, 0.5 M NaOH and brine, and dried over Na2SO4. Evaporation followed by purification of the resulting residue by flash chromatography (SiO2, CH2Cl2) afforded 250 mg pure (NMR) 3-benzyloxy-4- fluorobenzaldehyde.
[0160] 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. NaCNBH3 (82 mg, 1.3 mmol) was added under N2 atmosphere. The mixture was stirred for 2 h, quenched with aqueous NaOH and concentrated. Water was added and the aqueous solution extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated to give 0.2 g of crude 4-(3-benzyloxy-4-fluorobenzyl)amino-l-methylpiperidine (NMR), which was used in the next step without further purification.
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[0161] A solution of 4-benzyloxybenzylamine (0.26 g, 1.2 mmol) in CH2Cl2 (10 rnL) was added to 10 mL of 5% NaHCC>3. The resulting mixture was stirred for 15 min, COCl2 was added by syringe to the organic phase, and the resulting mixture was stirred for 1 h. The mixture was extracted with CH2Cl2 and the combined organic phases were dried (Na2SO4). After filtration, 4-(3-benzyloxy-4-fluorobenzyl)amino-l- methylpiperidine (0.2 g, 0.61 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2 N HCl, made basic with NaOH, extracted with CH2Cl2, and the combined extracts were dried (Na2SO4), filtered and evaporated. The resulting residue was purified by flash chromatography (SiO2, EtOAc :MeOH:NH4OH) to afford 0.17 g of l-(3-benzyloxy-4-fluorobenzyl)-3-(benzyloxybenzyl)-l-(l-methylpiperidin- 4-yl)urea.
[0162] The l-(3-benzyloxy-4-fluorobenzyl)-3-(benzyloxybenzyl)-l-(l- methylpiperidin-4-yl)urea isolated in the above stepwas dissolved (1 M) in MeOH:THF (1 :1) and Pd-C added and hydrogenated using an H-cube (1 mL/min) at 50 0C and 20 atmospheres. Filtration through Celite and evaporation gave 31 mg of pure product: 1H-NMR (DMSO-dβ, 400 MHz, Free base): δ 7.07-7.00 (m, 3H), 6.88 (m, IH), 6.69-6.65 (m, 2H), 6.55-6.50 (m, 2H), 4.27 (s, 2H), 4.17-4.13 (m, 2H), 3.90-3.80 (m, IH), 2.75-2.68 (m, 2H), 2.10 (s, 3H), 1.93-1.84 (m, 2H), 1.65-1.50 (m, 2H), 1.50-1.40 (m, 2H).
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l-f4-Fluoro-2-hvdroxybenzyl)-3-f4-hvdroxybenzyl)-l-fl-methylpiperidin-4-yl)urea
Figure imgf000065_0001
Figure imgf000065_0002
a Reagents: a) K2CO3, benzylbromide; b) LiAlH4; c) (COCl)2, Et3N; d) NaCNBH3; e) COCl2; f) Pd-C, H2
l-f4-Fluoro-2-hvdroxybenzyl)-3-f4-hvdroxybenzyl)-l-fl-methylpiperidin-4-yl)urea
[0163] Methyl 4-fluoro-2-hydroxybenzoate (0.3 g, 1.8 mmol), K2CO3 (0.15 g, 3.0 mmol) and benzylbromide (0.34 g, 2.0 mmol) were mixed in 2 mL dry DMF. The reaction
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mixture was heated for several hours and thereafter concentrated and extracted with CH2Cl2 after addition of water. The combined organic phases were dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2, CH2Cl2) to afford 400 mg of pure (NMR) methyl 2-benzyloxy-4-fluorobenzoate.
[0164] Methyl 2-benzyloxy-4-fluorobenzoate (400 mg, 1.54 mmol) and LiAlH4 (290 mg, 7.7 mmol) in dry THF were stirred at room temperature for 48 h under N2 atmosphere. The reaction mixture was quenched with 4N NaOH and extracted with ether and ethyl acetate. The combined organic phases were dried (Na2SO4) and evaporated to give the 0.33 g of 2-benzyloxy-4-fluorobenzyl alcohol, which was used in the next step without further purification.
[0165] 2-Benzyloxy-4-fluorobenzyl alcohol was subjected to a Swern oxidation.
DMSO (0.31 mL) was added dropwise to a solution of oxalyl chloride (0.280 g, 0.19 mL) in dry CH2Cl2 at - 76 0C. The resulting mixture was stirred for 30 min, and a solution of 2- benzyloxy-4-fluorobenzyl alcohol (0.32 g, 1.37 mmol) in 7 mL of dry CH2Cl2 was added. The resulting mixture was stirred at -76 0C for 1.5 h, 1.5 mL of triethylamine was added, and the mixture was stirred for 30 min and allowed to reach room temperature. Additional CH2Cl2 was added and the organic phase washed with 0.5 M HCl, 0.5 M NaOH and brine, then dried over Na2SO4. Evaporation followed by purification of the resulting residue by flash chromatography (SiO2, CH2Cl2) afforded 200 mg pure (NMR) 2-benzyloxy-4- fluorobenzaldehyde.
[0166] Acetic acid was added to 2-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 was stirred for 2 h at room temperature. NaCNBH3 (82 mg, 1.3 mmol) was added under N2 atmosphere. The mixture was stirred for 2 h, quenched with aqueous NaOH and concentrated. Water was added and the aqueous solution was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated to give 0.2 g of crude 4-(2-benzyloxy-4-fluorobenzyl)amino-l-methylpiperidine (NMR), which was used in the next step without further purification.
[0167] A solution of 4-benzyloxybenzylamine (0.26 g, 1.2 mmol) in CH2Cl2 (10 mL) was added to 10 mL of 5% NaHCO3. The resulting mixture was stirred for 15 min, COCl2 was added by syringe to the organic phase, and the resulting mixture stirred for 1 h.
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The resulting mixture was extracted with CH2Cl2 and the combined organic phases were dried (Na2SO4). After filtration, 4-(2-benzyloxy-4-fluorobenzyl)amino-l- methylpiperidine (0.2 g, 0.61 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2 N HCl, made basic with NaOH, extracted with CH2Cl2, and the combined extracts dried (Na2SO4), filtered and evaporated. The resulting residue was purified by flash chromatography (SiO2, EtOAc:MeOH:NH4OH) to afford 0.22 g ofΛ/-(2-benzyloxy-4-fluorobenzyl)-Λ/-(l-methylpiperidin-4-yl)-N'-(4- benzyloxybenzyl)carbamide.
[0168] Λ/-(2-benzyloxy-4-fluorobenzyl)-Λ/-(l-methylpiperidin-4-yl)-JV'-(4- benzyloxybenzyl)carbamide (0.217 g, 0.382 mmol) was dissolved (1 M) in MeOH:THF (1 :1). Pd-C was added and the mixture was hydrogenated using an H-cube (1 mL/min) at 50 0C and 20 atmospheres. Filtration through Celite and evaporation gave 55 mg of pure product: 1H-NMR (DMSO-J6, 400 MHz, Free base):δ 7.04-6.96 (m, 3H), 6.86-6.82 (m, IH), 6.69-6.59 (m, 4H), 4.31 (s, 2H), 4.16-4.12 (m, 2H), 3.95-3.85 (m, IH), 2.75-2.68 (m, 2H), 2.10 (s, 3H), 1.93-1.84 (m, 2H), 1.61-1.49 (m, 2H), 1.49-1.41 (m, 2H).
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l-(4-Fluorobenzyl)-3-(4-hvdroxybenzyl)-l-(piperidin-4-yl)urea
Figure imgf000068_0001
Scheme 8.fl
Figure imgf000068_0002
a Reagents: a) Boc2, NaHCO3; b) benzylbromide, Cs2CO3; c) TFA; d) COCl2; e) TFA; f) Pd-C, H2
Figure imgf000068_0003
fert-Butyl 4-hvdroxybenzylcarbamate
[0169] 4-(Aminomethyl)phenol hydrobromide (0.36 g, 1.75 mmol) was dissolved in
20 mL MeOH. Boc-anhydride (0.45 g, 2.08 mmol) and NaHCO3 (0.45 g, 5.36 mmol) were added. The mixture was stirred at room temperature over night. The reaction was quenched with water and the product was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated to give 0.48 g of crude product: 1H NMR (400
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MHz, CDCh) δ 7.15 (d, J= 8.2, 2H), 6.85 - 6.71 (m, 2H), 4.99 (s, IH), 4.76 (s, IH), 4.23 (d, J= 5.5, 2H), 1.48 (s, 9H).
Figure imgf000069_0001
(4-Benzyloxyphenyl)methanamine
[0170] tert-Butyl 4-hydroxybenzylcarbamate (0.48 g, 2.04 mmol) was dissolved in
20 mL MeCN. Benzylbromide (0.28 mL, 2.36 mmol) and Cs2CO3 (1.42 g, 4.34 mmol) were added. The resulting mixture was heated to 75 0C and stirred for 2 h. The reaction was quenched with water and the product was extracted into CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated. The resulting product was dissolved in 20 mL CH2Cl2 and 5 mL TFA was added, and the mixture was stirred at room temperature for 1.5 h. Water and CH2Cl2 were added. The acidic aqueous phase was washed 2 times with CH2Cl2, and made alkaline with 2M NaOH. CH2Cl2 was added and the product was extracted into CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated to give 0.30 g of (4-Benzyloxyphenyl)methanamine: 1H NMR (400 MHz, CDCh) δ 7.46 - 7.41 (m, 2H), 7.41 - 7.35 (m, 2H), 7.35 - 7.28 (m, IH), 7.25 - 7.20 (m, 2H), 6.98 - 6.91 (m, 2H), 5.07 (s, 2H), 3.81 (s, 2H).
Figure imgf000069_0002
tert-Buty\ 4-(3-(4-0)enzyloxy)benzyl)-l-(4-fluorobenzyl)ureido)piperidine-l-carboxylate
[0171] (4-Benzyloxyphenyl)methanamine (0.13 g, 0.60 mmol) was dissolved in 10 mL CH2Cl2 and cooled to 0 0C. A 5 % solution OfNaHCO3 (10 mL) was added, and the mixture was slowly stirred for 5 min. Stirring was stopped and phosgene (0.60 mL of a 2 M solution in toluene, 1.19 mmol) was added directly to the organic layer by syringe. After complete addition of phosgene, stirring was continued for 45 min. The organic layer was then
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separated and the aqueous layer extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. The flask containing the resulting product was equipped for magnetic stirring, and CH2Cl2 (15 mL) and tert-butyi 4-(4-fluorobenzylamino)- piperidine-1-carboxylate (0.36 g, 1.18 mmol) were added. The reaction mixture was stirred at room temperature over night. The reaction was quenched with 2 M HCl and extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. Purification over a short silica column (EtOAc:MeOH:NH4OH/8:l :1) gave tert-Butyl 4-(3- (4-(benzyloxy)benzyl)-l-(4-fluorobenzyl)ureido)piperidine-l-carboxylate (0.26 g, 78 %): 1H NMR (400 MHz, CDO3) δ 7.45 - 7.34 (m, 4H), 7.34 - 7.28 (m, IH), 7.22 - 7.13 (m, 2H), 7.04 - 6.95 (m, 4H), 6.89 - 6.82 (m, 2H), 5.02 (s, 2H), 4.56 - 4.43 (m, 2H), 4.33 - 4.23 (m, 4H), 4.14 (bs, 2H), 2.84 - 2.68 (m, 2H), 1.77 - 1.66 (m, 2H), 1.53 - 1.45 (m, 2H), 1.44 (s, 9H); LC-MS [M+H]+ = 548.2.
Figure imgf000070_0001
3-(4-Benzyloxybenzyl)-l-(4-fluorobenzyl)-l-(piperidin-4-yl)urea
[0172] tert-Butyl 4-(3-(4-(benzyloxy)benzyl)- 1 -(4-fluorobenzyl)ureido)piperidine- 1 - carboxylate (0.26 g, 0.47 mmol) was dissolved in 10 mL CH2Cl2 and 2 mL TFA was added. The reaction mixture was stirred at room temperature over night, and 2M NaOH and additional CH2Cl2 were added. The resulting product was extracted into CH2Cl2, and the combined organic phases were dried (Na2SO4), filtered and concentrated. Purification over a short silica column (EtO Ac:MeOH:NH4OH/8: 1 :1) gave 3-(4-Benzyloxybenzyl)-l-(4- fluorobenzyl)-l-(piperidin-4-yl)urea (0.13 g, 60 %): 1H NMR (400 MHz, CDCl3) δ 7.45 - 7.35 (m, 4H), 7.34 - 7.28 (m, IH), 7.23 - 7.16 (m, 2H), 7.06 - 6.95 (m, 4H), 6.89 - 6.83 (m, 2H), 5.06 (s, 2H), 4.50 - 4.44 (m, IH), 4.44 - 4.37 (m, IH), 4.36 (s, 2H), 4.28 (d, J= 5.4, 2H), 3.14 - 3.04 (m, 2H), 2.75 - 2.64 (m, 2H), 1.80 - 1.68 (m, 2H), 1.57 - 1.43 (m, 2H); LC- MS [M+H]+ = 448.1.
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Figure imgf000071_0001
l-(4-Fluorobenzyl)-3-(4-hvdroxybenzyl)-l-(piperidin-4-yl)urea
[0173] 3-(4-Benzyloxybenzyl)-l-(4-fluorobenzyl)-l-(piperidin-4-yl)urea (0.13 g,
0.28 mmol) was dissolved in 20 mL MeOH. The solution was passed through an H-cube (Pd/C, full H2-mode, 0 bar, 35 0C) and concentrated to give l-(4-Fluorobenzyl)-3-(4- hydroxybenzyl)-l-(piperidin-4-yl)urea (0.10 g, 98 %): 1H NMR (400 MHz, CD3OD) δ 7.28 - 7.21 (m, 2H), 7.06 - 6.98 (m, 4H), 6.72 - 6.66 (m, 2H), 4.51 (s, 2H), 4.36 - 4.27 (m, IH), 4.26 (s, 2H), 3.42 - 3.35 (m, 2H), 3.09 - 2.98 (m, 2H), 2.03 - 1.90 (m, 2H), 1.90 - 1.81 (m, 2H); LC-MS ([M+H]+ = 358.2.
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l-(4-Fluorobenzyl)-3-(4-hvdroxy-3-methoxybenzyl)-l-(piperidin-4-yl)urea
Figure imgf000072_0001
Scheme 9.a
Figure imgf000072_0002
a Reagents: a) Boc2, NaHCO3; b) benzylbromide, Cs2CO3 ; c) TFA; d) COCl2; e) TFA; f) Pd- Q H2
Figure imgf000072_0003
fe^-Butyl 4-hvdroxy-3-methoxybenzylcarbamate
[0174] 4-(aminomethyl)-2-methoxyphenol hydrobromide (0.26 g, 1.36 mmol) was dissolved in 20 niL MeOH. Boc-anhydride (0.33 g, 1.58 mmol) and NaHCO3 (0.35 g, 4.11 mmol) were added. The mixture was stirred at room temperature over night. The reaction was quenched with water and the product was extracted into CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated to afford 0.39 g of tert-butyl A-
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hydroxy-3-methoxybenzylcarbamate: 1U NMR (400 MHz, CDCl3) δ 6.88 - 6.84 (m, IH), 6.84 - 6.80 (m, IH), 6.79 - 6.75 (m, IH), 4.75 (bs, IH), 4.23 (d, J= 5.8, 2H), 3.89 (s, 3H), 1.46 (s, 9H).
Figure imgf000073_0001
(4-Benzyloxy-3-methoxyphenyl)methanamine
[0175] 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 Cs2CO3 (0.93 g, 2.85 mmol) were added. The reaction mixture was heated to 75 0C and stirred for 2 h. The reaction was quenched with water and the product was extracted into CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. The resulting product was dissolved in 20 mL CH2Cl2 and 5 mL TFA was added. The mixture was stirred at room temperature for 1.5 h. Water and CH2Cl2 were added. The organic phase was concentrated and passed through an ion exchange column. The ion exchange column was washed with MeOH and the product was eluted with 7M NH3 in MeOH to give 0.27 g of (4-Benzyloxy-3- methoxyphenyl)methanamine: 1H NMR (400 MHz, CDCl3) δ 7.46 - 7.27 (m, 5H), 6.98 - 6.75 (m, 3H), 5.14 (s, 2H), 3.89 (s, 3H), 3.82 (s, 2H).
Figure imgf000073_0002
tert-Buty\ 4-(3-(4-benzyloxy-3-methoxybenzyl)-l-(4-fluorobenzyl)ureido)piperidine-l- carboxylate
[0176] (4-Benzyloxy-3-methoxyphenyl)methanamine (0.09 g, 0.37 mmol) was dissolved in 10 mL CH2Cl2 and cooled to 0 0C. A 5 % solution OfNaHCO3 (15 mL) was then added and the mixture was slowly stirred for 5 min. Stirring was stopped and phosgene (0.37 ml of a 2 M solution in toluene, 0.74 mmol) was added directly to the organic layer through a syringe. After complete addition of phosgene, stirring was continued for 45 min. The organic
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layer was then separated and the aqueous layer extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. The flask containing the resulting product was equipped for magnetic stirring, and CH2Cl2 (15 mL) and tert-butyi 4-(4- fluorobenzyl)amino-piperidine-l-carboxylate (0.22 g, 0.72 mmol) were added. The resulting mixture was stirred at room temperature over night. The reaction was quenched with 2 M HCl and extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. Purification over a short silica column (MeOH: CH2Cl2 , 1 :99) gave tert- Butyl 4-(3 -(4-benzyloxy-3 -methoxybenzyl)- 1 -(4-fluorobenzyl)ureido)piperidine- 1 - carboxylate (0.12 g, 56 %): 1H NMR (400 MHz, CDO3) δ 7.44 - 7.39 (m, 2H), 7.39 - 7.32 (m, 2H), 7.32 - 7.28 (m, IH), 7.21 - 7.14 (m, 2H), 7.02 - 6.94 (m, 2H), 6.77 - 6.73 (m, IH), 6.68 - 6.64 (m, IH), 6.57 - 6.52 (m, IH), 5.13 (s, 2H), 4.56 - 4.43 (m, 2H), 4.35 - 4.23 (m, 4H), 4.23 (bs, 2H), 3.80 (s, 3H), 2.85 - 2.69 (m, 2H), 1.78 - 1.68 (m, 2H), 1.53 - 1.45 (m, 2H), 1.45 (s, 9H); LC-MS [M+H]+ = 578.2
Figure imgf000074_0001
3-(4-Benzyloxy-3-methoxybenzyl)-l-(4-fluorobenzyl)-l-(piperidin-4-yl)urea
[0177] tert-Butyl 4-(3-(4-(benzyloxy)-3 -methoxybenzyl)- 1 -(4- fluorobenzyl)ureido)piperidine-l -carboxylate (0.12 g, 0.21 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature over night and 2M NaOH and CH2Cl2 were added. The resulting mixture was extracted with CH2Cl2, and the combined organic phases were dried (Na2SO4), filtered and concentrated. Flash chromatography (EtOAc:MeOH:NH4OH, 8:1 :1) gave a product which was further purified by preparative HPLC to give 3 -(4-Benzyloxy-3 -methoxybenzyl)- l-(4-fluorobenzyl)- l-(piperidin-4-yl)urea (0.04 g, 35%): 1H NMR (400 MHz, CD3OD) δ 7.44 - 7.39 (m, 2H), 7.37 - 7.31 (m, 2H), 7.30 - 7.19 (m, 3H), 7.02 - 6.95 (m, 2H), 6.89 - 6.82 (m, 2H), 6.71 - 6.65 (m, IH), 5.06 (s, 2H), 4.48 (s, 2H), 4.27 (s, 2H), 4.24 - 4.13 (m, IH), 3.78 (s, 3H), 3.06 - 2.96 (m, 2H), 2.67 - 2.55 (m, 2H), 1.70 - 1.49 (m, 4H); LC-MS ([M+H]+ = 478.2
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Figure imgf000075_0001
l-f4-Fluorobenzyl)-3-f4-hvdroxy-3-methoxybenzyl)-l-fpiperidin-4-yl)urea
[0178] 3-(4-Benzyloxy-3-methoxybenzyl)- 1 -(4-fluorobenzyl)- 1 -(piperidin-4-yl)urea
(0.04 g, 0.07 mmol) was dissolved in 20 mL MeOH and 19 μM of 4M HCl in dioxane was added. The resulting solution was passed through an H-cube (Pd/C, full H2-mode, O bar, 35 0C), concentrated, and the residue purified by column chromatography on a short silica column (EtO Ac:MeOH:NH4OH, 8:1 :1). The resulting product was dissolved in CH2Cl2 and filtered though a pad of Celite, and the filtrate was concentrated to yield l-(4-Fluorobenzyl)- 3-(4-hydroxy-3-methoxybenzyl)-l-(piperidin-4-yl)urea (0.01 g, 35%): 1H NMR (400 MHz, CD3OD) 57.27 - 7.20 (m, 2H), 7.03 - 6.96 (m, 2H), 6.79 - 6.76 (m, IH), 6.71 - 6.67 (m, IH), 6.65 - 6.60 (m, IH), 4.48 (s, 2H), 4.27 - 4.14 (m, 3H), 3.78 (s, 3H), 3.07 - 2.99 (m, 2H), 2.68 - 2.58 (m, 2H), 1.70 - 1.51 (m, 4H); LC-MS [M+H]+ = 388.1.
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l-(4-Fluorobenzyl)-3-(3-hvdroxy-4-methoxybenzyl)-l-(piperidin-4-yl)urea
Figure imgf000076_0001
Scheme 10.fl
Figure imgf000076_0002
Ω Reagents: a) Boc2, NaHCO3; b) benzylbromide, Cs2CO3 ; c) TFA; d) COCl2; d) e) TFA; f) Pd-C, H2
Figure imgf000076_0003
fe^-Butyl 3-hvdroxy-4-methoxybenzylcarbamate
[0179] 5-(Aminomethyl)-2-methoxyphenol hydrobromide (0.24 g, 1.28 mmol) was dissolved in MeOH (20 niL). Boc-anhydride (0.32 g, 1.48 mmol) and NaHCO3 (0.33 g, 3.98 mmol) were added. The mixture was stirred at room temperature over night. The reaction was quenched with water and the resulting product was extracted into CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated to give 0.36 g of tert-Butyl 3-
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hydroxy-4-methoxybenzylcarbamate: 1U NMR (400 MHz, CDCl3) δ6.86 (d, J= 1.7, IH), 6.82 - 6.78 (m, IH), 6.78 - 6.73 (m, IH), 4.75 (bs, IH), 4.21 (d, J= 5.5, 2H), 3.90 (s, 3H), 1.47 (s, 9H).
Figure imgf000077_0001
(3-(Benzyloxy-4-methoxyphenyl)methanamine
[0180] 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 Cs2CO3 (1.03 g, 3.16 mmol) were added. The reaction mixture was heated to 75 0C and stirred for 2 h. The reaction was quenched with water and the resulting product was extracted into CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. The product was re-dissolved in 20 mL CH2Cl2 and 5 mL TFA was added. The mixture was stirred at room temperature for 1.5 h and thereafter water and CH2Cl2 were added. The organic phase was concentrated and passed through an ion exchange column. The ion exchange column was washed with MeOH and the resulting product was eluted with 7M NH3 in MeOH to give 0.26 g of (3-(Benzyloxy-4-methoxyphenyl)methanamine: 1H NMR (400 MHz, CDCl3) δ 7.48 - 7.26 (m, 5H), 6.92 - 6.81 (m, J= 7.5, 3H), 5.20 (s, 2H), 3.91 (s, 3H), 3.79 (s, 2H).
Figure imgf000077_0002
fert-Butyl 4-(3-(3-benzyloxy-4-methoxybenzyl)-l-(4-fluorobenzyl)ureido)piperidine-l- carboxylate
[0181] (3-Benzyloxy-4-methoxyphenyl)methanamine (0.18 g, 0.74 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to 0 0C. A 5 % solution OfNaHCO3 (20 mL) was added, and the mixture was slowly stirred for 5 min. Stirring was stopped and phosgene (0.74 ml of a 2 M solution in toluene, 1.48 mmol) was added directly to the organic layer by syringe. After complete addition of the phosgene solution, stirring was continued for 45 min.
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The organic layer was separated and the aqueous layer extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. The flask containing the resulting product was equipped for magnetic stirring, and CH2Cl2 (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 CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. Purification over a short silica column (MeOH: CH2Cl2 , 1 :99) gave tert-Butyl 4-(3-(3-benzyloxy-4-methoxybenzyl)-l-(4- fluorobenzyl)ureido)piperidine-l-carboxylate.(0.36 g, 83 %): 1H NMR (400 MHz, CDCl3) δ 7.42 - 7.37 (m, 2H), 7.36 - 7.30 (m, 2H), 7.30 - 7.24 (m, IH), 7.16 - 7.09 (m, 2H), 6.99 - 6.92 (m, 2H), 6.76 - 6.72 (m, IH), 6.71 - 6.68 (m, IH), 6.65 - 6.60 (m, IH), 5.05 (s, 2H), 4.58 - 4.49 (m, IH), 4.49 - 4.37 (m, IH), 4.27 - 4.18 (m, 4H), 4.18 - 4.07 (m, 2H), 3.80 (s, 3H), 2.81 - 2.65 (m, 2H), 1.73 - 1.63 (m, 2H), 1.49 - 1.43 (m, 2H), 1.43 (s, 9H); LC-MS [M+H]+ = 578.3.
Figure imgf000078_0001
3-(3-Benzyloxy-4-methoxybenzyl)-l-(4-fluorobenzyl)-l-(piperidin-4-yl)urea
[0182] 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 CH2Cl2 and 5 mL TFA was added. The reaction mixture was stirred at room temperature for 2 h before 2M NaOH and additional CH2Cl2 were added. The product was extracted with CH2Cl2, and the combined organic phases were dried (Na2SO4), filtered and concentrated. Flash chromatography (EtOAc:MeOH:NH4OH, 9:0.5:0.5) gave a product which was further purified by preparative HPLC to give 3-(3-Benzyloxy-4-methoxybenzyl)-l-(4-fluorobenzyl)- l-(piperidin-4-yl)urea.(0.16 g, 54 %): 1H NMR (400 MHz, CD3OD) δ 7.44 - 7.39 (m, 2H), 7.38 - 7.32 (m, 2H), 7.31 - 7.25 (m, IH), 7.25 - 7.18 (m, 2H), 7.02 - 6.94 (m, 2H), 6.90 - 6.84 (m, 2H), 6.79 - 6.73 (m, IH), 5.03 (s, 2H), 4.46 (s, 2H), 4.25 (s, 2H), 4.21 - 4.11 (m, IH), 3.80 (s, 3H), 3.05 - 2.96 (m, 2H), 2.66 - 2.55 (m, 2H), 1.67 - 1.47 (m, 4H); LC-MS [M+H]+ = 478.2.
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Figure imgf000079_0001
l-f4-Fluorobenzyl)-3-f3-hvdroxy-4-methoxybenzyl)-l-fpiperidin-4-yl)urea
[0183] tert-Butyl 4-(3-(3-(benzyloxy)-4-methoxybenzyl)- 1 -(4- fluorobenzyl)ureido)piperidine-l-carboxylate (0.16 g, 0.33 mmol) was dissolved in 40 mL MeOH and 83 μM of 4M HCl in dioxane was added. The solution was passed through an H- cube (Pd/C, full H2-mode, O bar, 35 0C) and concentrated to give l-(4-Fluorobenzyl)-3-(3- hydroxy-4-methoxybenzyl)-l-(piperidin-4-yl)urea_as the HCl salt (0.14 g, 97%): 1H NMR (400 MHz, CD3OD) δ 7.29 - 7.22 (m, 2H), 7.07 - 6.99 (m, 2H), 6.83 - 6.79 (m, IH), 6.73 - 6.70 (m, IH), 6.67 - 6.62 (m, IH), 4.50 (s, 2H), 4.35 - 4.25 (m, IH), 4.23 (s, 2H), 3.81 (s, 3H), 3.43 - 3.35 (m, 2H), 3.09 - 2.98 (m, 2H), 2.02 - 1.82 (m, 4H): LC-MS [M+H]+ = 388.1.
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l-(4-Fluorobenzyl)-3-(4-(3-hydroxy-2-methylpropoxy)benzyl)-l-(piperidin-4-yl)urea hydrochloride
Figure imgf000080_0001
Scheme 11."
Figure imgf000080_0002
a Reagents: a) Diisopropyl azodicarboxylate, Ph3P; b) TFA ; C)COCl2; d) Pd-C, H2
Figure imgf000080_0003
3-Benzyloxy-2-methylpropan-l-ol
[0184] A solution of 2-methyl-l,3-propanediol (2.0 g, 22 mmol) in THF (10 niL) was added drop-wise to a suspension of NaH (0.9 g, 60 % in mineral oil, 22 mmol) in THF (20 mL) . After complete addition, the mixture was stirred at 50 0C for 1 h. Benzyl bromide (2.6 mmol, 22 mmol) was added drop-wise and the resulting mixture was stirred at 65 0C overnight. The reaction was quenched by addition of saturated aqueous NH4Cl-solution. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl-solution, dried
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(Na2SO4), concentrated, and purified by flash chromatography (SiO2, heptane:EtOAc, 10:1- 2:1) to give 2.4 g (61%) of 3-Benzyloxy-2-methylpropan-l-ol: 1U NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 4.53 (s, 2H), 3.58 (m, 4H), 3.43 (dd, J= 8.0, 9.0 Hz, IH), 2.45 (dd, J = 4.6, 7.0 Hz, IH), 2.06 (m, IH), 0.90 (d, J= 7.0 Hz, 3H).
Figure imgf000081_0001
?-Butyl 4-(3-benzyloxy-2-methylpropoxy)benzylcarbamate
[0185] Diisopropylazodicarboxylate (0.22 rnL, 1.1 mmol) and triphenyl phosphine
(289 mg, 1.1 mmol) were added to a mixture of 3-benzyloxy-2-methylpropan-l-ol (180 mg, 1.0 mmol) and t-Butyl 4-hydroxybenzylcarbamate (223 mg, 1.0 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature over night. The mixture was then concentrated onto Celite, and purified by flash chromatography (SiO2, heptane:EtOAc, 5:1) to give 265 mg (68%) of t-Butyl 4-(3-benzyloxy-2-methylpropoxy)benzylcarbamate: 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 7.18 (m, 2H), 6.85 (m, 2H), 4.73 (bs, IH), 4.52 (s, 2H), 4.24 (m, 2H), 3.98 (dd, J= 5.9, 9.0 Hz, IH), 3.85 (dd, J= 6.0, 9.1 Hz, IH), 3.49 (m, 2H), 2.26 (m, IH), 1.46 (s, 9H) 1.09 (d, J= 6.9 Hz, 3H).
Figure imgf000081_0002
(4-(3-Benzyloxy-2-methylpropoxy)phenyl)methanamine
[0186] Trifluoro acetic acid (1 mL) was added to a mixture of t-butyl 4-(3-
(benzyloxy)-2-methylpropoxy)benzylcarbamate (125 mg, 0.32 mmol) in CH2Cl2 (4 mL), and the resulting mixture was stirred at room temperature for 1 h. The resulting product was purified on a SCX-2 (2 g) column to give 79 mg (85%) of (4-(3-Benzyloxy-2- methylpropoxy)phenyl)methanamine: 1H NMR (400 MHz, CDCl3) δ 7.35-7.25 (m, 5H), 7.19 (m, 2H), 6.85 (m, 2H)), 4.51 (s, 2H), 3.97 (dd, J= 5.8, 9.1 Hz, IH), 3.85 (dd, J= 6.1, 9.2 Hz, IH), 3.78 (s, 2H), 3.49 (m, 2H), 2.26 (m, IH), 1.07 (d, J= 6.9 Hz, 3H).
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Figure imgf000082_0001
Benzyl 4-(3-(4-(3-0)enzyloxy)-2-methylpropoxy)benzyl)-l-(4-fluorobenzyl)ureido)- piperidine-1-carboxylate
[0187] 9 rnL of 5% aqueous Na2Cθ3-solution was added to a mixture of (4-(3-
(benzyloxy)-2-methylpropoxy)phenyl)methanamine (185 mg, 0.65 mmol) in CH2Cl2 (10 rnL), and the mixture was stirred at 0 0C for 5 min. Stirring was stopped and phosgene solution (0.65 mL, 20 % in toluene, 1.30 mmol) was added directly to the organic layer by syringe. Stirring was continued for 1 h at 0 0C. The resulting mixture was diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4) and concentrated. The crude product was dissolved in 10 mL Of CH2Cl2. 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 (SiO2, heptane:EtOAc, 2:1, 0.3 % 7 N NH3 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.
Figure imgf000082_0002
l-f4-Fluorobenzyl)-3-f4-f3-hvdroxy-2-methylpropoxy)benzyl)-l-fpiperidin-4-yl)urea hydrochloride)
[0188] 4 M aqueous HCl (0.105 mL) and Pd (catalytic amount, 10 % on activated carbon) were added to a mixture of benzyl 4-(3-(4-(3-(benzyloxy)-2-methylpropoxy)benzyl)-
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l-(4-fluorobenzyl)ureido)piperidine-l-carboxylate (138 mg, 0.21 mmol) in MeOH (2 rnL) and EtOAc (2 rnL). The resulting mixture was stirred under H2 (1 atm) for 2 h, and Et3N (0.2 rnL) was added. The resulting mixture was filtered through Celite and concentrated to give a first batch of crude material.
[0189] The above reaction was repeated with 142 mg (0.22 mmol) of benzyl 4-(3-(4-
(3 -(benzyloxy)-2-methylpropoxy)benzyl)- 1 -(4-fluorobenzyl)ureido)piperidine- 1 -carboxylate to give a second batch of crude material. The two batches were combined and purified by preparative TLC (SiO2, EtOAc:MeOH:NH4OH(aq), 200:15:15) to give 86 mg of l-(4- Fluorobenzyl)-3-(4-(3-hydroxy-2-methylpropoxy)benzyl)-l-(piperidin-4-yl)urea: 1H NMR (400 MHz, CDCl3) δ 7.17 (m, 2H), 6.97 (m, 4H), 6.76 (m, 2H), 4.48 (m, IH), 4.35 (m, 3H), 4.24 (d, J= 5.4 Hz, 2H), 3.88 (d, J= 6.0 Hz, 2H), 3.64 (d, J= 5.8 Hz, 2H), 3.08 (m, 2H), 2.67 (at, J = 2.4, 12.2 Hz, 2H), 2.35 (bs, 2H), 2.15 (m, IH), 1.72 (m, 2H), 1.52 (m, 2H), 1.0 (d, J= 6.9 Hz, 3H); LC-MS [M+H] + = 430.
[0190] The 1 -(4-Fluorobenzyl)-3-(4-(3-hydroxy-2-methylpropoxy)benzyl)- 1 -
(piperidin-4-yl)urea prepared above was taken up in acetone, HCl (0.050 mL, 4 N in dioxane) was added and the mixture was concentrated. The resulting salt was dissolved in a small amount of hot EtOH and Et2O was added in portions. A white solid formed and was filtered off to yield 75 mg of l-(4-Fluorobenzyl)-3-(4-(3-hydroxy-2-methylpropoxy)benzyl)- l-(piperidin-4-yl)urea hydrochloride: LC-MS [M+H] + = 430.
In vitro determination of receptor activity
[0191] Receptor Selection and Amplification (R-SAT) Assays. The functional receptor assay, Receptor Selection and Amplification Technology (R-S AT®), was used (with minor modifications from the procedure described previously (Brann, M. R. US Patent 5,707,798, 1998; Chem. Abstr. 1998, 128, 111548) to screen compounds for efficacy at the 5- HT2A receptor. Briefly, NIH3T3 cells were grown in 96 well tissue culture plates to 70-80% confluence. Cells were transfected for 12-16 h with plasmid DNAs using superfect (Qiagen Inc.) as per manufacturer's protocols. R-SAT's were generally performed with 50 ng/well of receptor and 20 ng/well of β-galactosidase plasmid DNA. All receptor and G-protein constructs used were in the pSI mammalian expression vector (Promega Inc) as described previously. The 5-HT2A or 5-HT2c receptor gene was amplified by nested PCR from brain
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cDNA using the oligodeoxynucleotides based on the published sequence (Saltzman et. al, Biochem. Biophys. Res. Comm. 1991, 181, 1469). For large-scale transfections, 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 CO2 for five days. Media was then removed from the plates and marker gene activity was measured by the addition of the β-galactosidase substrate o-nitrophenyl β-D-galactopyranoside (ONPG, in PBS with 5% NP-40). The resulting colorimetric reaction was measured in a spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data were analyzed using the computer program XLFit (IDBSm). Efficacy is the percent maximal repression compared to repression by a control compound (ritanserin in the case of 5-HT2A)- pICso is the negative of the log(ICso), where IC50 is the calculated concentration in Molar that produces 50% maximal repression. The compounds as provided herein were assayed as described herein. Compounds of Formulae (I), (II), (III), (IV) and (V), however, demonstrated high inhibition of the 5- HT2a receptor activity as shown in the table below. This data below indicates that compounds as provide herein may be useful as pharmaceutical agents.
Compound Name 5-HT2a % 5-HT2a
Inhibition pIC50
1-(4-fluorobenzyl)-3-(4- 90 7.4 methoxybenzyl)-
1-(1-methylpiperidin-4-yl)urea
1-(4-fluorobenzyl)-3-(3-hydroxy-4- 89 6.5 isobutoxybenzyl)- 1-(1-methylpiperidin-4-yl)urea
1-(4-fluorobenzyl)-3-(4-hydroxybenzyl)- 87 6-7
(piperidin-4-yl)urea
Figure imgf000084_0001
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54
55
89 8.0
108 8.6 105 8.4
101 7.9
93 7.0
Figure imgf000085_0001
[0192] It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure.
[0193] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures.
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[0194] All such equivalents are considered to be within the scope of the claimed subject matter and are encompassed by the appended claims.
[0195] All of the patents, patent applications and publications referred to herein are incorporated herein in their entireties. Citation or identification of any reference in this application is not an admission that such reference is available as prior art to the claimed subject matter.
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Claims

Attorney Docket No. 12560-046-228WHAT IS CLAIMED IS:
1. A substantially pure form of a compound selected from the group consisting of Formulae (I), (II), (III), (IV) and (V), wherein the compounds of Formulae (I), (II), (III), (IV) and (V) have the following structures:
Figure imgf000087_0001
(HI)
Figure imgf000087_0002
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is H or CH3; and Ri is H or acyl.
2. The compound of claim 1 , wherein R is H.
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3. The compound of claim 1 , wherein R is CH3.
4. The compound of claim 1, wherein Ri is H.
5. The compound of claim 1, wherein Ri is an acyl comprising -CO-R2, wherein R2 is Ci-Ci2-alkyl.
6. The compound of claim 1, selected from:
Figure imgf000088_0001
or a pharmaceutically acceptable salt or stereoisomer thereof.
7. A pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is suitable for oral administration.
9. The pharmaceutical composition of claim 7, further comprising an additional therapeutic agent.
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10. A method of inhibiting the activity of a serotonin receptor comprising contacting the serotonin receptor or a system containing a serotonin receptor with at least one substantially pure form of a compound of any one of claims 1-6 or the pharmaceutical composition of claim 9.
11. The method of claim 10, wherein the serotonin receptor is a subclass selected from the group consisting of in the 5-HT2A subclass and 5-HT2C subclass.
12. The method of claim 10, wherein the serotonin receptor is mutated or modified.
13. A method of treating or managing a disease condition comprising administering to a patient in need of such treatment or management a therapeutically effective amount of at least one substantially pure form of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the disease condition is associated with a serotonin receptor.
14. The method of claim 13, wherein the disease condition is a neuropsychiatric disorder or a neurodegenerative disorder.
15. The method of claim 14, wherein the disease condition is a neuropsychiatric disorder.
16. The method of claim 15, wherein the neuropsychiatric disorder is selected from the group consisting of 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 serotonin syndrome.
17. The method of claim 16 wherein the disease condition is psychosis.
18. The method of claim 17 wherein the psychosis is selected from (i) drug- induced psychosis, (ii) treatment-induced psychosis and (iii) psychosis associated with a disease selected from the group selected from dementia, post traumatic stress disorder, Alzheimer's disease, Parkinson's disease and schizophrenia.
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19. The method of claim 14, wherein the disease condition is a neurodegenerative disorder.
20. The method of claim 19, wherein the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease, Huntington's chorea, sphinocerebellar atrophy, frontotemporal dementia, supranuclear palsy and Lewy body dementia.
21. The method of claim 13, wherein the disease condition is selected from the group consisting of 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, cardiac insufficiency, asthma, emphysema, and an appetite disorder.
22. The method of claim 13, wherein the disease condition is associated with dysfunction of the serotonin receptor, activation of the serotonin receptor or increased activity of the serotonin receptor.
23. The method of claim 13, wherein the serotonin receptor is a subclass selected from the group consisting of in the 5-HT2A subclass and 5-HT2C subclass.
24. The method of claim 13, wherein the serotonin receptor is mutated or modified.
25. The method of claim 13, which further comprises administration of one or more additional therapeutic agent.
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