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WO2016109359A1 - Modulateurs de récepteurs de la mélatonine à base de cyclopropyl dihydrobenzofurane - Google Patents

Modulateurs de récepteurs de la mélatonine à base de cyclopropyl dihydrobenzofurane Download PDF

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WO2016109359A1
WO2016109359A1 PCT/US2015/067541 US2015067541W WO2016109359A1 WO 2016109359 A1 WO2016109359 A1 WO 2016109359A1 US 2015067541 W US2015067541 W US 2015067541W WO 2016109359 A1 WO2016109359 A1 WO 2016109359A1
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compound
recited
deuterium
salt
disorder
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Chengzhi Zhang
Justin CHAKMA
Ralph Laufer
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Auspex Pharmaceuticals Inc
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Auspex Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/12—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings condensed with a carbocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • Methods of modulation of melatonin receptor activity in a subject are also provided for the treatment of disorders such as non-24-hour sleep-wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency.
  • disorders such as non-24-hour sleep-wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia,
  • Tasimelteon (Hetlioz; BMS 214778; VEC 162; MA 1; CAS # 609799-22-6; (1R- trans)-N-[[2-(2,3-Dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide; N-[[(1R,2R)-2- (2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide); (1R, 2R)-N-[2-(2,3- dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide) is a melatonin receptor MT1R and MT2R agonist.
  • Tasimelteon is currently approved for the treatment of non-24-hour sleep- wake disorder. Tasimelteon is currently under investigation for the treatment of Smith- Magenis syndrome, major depressive disorder, and primary insomnia. Tasimelteon has also shown promise in treating circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency. US 5,856,529; US 8,785,492; WO 199825606; WO 2007137244; WO
  • Tasimelteon is subject to extensive CYP450-mediated oxidative metabolism, including hydroyxlation of the propylamide group, oxidation of the amine methylene group and/or cyclopropyl ring, CYP1A2-, CYP1A1-, and CYP3A4-mediated hydroxylation of the 3-position of the dihydrobenzofuran ring, and CYP1A2-, CYP2D6-, and CYP2C19-mediated hydroxylation/oxidation and ring-cleavage at the 2-position of the dihydrobenzofuran ring leading to active metabolites M9 and M11. Vachharajani et al., J. Pharm. Sci., 2003, 92(4), 760-772; US 8,785,492.
  • Adverse effects associated with tasimelteon include headache, increased alanine monotransferase, nightmares or abnormal dreams, upper respiratory tract infection, and urinary tract infection.
  • the animal body expresses various enzymes, such as the cytochrome P 450 enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
  • CYPs cytochrome P 450 enzymes
  • esterases proteases
  • reductases reductases
  • dehydrogenases dehydrogenases
  • monoamine oxidases monoamine oxidases
  • Such metabolic reactions frequently involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or a carbon-carbon (C-C) ⁇ -bond.
  • C-H carbon-hydrogen
  • C-O carbon-oxygen
  • C-C carbon-carbon
  • the resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term
  • the Arrhenius equation states that, at a given temperature, the rate of a chemical reaction depends exponentially on the activation energy (Eact).
  • the transition state in a reaction is a short lived state along the reaction pathway during which the original bonds have stretched to their limit.
  • the activation energy E act for a reaction is the energy required to reach the transition state of that reaction. Once the transition state is reached, the molecules can either revert to the original reactants, or form new bonds giving rise to reaction products.
  • a catalyst facilitates a reaction process by lowering the activation energy leading to a transition state. Enzymes are examples of biological catalysts.
  • Carbon-hydrogen bond strength is directly proportional to the absolute value of the ground-state vibrational energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) has twice the mass of protium ( 1 H), a C-D bond is stronger than the corresponding C- 1 H bond. If a C- 1 H bond is broken during a rate- determining step in a chemical reaction (i.e. the step with the highest transition state energy), then substituting a deuterium for that protium will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE).
  • DKIE Deuterium Kinetic Isotope Effect
  • the magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C- 1 H bond is broken, and the same reaction where deuterium is substituted for protium.
  • the DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more.
  • Deuterium ( 2 H or D) is a stable and non-radioactive isotope of hydrogen which has approximately twice the mass of protium ( 1 H), the most common isotope of hydrogen.
  • Deuterium oxide (D2O or“heavy water”) looks and tastes like H2O, but has different physical properties.
  • PD pharmacodynamics
  • toxicity profiles has been demonstrated previously with some classes of drugs.
  • the DKIE was used to decrease the hepatotoxicity of halothane, presumably by limiting the production of reactive species such as trifluoroacetyl chloride.
  • this method may not be applicable to all drug classes.
  • deuterium incorporation can lead to metabolic switching.
  • Metabolic switching occurs when xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching is enabled by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity. Such pitfalls are non-obvious and are not predictable a priori for any drug class.
  • Tasimelteon is a melatonin receptor modulator.
  • the carbon-hydrogen bonds of tasimelteon contain a naturally occurring distribution of hydrogen isotopes, namely 1 H or protium (about 99.9844%), 2 H or deuterium (about 0.0156%), and 3 H or tritium (in the range between about 0.5 and 67 tritium atoms per 10 18 protium atoms).
  • Increased levels of deuterium incorporation may produce a detectable Deuterium Kinetic Isotope Effect (DKIE) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of such tasimelteon in comparison with the compound having naturally occurring levels of deuterium.
  • DKIE Deuterium Kinetic Isotope Effect
  • a medicine with a longer half-life may result in greater efficacy and cost savings.
  • Various deuteration patterns can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (c) decrease the number of doses needed to achieve a desired effect, (d) decrease the amount of a dose needed to achieve a desired effect, (e) increase the formation of active metabolites, if any are formed, (f) decrease the production of deleterious metabolites in specific tissues, and/or (g) create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not.
  • R1-R19 are independently chosen from hydrogen and deuterium
  • R1-R19 is deuterium.
  • enantiomers of compounds of Formula I designated Formulas Ia, Ib, Ic, and Id:
  • R1-R19 are independently chosen from hydrogen and deuterium
  • At least one of R 1 -R 19 is deuterium.
  • R6 and R9-R15 are hydrogen.
  • R 9 -R 15 are hydrogen.
  • R16 and R17 are deuterium.
  • R18 and R19 are deuterium.
  • R 16 -R 19 are deuterium.
  • R7 and R8 are deuterium.
  • R 7 , R 8 , R 16 , and R 17 are deuterium.
  • R7, R8, R18, and R19 are deuterium.
  • R 7 , R 8 , and R 16 -R 19 are deuterium.
  • R1-R5 are deuterium.
  • R 1 -R 5 , R 7 , and R 8 are deuterium.
  • R1-R5, R16, and R17 are deuterium.
  • R 1 -R 5 , R 18 , and R 19 are deuterium.
  • R1-R5 and R16-R19 are deuterium.
  • R1-R5, R7, R8, R16, and R17 are deuterium.
  • R1-R5, R7, R8, R18, and R19 are deuterium.
  • R1-R5, R7, R8, and R16-R19 are deuterium.
  • R 1 -R 3 are deuterium.
  • R1-R3, R7, and R8 are deuterium.
  • R 1 -R 3 , R 16 , and R 17 are deuterium.
  • R1-R3, R18, and R19 are deuterium.
  • R 1 -R 3 and R 16 -R 19 are deuterium.
  • R1-R3, R7, R8, R16, and R17 are deuterium.
  • R 1 -R 3 , R 7 , R 8 , R 18 , and R 19 are deuterium.
  • R1-R3, R7, R8, and R16-R19 are deuterium.
  • R 4 and R 5 are deuterium.
  • R4, R5, R7, and R8 are deuterium.
  • R 4 , R 5 , R 16 , and R 17 are deuterium.
  • R4, R5, R18, and R19 are deuterium.
  • R 4 , R 5 , and R 16 -R 19 are deuterium.
  • R4, R5, R7, R8, R16, and R17 are deuterium.
  • R 4 , R 5 , R 7 , R 8 , R 18 , and R 19 are deuterium.
  • R4, R5, R7, R8, and R16-R19 are deuterium.
  • R9-R12 are deuterium.
  • R9-R12 are deuterium.
  • every other substituent among R 1 -R 19 not specified as deuterium is hydrogen.
  • R 1 -R 19 independently has deuterium enrichment of no less than about 1%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1- R 19 independently has deuterium enrichment of no less than about 10%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 50%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 90%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 95%. In certain embodiments are provided compounds as disclosed herein, wherein at least one of R1-R19 independently has deuterium enrichment of no less than about 98%.
  • R 20 -R 40 are independently chosen from hydrogen and deuterium
  • At least one of R20-R40 is deuterium.
  • R 25 and R 28 -R 34 are hydrogen.
  • R28-R34 are hydrogen.
  • R 35 and R 36 are deuterium.
  • R37 and R38 are deuterium.
  • R 35 -R 38 are deuterium.
  • R26 and R27 are deuterium.
  • R26, R27, R35, and R36 are deuterium.
  • R 26 , R 27 , R 37 , and R 38 are deuterium.
  • R26, R27, and R35-R38 are deuterium.
  • R 20 -R 24 are deuterium.
  • R20-R24, R26 and R27 are deuterium.
  • R 20 -R 24 , R 35 , and R 36 are deuterium.
  • R20-R24, R37, and R38 are deuterium.
  • R 20 -R 24 and R 35 -R 38 are deuterium.
  • R20-R24, R26, R27, R35, and R36 are deuterium.
  • R 20 -R 24 , R 26 , R 27 , R 37 , and R 38 are deuterium.
  • R20-R24, R26, R27, and R35-R38 are deuterium.
  • R20-R22 are deuterium.
  • R20-R22, R26 and R27 are deuterium.
  • R20-R22, R35, and R36 are deuterium.
  • R 20 -R 22 , R 37 , and R 38 are deuterium.
  • R20-R22 and R35-R38 are deuterium.
  • R 20 -R 22 , R 26 , R 27 , R 35 , and R 36 are deuterium.
  • R20-R22, R26, R27, R37, and R38 are deuterium.
  • R 20 -R 22 , R 26 , R 27 , and R 35 -R 38 are deuterium.
  • R23 and R24 are deuterium.
  • R 23 , R 24 , R 26 and R 27 are deuterium.
  • R23, R24, R35, and R36 are deuterium.
  • R 23 , R 24 , R 37 , and R 38 are deuterium.
  • R23, R24, and R35-R38 are deuterium.
  • R 23 , R 24 , R 26 , R 27 , R 35 , and R 36 are deuterium.
  • R23, R24, R26, R27, R37, and R38 are deuterium.
  • R 23 , R 24 , R 26 , R 27 , and R 35 -R 38 are deuterium.
  • R28-R31 are deuterium.
  • R41-R59 are independently chosen from hydrogen and deuterium
  • At least one of R 41 -R 59 is deuterium.
  • R46 and R49-R55 are hydrogen.
  • R 49 -R 55 are hydrogen.
  • R56 and R57 are deuterium.
  • R47 and R48 are deuterium.
  • R47, R48, R56, and R57 are deuterium.
  • R41-R45 are deuterium.
  • R41-R45, R47, and R48 are deuterium.
  • R41-R45, R56, and R57 are deuterium.
  • R 41 -R 45 , R 47 , R 48 , R 56 , and R 57 are deuterium.
  • R41-R43 are deuterium.
  • R 41 -R 43 , R 26 and R 27 are deuterium.
  • R41-R43, R56, and R57 are deuterium.
  • R 41 -R 43 , R 47 , R 48 , R 56 , and R 57 are deuterium.
  • R44 and R45 are deuterium.
  • R 44 , R 45 , R 47 , and R 48 are deuterium.
  • R44, R45, R56, and R57 are deuterium.
  • R 44 , R 24 , R 47 , R 48 , R 56 , and R 57 are deuterium.
  • R49-R52 are deuterium.
  • R49-R52 are deuterium.
  • every other substituent among R 41 -R 59 not specified as deuterium is hydrogen.
  • the compounds as disclosed herein may also contain less prevalent isotopes for other elements, including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 O or 18 O for oxygen.
  • the compound disclosed herein may expose a patient to a maximum of about 0.000005% D 2 O or about 0.00001% DHO, assuming that all of the C-D bonds in the compound as disclosed herein are metabolized and released as D2O or DHO.
  • the levels of D 2 O shown to cause toxicity in animals is much greater than even the maximum limit of exposure caused by administration of the deuterium enriched compound as disclosed herein.
  • the deuterium-enriched compound disclosed herein should not cause any additional toxicity due to the formation of D2O or DHO upon drug metabolism.
  • each position represented as D has deuterium enrichment of no less than about 1%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 10%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 50%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 90%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 95%. In certain embodiments are provided compounds as disclosed herein wherein each position represented as D has deuterium enrichment of no less than about 98%.
  • the deuterated compounds disclosed herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half- life (T1/2), lowering the maximum plasma concentration (Cmax) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism-related toxicity, and/or lowering the probability of drug-drug interactions.
  • All publications and references cited herein are expressly incorporated herein by reference in their entirety. However, with respect to any similar or identical terms found in both the incorporated publications or references and those explicitly put forth or defined in this document, then those terms definitions or meanings explicitly put forth in this document shall control in all respects.
  • compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions.
  • Certain embodiments provide methods for modulating melatonin receptor.
  • Other embodiments provide methods for treating a melatonin receptor-mediated disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or composition according to the present invention.
  • certain compounds disclosed herein for use in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by the modulation of melatonin receptors.
  • Also provided is a method of treatment of a melatonin receptor-mediated disorder comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as disclosed herein to a patient in need thereof.
  • the disorder is chosen from non-24-hour sleep- wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night-time hypertension, obesity, type 2 diabetes, and testosterone insufficiency.
  • the disorder is non-24-hour sleep-wake disorder.
  • the additional therapeutic agent is chosen from antipsychotics, antidepressants, or medications having side effects such as sexual side effects, sleep disturbances, and daytime drowsiness.
  • the additional therapeutic agent is an antipsychotic chosen from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, haloperidol, haloperidol decanoate, droperidol, pimozide, amisulpride, aripiprazole, bifeprunox, clozapine, melperone, norclozapine, olanzapine, risperidone, paliperidone, quetapine, symbyax, tetrabenazine, and ziprazidone.
  • the additional therapeutic agent is an antidepressant chosen from amitriptyline, bupropion, citalopram, clomipramine, dapoxetine, desipramine, dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iofepramine, nortriptyline, paroxetine, protriptyline, sertraline, trazodone, trimipramine, and venlafaxine.
  • an antidepressant chosen from amitriptyline, bupropion, citalopram, clomipramine, dapoxetine, desipramine, dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iofepramine, nortriptyline, paroxetine, protriptyline, sertraline, trazodone, trimipramine, and venlafaxine.
  • the additional therapeutic agent is a medications having a side effect chosen from sexual side effects, sleep disturbances, and daytime drowsiness.
  • the method of treatment further results in at least one effect chosen from:
  • the method further results in at least two effects chosen from:
  • the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound.
  • the cytochrome P 450 isoform is chosen from CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
  • the compound is characterized by decreased inhibition of at least one cytochrome P450 or monoamine oxidase isoform in the subject per dosage unit thereof as compared to the non-isotopically enriched compound.
  • the cytochrome P 450 or monoamine oxidase isoform is chosen from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP1 CYP4Z1,
  • the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.
  • the diagnostic hepatobiliary function endpoint is chosen from alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST,”“SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “ ⁇ -GTP,”“GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5’-nucleotidase, and blood protein.
  • ALT alanine aminotransferase
  • SGPT serum glutamic-pyruvic transaminase
  • AST aspartate aminotransferase
  • ALT/AST ratios ALT/AST ratios
  • serum aldolase serum aldolase
  • alkaline phosphatase
  • Also provided herein is a method of treating a demyelinating disease comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited herein to a patient in need thereof.
  • the demyelinating disease is multiple sclerosis.
  • the multiple sclerosis is primary progressive multiple sclerosis.
  • Also provided is a method of treating a neurodegenerative disease comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited herein to a patient in need thereof.
  • the neurodegenerative disease or disorder is Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and
  • the multiple sclerosis is primary progressive multiple sclerosis.
  • Also provided is a method of treating a mitochondrial disease comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited herein to a patient in need thereof.
  • Also provided is a method of reducing demyelination of the corpus callosum comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as recited herein to a patient in need thereof.
  • a compound, or a salt thereof, as recited herein for use in the manufacture of a medicament for the prevention or treatment of a melatonin receptor- mediated disorder.
  • the terms below have the meanings indicated.
  • deuterium enrichment refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
  • deuterium when used to describe a given position in a molecule such as R1-R59 or the symbol“D”, when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium.
  • deuterium enrichment is no less than about 1%, in another no less than about 5%, in another no less than about 10%, in another no less than about 20%, in another no less than about 50%, in another no less than about 70%, in another no less than about 80%, in another no less than about 90%, or in another no less than about 98% of deuterium at the specified position.
  • isotopic enrichment refers to the percentage of incorporation of a less prevalent isotope of an element at a given position in a molecule in the place of the more prevalent isotope of the element.
  • non-isotopically enriched refers to a molecule in which the percentages of the various isotopes are substantially the same as the naturally occurring percentages.
  • Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols“R” or“S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds disclosed herein may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
  • bonds refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • a bond may be single, double, or triple unless otherwise specified.
  • a dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
  • disorder as used herein is intended to be generally synonymous, and is used interchangeably with, the terms“disease” and“condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.
  • A“demyelinating disease” is a disease of the nervous system in which the myelin sheath of neurons is damaged.
  • Myelin sheaths which cover many nerve fibers, are composed of lipoprotein layers formed in early life.
  • Myelin formed by the oligodendroglia in the CNS differs chemically and immunologically from that formed by the Schwann cells peripherally, but both types have the same function: to promote transmission of a neural impulse along an axon.
  • Demyelination in later life is a feature of many neurologic disorders; it can result from damage to nerves or myelin due to local injury, ischemia, toxic agents, or metabolic disorders.
  • adrenomyeloneuropathy metachromatic leukodystrophy, globoid cell leukodystrophy (Krabbe disease), Canavan disease, vanishing white matter disease, Alexander disease, Refsum disease, and Pelizaeus-Merzbacher disease.
  • the most well known demyelinating disease is multiple sclerosis.
  • A“neurodegenerative disease” is a disease characterized by progressive nervous system dysfunction, often associated with atrophy of the affected central or peripheral structures of the nervous system.
  • Neurodegenerative diseases include Alzheimer's Disease and other dementias, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Huntington's disease, and prion diseases such as Creutzfeldt– Jakob disease.
  • A“mitochondrial disease” is a disease caused by dysfunctional mitochondria, resulting in reduced cellular energy output, often resulting in one or more of poor growth, loss of muscle coordination, muscle weakness, visual or hearing problems, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory disorders, neurological problems, autonomic dysfunction and dementia.
  • Mitochondrial diseases include mitochondrial myopathy, Leber's Hereditary Optic Neuropathy (LHON), Leigh syndrome, subacute sclerosing encephalopathy, Neuropathy, Ataxia, Retinitis Pig mentosa, and Ptosis (NARP), Myoneurogenic Gastrointestinal Encephalopathy (MNGIE), Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Mitochondrial myopathy,
  • the terms“treat,”“treating,” and“treatment” are meant to include alleviating or abrogating a disorder or one or more of the symptoms associated with a disorder; or alleviating or eradicating the cause(s) of the disorder itself.
  • treatment of a disorder is intended to include prevention.
  • the terms“prevent,” “preventing,” and“prevention” refer to a method of delaying or precluding the onset of a disorder; and/or its attendant symptoms, barring a subject from acquiring a disorder, or reducing a subject’s risk of acquiring a disorder.
  • the term“therapeutically effective amount” refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder being treated.
  • the term“therapeutically effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • the term“subject” refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like.
  • a primate e.g., human, monkey, chimpanzee, gorilla, and the like
  • rodents e.g., rats, mice, gerbils, hamsters, ferrets, and the like
  • lagomorphs e.g., pig, miniature pig
  • swine e.g., pig, miniature pig
  • equine canine
  • feline feline
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the disorders described herein.
  • “melatonin receptor” or“MT receptor” refers to receptors which bind the hormone melatonin.
  • “melatonin receptor” or“MT receptor” would include the G-protein coupled melatonin M 1 receptor (also known as MT1R) and the G-protein coupled melatonin M2 receptor (also known as MT2R).
  • melatonin receptor-mediated disorder refers to a disorder that is characterized by abnormal melatonin receptor activity or melatonin receptor activity that, when modulated, leads to the amelioration of other abnormal biological processes.
  • a melatonin receptor-mediated disorder may be completely or partially mediated by modulating melatonin receptors.
  • a melatonin receptor-mediated disorder is one in which modulation of melatonin receptors results in some effect on the underlying disorder e.g., administration of a melatonin receptor modulator results in some improvement in at least some of the patients being treated.
  • Progressive MS includes, for example, primary progressive MS, secondary progressive MS, and progressive relapsing MS. These subtypes may or may not feature episodic flare-ups of the disease, but are each associated with increased symptoms, such as increased demyelination or pain and reduced capacity for movement, over time.
  • a modulator may activate the activity of an melatonin receptor, may activate or inhibit the activity of an melatonin receptor depending on the concentration of the compound exposed to the melatonin receptor, or may inhibit the activity of an melatonin receptor.
  • melatonin receptor modulator or“modulation of melatonin receptors” also refers to altering the function of an melatonin receptor by increasing or decreasing the probability that a complex forms between an melatonin receptor and a natural binding partner.
  • a melatonin receptor modulator may increase the probability that such a complex forms between the melatonin receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the melatonin receptor and the natural binding partner depending on the concentration of the compound exposed to the melatonin receptor, and or may decrease the probability that a complex forms between the melatonin receptor and the natural binding partner.
  • modulation of the melatonin receptor may be assessed using Receptor Selection and Amplification Technology (R-SAT) as described in US 5,707,798, the disclosure of which is incorporated herein by reference in its entirety.
  • terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, immunogenicity, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • Each component must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the terms“active ingredient,”“active compound,” and“active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.
  • the terms“drug,”“therapeutic agent,” and“chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.
  • release controlling excipient refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.
  • nonrelease controlling excipient refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.
  • prodrug refers to a compound functional derivative of the compound as disclosed herein and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
  • the compounds disclosed herein can exist as therapeutically acceptable salts.
  • the term“therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are therapeutically acceptable as defined herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound with a suitable acid or base.
  • Therapeutically acceptable salts include acid and basic addition salts.
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohe
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H- imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl
  • compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • 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., in Remington’s Pharmaceutical Sciences.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.
  • compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • 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 or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • 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.
  • 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.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • 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 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
  • ion exchange resins for example as an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • 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, polyethylene glycol, or other glycerides.
  • Certain compounds disclosed herein may be administered topically, that is by non- systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • compounds may be delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day.
  • the dose range for adult humans is generally from 5 mg to 2 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds can be administered in various modes, e.g. orally, topically, or by injection.
  • the precise amount of compound administered to a patient will be the
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the disorder being treated. Also, the route of administration may vary depending on the disorder and its severity.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disorder.
  • the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (i.e., a“drug holiday”).
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disorder is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • Disclosed herein are methods of treating a melatonin receptor-mediated disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • Melatonin receptor-mediated disorders include, but are not limited to, non-24- hour sleep-wake disorder, Smith-Magenis syndrome, major depressive disorder, primary insomnia circadian rhythm-related disorders, depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproductive disorders, cancer, benign prostatic hyperplasia, immune disorders, neuroendocrine disorders, dysthymia, bipolar disorder, delayed sleep phase disorder, general anxiety disorder, seasonal affective disorder, attention deficit hyperactivity disorder, Alzheimer's, Angelman syndrome, schizophrenia, autism, epilepsy, migraine, night- time hypertension, obesity, type 2 diabetes, and testosterone insufficiency, and/or any disorder which can lessened, alleviated, or prevented by administering a melatonin receptor modulator.
  • Also disclosed herein are methods of treating a demyelinating disease or disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the demyelinating disease is multiple sclerosis.
  • the multiple sclerosis is primary progressive multiple sclerosis.
  • Also disclosed herein are methods of treating a neurodegenerative disease or disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the neurodegenerative disease or disorder is Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and
  • the multiple sclerosis is primary progressive multiple sclerosis.
  • Also disclosed herein are methods of treating a mitochondrial disease or disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • Also disclosed herein are methods of reducing demyelination of the corpus callosum comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • a method of treating a melatonin receptor-mediated disorder, a demyelinating disease or disorder, a neurodegenerative disease or disorder, or a mitochondrial disease or disorder comprises administering to the subject a therapeutically effective amount of a compound of as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to affect: (1) decreased inter-individual variation in plasma levels of the compound or a metabolite thereof; (2) increased average plasma levels of the compound or decreased average plasma levels of at least one metabolite of the compound per dosage unit; (3) decreased inhibition of, and/or metabolism by at least one cytochrome P450 or monoamine oxidase isoform in the subject; (4) decreased metabolism via at least one polymorphically-expressed cytochrome P450 isoform in the subject; (5) at least one statistically-significantly improved disorder-control and/or disorder-eradication endpoint; (6) an improved clinical effect during the treatment of the disorder, (7) prevention of recurr
  • inter-individual variation in plasma levels of the compounds as disclosed herein, or metabolites thereof is decreased; average plasma levels of the compound as disclosed herein are increased; average plasma levels of a metabolite of the compound as disclosed herein are decreased; inhibition of a cytochrome P450 or monoamine oxidase isoform by a compound as disclosed herein is decreased; or metabolism of the compound as disclosed herein by at least one polymorphically-expressed cytochrome P 450 isoform is decreased; by greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or by greater than about 50% as compared to the corresponding non-isotopically enriched compound.
  • Plasma levels of the compound as disclosed herein, or metabolites thereof may be measured using the methods described in Vachharajani et al., J. Pharm. Sci., 2003, 92(4), 760-772 and US 8,785,492, which are hereby incorporated by reference.
  • Examples of cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1,
  • Examples of monoamine oxidase isoforms in a mammalian subject include, but are not limited to, MAOA, and MAOB.
  • the inhibition of the cytochrome P450 isoform is measured by the method of Ko et al. (British Journal of Clinical Pharmacology, 2000, 49, 343-351).
  • the inhibition of the MAOA isoform is measured by the method of Weyler et al. (J. Biol Chem.1985, 260, 13199- 13207).
  • the inhibition of the MAOB isoform is measured by the method of Uebelhack et al. (Pharmacopsychiatry, 1998, 31, 187-192).
  • Examples of polymorphically-expressed cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
  • liver microsomes cytochrome P 450 isoforms
  • monoamine oxidase isoforms are measured by the methods described herein.
  • Examples of improved disorder-control and/or disorder-eradication endpoints, or improved clinical effects include, but are not limited to, nighttime total sleep time (nTST), lower quartile of nTST (LQ-nTST), daytime total sleep duration (dTSD), upper quartile of dTSD (UQ-dTSD), clinical global impression of change (CGI-C), midpoint of sleep timing (MoST), non-24 clinical response scale, Hamilton depression rating scale (HAM-D), Arizona sexual experience scale (ASEX) and Sheehan disability scale (SDS), Columbia-suicide severity rating scale (C-SSRS). US 8,785,492.
  • diagnostic hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase
  • SGPT aspartate aminotransferase
  • AST aspartate aminotransferase
  • ALT/AST ratios serum aldolase
  • alkaline phosphatase ALP
  • ALP alkaline phosphatase
  • ammonia levels bilirubin
  • GGTP gamma-glutamyl transpeptidase
  • LAP leucine aminopeptidase
  • liver biopsy liver ultrasonography
  • liver nuclear scan 5’-nucleotidase
  • 5’-nucleotidase and blood protein.
  • Hepatobiliary endpoints are compared to the stated normal levels as given in“Diagnostic and Laboratory Test Reference”, 4 th edition, Mosby, 1999. These assays are run by accredited laboratories according to standard protocol.
  • the compounds disclosed herein may also be combined or used in combination with other agents useful in the treatment of melatonin receptor-mediated disorders.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • Such other agents, adjuvants, or drugs may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound as disclosed herein.
  • a pharmaceutical composition containing such other drugs in addition to the compound disclosed herein may be utilized, but is not required.
  • the compounds disclosed herein can be combined with one or more antipsychotics, antidepressants , or medications having side effects such as sexual side effects, sleep disturbances, daytime drowsiness, and the withdrawal symptoms commonly associated with antidepressant discontinuation.
  • the compounds disclosed herein can be combined with one or more antipsychotics chosen from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, haloperidol, haloperidol decanoate, droperidol, pimozide, amisulpride, aripiprazole, bifeprunox, clozapine, melperone, norclozapine, olanzapine, risperidone, paliperidone, quetapine, symbyax, tetrabenazine, and ziprazidone.
  • antipsychotics chosen from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, haloperidol, haloperidol decanoate, droperidol, pimozide, amisulpride, arip
  • the compounds disclosed herein can be combined with one or more antidepressants chosen from amitriptyline, bupropion, citalopram, clomipramine, dapoxetine, desipramine, dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iofepramine, nortriptyline, paroxetine, protriptyline, sertraline, trazodone, trimipramine, and venlafaxine.
  • antidepressants chosen from amitriptyline, bupropion, citalopram, clomipramine, dapoxetine, desipramine, dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iofepramine, nortriptyline, paroxetine, protriptyline, sertraline, trazodone, trimipramine, and venlafaxine.
  • the compounds disclosed herein can, when used in conjunction with other medications, may alleviate unwanted symptoms associated with the use of such medications including, but not limited to, sexual side effects, sleep disturbances, daytime drowsiness, and the withdrawal symptoms commonly associated with antidepressant discontinuation.
  • the compounds disclosed herein can also be administered in combination with other classes of compounds, including, but not limited to, norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as
  • SNRIs serotonin-norepinephrine reuptake inhibitors
  • NDRIs norepinephrine-dopamine reuptake inhibitor
  • SNDRIs serotonin-norepinephrine-dopamine-reuptake-inhibitors
  • venlafaxine monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti- platelet agents
  • PAF platelet activating factor
  • vasopepsidase inhibitors such as omapatrilat and gemopatrilat
  • HMG CoA reductase inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, NK- 104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP
  • Inhibitors calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta-muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothlazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,
  • trichloromethiazide polythiazide, benzothlazide, ethacrynic acid, tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide, triamterene, amiloride, and spironolactone;
  • thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g.
  • metformin glucosidase inhibitors
  • glucosidase inhibitors e.g., acarbose
  • insulins meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors;
  • glucosidase inhibitors e.g., acarbose
  • insulins e.g., meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,
  • phosphodiesterase inhibitors such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors;
  • antiinflammatories such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antimetabolites, such as folate antagonists, purine analogues, and pyrridine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone),
  • microtubule-disruptor agents such as ecteinascidins
  • microtubule-stabilizing agents such as paclitaxel, docetaxel, and epothilones A-F
  • plant-derived products such as vinca alkaloids, epipodophyllotoxins, and taxanes
  • topoisomerase inhibitors prenyl-protein transferase inhibitors
  • cytotoxic drugs such as azathiprine and
  • TNF-alpha inhibitors such as tenidap
  • anti-TNF antibodies or soluble TNF receptor such as etanercept, rapamycin, and leflunomide
  • cyclooxygenase-2 (COX- 2) inhibitors such as celecoxib and rofecoxib
  • miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin.
  • certain embodiments provide methods for treating melatonin receptor- mediated disorders in a human or animal subject in need of such treatment comprising administering to the subject an amount of a compound disclosed herein effective to reduce or prevent the disorder in the subject, in combination with at least one additional agent for the treatment of the disorder that is known in the art.
  • certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of melatonin receptor-mediated disorders.
  • Isotopic hydrogen can be introduced into a compound as disclosed herein by synthetic techniques that employ deuterated reagents, whereby incorporation rates are predetermined; and/or by exchange techniques, wherein incorporation rates are determined by equilibrium conditions, and may be highly variable depending on the reaction conditions.
  • Synthetic techniques where tritium or deuterium is directly and specifically inserted by tritiated or deuterated reagents of known isotopic content, may yield high tritium or deuterium abundance, but can be limited by the chemistry required.
  • Exchange techniques on the other hand, may yield lower tritium or deuterium incorporation, often with the isotope being distributed over many sites on the molecule.
  • the compounds as disclosed herein can be prepared by methods known to one of skill in the art and routine modifications thereof, and/or following procedures similar to those described in the Example section herein and routine modifications thereof, and/or procedures found in US 5,856,529, WO 199825606, and WO 2013173707, which are hereby incorporated in their entirety, and references cited therein and routine modifications thereof.
  • Compounds as disclosed herein can also be prepared as shown in any of the following schemes and routine modifications thereof.
  • Compound 1 is treated with an appropriate reducing agent, such as a combination of hydrogen gas and palladium on carbon, in an appropriate solvent, such as acetic acid, to give compound 2.
  • Compound 2 is treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at an elevated temperature, to give compound 3.
  • Compound 3 is treated with an appropriate oxidizing agent, such as a combination of dimethyl sulfoxide and oxalyl chloride, in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, such as dichloromethane, at a reduced temperature, to give compound 4.
  • Compound 4 is reacted with malonic acid, in the presence of an appropriate base, such as pyrrolidine, in an appropriate solvent, such as pyridine, at an elevated temperature, to give compound 5.
  • Compound 5 is treated with an appropriate activating agent, such as thionyl chloride, in an appropriate solvent, such as toluene, to give an intermediate acyl chloride, which is further reacted with (-)- camphorsultam in the presence of an appropriate base, such as sodium hydride, in an appropriate solvent, such as toluene, to give compound 6.
  • an appropriate activating agent such as thionyl chloride
  • an appropriate solvent such as toluene
  • Compound 6 is reacted with compound 7 (prepared as an ethereal solution by reacting an ethereal solution of 1-methyl-3- nitro-1-nitrosoguanidine or a deuterated analog thereof and aqueous sodium hydroxide) in the presence of an appropriate catalyst, such as palladium acetate, in an appropriate solvent, such as methylene chloride, to give compound 8.
  • compound 8 is treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a reduced temperature, to give compound 9.
  • Compound 9 is treated with an appropriate oxidizing agent, such as a combination of dimethyl sulfoxide and oxalyl chloride, in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, such as dichloromethane, at a reduced temperature, to give compound 10.
  • an appropriate oxidizing agent such as a combination of dimethyl sulfoxide and oxalyl chloride
  • an appropriate base such as triethylamine
  • an appropriate solvent such as dichloromethane
  • compound 10 is reacted with hydroxylamine hydrochloride, in the presence of an appropriate base, such as sodium hydroxide, in an appropriate solvent, such as a mixture of ethanol and water, at an elevated temperature, to give an intermediate oxime that is then treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a reduced temperature, to give compound 11.
  • Compound 11 is reacted with compound 12 in the presence of an
  • corresponding deuterium substitutions can be used.
  • compound 1 with the corresponding deuterium substitutions can be used.
  • To introduce deuterium at one or more positions of R17-R18 deuterium gas can be used.
  • To introduce deuterium at R 7 , R 8 , and/or R 10 lithium aluminum deuteride can be used.
  • To introduce deuterium at R8, malonic acid and/or pyrrolidine with the corresponding deuterium substitutions can be used.
  • compound 7 with the corresponding deuterium substitutions can be used.
  • compound 12 with the corresponding deuterium substitutions can be used.
  • Compound 1 is treated with an appropriate base, such as sodium hydride, in the presence of an appropriate catalyst, such as copper(I) chloride, in an appropriate solvent, such as pyridine, to effect intramolecular Friedel-Crafts alkylation to give Compound 2.
  • an appropriate base such as sodium hydride
  • an appropriate catalyst such as copper(I) chloride
  • an appropriate solvent such as pyridine
  • Compound 2 is treated with an appropriate vinyl tin reagent, such as tri-(tert-butyl)vinyl tin, in the presence of an appropriate palladium catalyst, such as
  • Compound 5 is treated with an appropriate activating agent, such as thionyl chloride, in an appropriate solvent, such as dichloromethane, to give an intermediate acyl chloride, which is further reacted with O-methyl N-methylhydroxylamine in the presence of an appropriate base, such as sodium carbonate, to give compound 6.
  • an appropriate activating agent such as thionyl chloride
  • an appropriate solvent such as dichloromethane
  • Compound 6 is reacted with the ylid generated by reacting trimethylsulfonium iodide with a suitable base, such as sodium hydride, in a suitable solvent, such as DMSO, to give cyclopropane Compound 7.
  • a suitable base such as sodium hydride
  • a suitable solvent such as DMSO
  • Compound 7 is treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a reduced temperature, to give compound 8.
  • Compound 8 is treated with hydroxylamine in an appropriate solvent, such as ethanol-water, to give oxime compound 9.
  • Compound 9 is then treated with an appropriate reducing agent, such as lithium aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a reduced temperature, to give compound 10.
  • Compound 10 is reacted with compound 11 in the presence of an appropriate base, such as triethylamine, in an appropriate solvent, such as dichlorome
  • Deuterium can be incorporated to various positions having an exchangeable proton, such as the amine N-H, via proton-deuterium equilibrium exchange. For example, to introduce deuterium at R 6 this proton may be replaced with deuterium selectively or non- selectively through a proton-deuterium exchange method known in the art. [00235] The invention is further illustrated by the following examples. All IUPAC names were generated using CambridgeSoft’s ChemDraw 10.0. EXAMPLE 1
  • Step 1 4-chloro-2,3-dihydro-1-benzofuran: To a solution of 2-(2,6-dichlorophenyl)ethan- 1-ol (20 g, 104.68 mmol, 1.00 equiv) in pyridine (500 mL) was added sodium hydride (5.2 g, 216.67 mmol, 1.25 equiv). The resulting solution was stirred at 0 o C for 1 h. Then CuCl (600 mg, 6.12 mmol, 0.05 equiv) was added. The resulting solution was stirred overnight at 115 o C. The resulting mixture was concentrated under vacuum. The reaction was then diluted with 500 mL of H2O.
  • the resulting solution was stirred for 24 h at 110 o C.
  • the reaction progress was monitored by GCMS.
  • the resulting solution was diluted with 300 mL of ethyl acetate. Then the solids were filtered out. The organic layers were washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by SiO2 chromatography, eluted with petroleum ether to afford 5 g (46%) of 4-ethenyl-2,3-dihydro-1-benzofuran as light yellow oil.
  • Step 3 2,3-dihydro-1-benzofuran-4-carbaldehyde: To a solution of 4-ethenyl-2,3- dihydro-1-benzofuran (5 g, 34.20 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) and water (50 mL) was added OsO4 (440 mg, 1.73 mmol, 0.05 equiv). The resulting solution was stirred for 30 min at 20 o C. Then NaIO 4 (14.7 g, 68.69 mmol, 2.00 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h at room temperature.
  • (2E)-3-(2,3-dihydro-1-benzofuran-4-yl)prop-2-enoic acid A mixture of 2,3- dihydro-1-benzofuran-4-carbaldehyde (3.5 g, 23.62 mmol, 1.00 equiv), (4.9 g, 47.09 mmol, 2.00 equiv), pyrrolidine (1.4 mL), Pyridine (35 mL) was heated for 2 h at 120 o C. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers were combined.
  • (2E)-3-(2,3-dihydro-1- benzofuran-4-yl)-N-methoxyprop-2-enamide A mixture of (2E)-3-(2,3-dihydro-1-benzofuran-4-yl)prop-2-enoic acid (3.7 g, 19.45 mmol, 1.00 equiv), thionyl chloride (8 mL) and dichloromethane (50 mL) was heated to reflux for 1 h. The mixture was concentrated under vacuum.
  • N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl]propanamide To a solution of [(1R,2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl] methanamine (500 mg, 2.64 mmol, 1.00 equiv) and TEA (801.6 mg, 7.92 mmol, 3.00 equiv) in DCM (10 mL) was added propionyl chloride (267.7 mg, 2.89 mmol, 1.10 equiv). The mixture was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS.
  • Step 2 4-chloro-2,3-dihydro(2,2- 2 H2)-1-benzofuran: To a solution of 2-(2,6- dichlorophenyl)(1,1- 2 H 2 )ethan-1-ol (14 g, 72.51 mmol, 1.00 equiv) in pyridine (200 mL) was added sodium hydride (3.6 g, 150.00 mmol, 1.25 equiv), in portions. The resulting solution was stirred at 0 o C for 1 h. Then CuCl (350 mg, 3.57 mmol, 0.05 equiv) was added. The resulting solution was stirred overnight at 115 o C.
  • the resulting solution was stirred for 24 h at 110 o C.
  • the reaction progress was monitored by GCMS.
  • the resulting solution was diluted with 100 mL of ethyl acetate. Then the solids were filtered out. The organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by SiO2 chromatography eluted with petroleum ether to afford 4 g (64%) of 4-ethenyl-2,3-dihydro (2,2- 2 H 2 )-1- benzofuran as light brown oil.
  • (2E)-3-[2,3-dihydro(2,2- 2 H2)-1-benzofuran-4-yl]prop-2-enoic acid A mixture of 2,3-dihydro(2,2- 2 H 2 )-1-benzofuran-4-carbaldehyde (3.2 g, 21.31 mmol, 1.00 equiv), malonic acid (4.44 g, 42.67 mmol, 2.00 equiv), pyrrolidine (1.75 mL), Pyridine (35 mL) was heated for 2 h at 120 o C. The resulting solution was diluted with 50 mL of water.
  • (2E)-3-[2,3-dihydro(2,2- 2 H 2 )-1-benzofuran-4-yl]-N-methoxy-N-methylprop-2- enamide A mixture of (2E)-3-[2,3-dihydro(2,2- 2 H2)-1-benzofuran-4-yl]prop-2-enoic acid (3.6 g, 18.75 mmol, 1.00 equiv), thionyl chloride (7.2 mL) and dichloromethane (40 mL) was heated to reflux for 1 h. The mixture was concentrated under vacuum.
  • the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50 o C.
  • the reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M).
  • the resulting solution was extracted with dichloromethane.
  • the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M).
  • the resulting solution was extracted with DCM (2 x 20 mL).
  • the crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 120 mg of N- [[(1R,2R)-2-[2,3-dihydro(2,2- 2 H 2 )-1-benzofuran-4-yl]cyclopropyl]methyl]propanmide as a white solid.
  • the resulting solution was diluted with 300 mL of water. The pH value of the solution was adjusted to 7 with HCl (3 M). The solids were filtered out. The resulting solution was extracted with ethyl acetate (3 x 200 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). The collected fractions were combined and concentrated under vacuum to afford 18.56 g (65%) of 4-chloro-2,3- dihydro(3,3- 2 H2)- 1-benzofuran as light brown oil.
  • the resulting solution was stirred for 24 h at 110 o C.
  • the reaction progress was monitored by GCMS.
  • the resulting solution was diluted with 200 mL of ethyl acetate. Then the solids were filtered out. The organic layers were washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by SiO2 chromatography eluted with ethyl acetate/petroleum ether (0:1) to afford 7.5 g (45%) of 4-ethenyl-2,3-dihydro(3,3- 2 H 2 )-1- benzofuran as light yellow oil.
  • Step 5 2,3-dihydro(3,3- 2 H2)-1-benzofuran-4-carbaldehyde: To a solution of 4-ethenyl- 2,3-dihydro(3,3- 2 H 2 )-1-benzofuran (7.5 g, 50.61 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) and water (50 mL) was added OsO4 (in tetrahydrofuran 0.2 M) (12.7 mL, 0.05 equiv). The resulting solution was stirred for 30 min at 20 o C. Then NaIO 4 (21.69 g, 101.36 mmol, 2.00 equiv) was added.
  • OsO4 in tetrahydrofuran 0.2 M
  • (2E)-3-[2,3-dihydro(3,3- 2 H2)-1-benzofuran-4-yl]prop-2-enoic acid A mixture of 2,3-dihydro(3,3- 2 H 2 )-1-benzofuran-4-carbaldehyde (7.5 g, 49.94 mmol, 1.00 equiv), malonic acid (10.4 g, 99.94 mmol, 2.00 equiv), pyrrolidine (4 mL), Pyridine (80 mL) was heated for 2 h at 120 o C. The resulting solution was diluted with 50 mL of water.
  • (2E)-3-[2,3-dihydro(3,3- 2 H2)-1-benzofuran-4-yl]-N-methoxy-N-methylprop-2- enamide A mixture of (2E)-3-[2,3-dihydro(3,3- 2 H 2 )-1-benzofuran-4-yl]prop-2-enoic acid (7.2 g, 37.46 mmol, 1.00 equiv), thionyl chloride (14 mL) and dichloromethane (70 mL) was heated to reflux for 1 hour. The mixture was concentrated under vacuum.
  • the crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20 um; mobile phase, CO 2 (75%), ethanol (25%); Detector, UV 220 nm to afford 250 mg of N- [[(1R,2R)-2-[2,3-dihydro(3,3- 2 H2)-1-benzofuran-4-yl]cyclopropyl]methyl]propanamide as a white solid.
  • 2-(2,6-dichlorophenyl)( 2 H 4 )ethan-1-ol To 2-(2,6-dichlorophenyl)( 2 H 2 )acetic acid (20 g, 96.60 mmol, 1.00 equiv), obtained, for example, by the method of Example 3, step 1, was added BD 3 (in THF,1 M) (100 mL, 1.00 equiv) dropwise with stirring. The resulting solution was stirred at 0 o C for 3 h. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of D 2 O. The resulting solution was extracted with ethyl acetate (3 x 50 mL).
  • Step 2 4-chloro-2,3-dihydro(2,2,3,3- 2 H4)-1-benzofuran: A solution of 2-(2,6- dichlorophenyl)( 2 H 4 )ethan-1-ol (18 g, 92.27 mmol, 1.00 equiv) in pyridine (200 mL) was stirred at 0 o C. Then sodium hydride (4.62 g, 192.50 mmol, 1.25 equiv) was added. The resulting solution was stirred at 0 o C for 1 h. To this was added CuCl (450 mg, 4.59 mmol, 0.05 equiv). The resulting solution was stirred overnight at 115 o C.
  • the resulting solution was stirred for 24 h at 110 o C.
  • the reaction progress was monitored by GCMS.
  • the resulting solution was diluted with 100 mL of ethyl acetate. Then the solids were filtered out. The organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by SiO 2
  • Step 4 2,3-dihydro(2,2,3,3- 2 H 4 )-1-benzofuran-4-carbaldehyde: To a solution of 4- ethenyl-2,3-dihydro(2,2,3,3- 2 H4)-1-benzofuran (6 g, 40.00 mmol, 1.00 equiv) in THF/H2O (2:1) (100 mL), was added OsO 4 (in THF 0.2 M) (10 mL, 0.05 equiv). The resulting solution was stirred for 30 min at 20 o C. Then NaIO4 (17.12 g, 2.00 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 1 hour at room temperature.
  • the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50 o C.
  • the reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M).
  • the resulting solution was extracted with dichloromethane.
  • the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M).
  • the resulting solution was extracted with dichloromethane.
  • the crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 160 mg of N- [[(1R,2R)-2-[2,3-dihydro(2,2,3,3- 2 H 4 )-1-benzofuran-4-yl]cyclopropyl]methyl]propanamide as a white solid.
  • Example 1 (3.2 g, 12.94 mmol, 1.00 equiv) in THF dropwise. The resulting solution was stirred for 30 min at -5 o C. The reaction was quenched by the addition of water. Then KHSO 4 (3.2 g, 1.70 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 10 min at 20 o C. The resulting solution was extracted with ethyl acetate (2 x 30 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 30 mL).
  • the crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 250 mg (24%) of N-[[(1R,2R)-2-(2,3-dihydro-1-benzofuran-4- yl)cyclopropyl]( 2 H2)methyl]propanamide as a white solid.
  • PH-APX-SD-1084 was synthesized as follows:
  • the resulting solution was stirred for 30 min at -5 o C. The reaction was quenched by the addition of water. Then KHSO 4 (1.86 g, 1.70 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 10 min at 20 o C. The resulting solution was extracted with ethyl acetate (2 x 50 mL) and the organic layers combined. The resulting mixture was washed with brine (2 x 50 mL).
  • the resulting solution was allowed to react, with stirring, for an additional 4 h while the temperature was maintained at 50 o C.
  • the reaction was quenched by the addition of water and the pH value of the solution was adjusted to 1 with hydrochloric acid (1 M).
  • the resulting solution was extracted with dichloromethane.
  • the pH value of the aqueous solution was adjusted to 10 with sodium hydroxide (3 M).
  • the resulting solution was extracted with dichloromethane.
  • the crude product was purified by Prep-SFC with the f following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 260 mg of N-[[(1R,2R)-2-[2,3-dihydro(3,3- 2 H 2 )-1-benzofuran-4- yl]cyclopropyl]( 2 H2)methyl]propanamide as a white solid.
  • step 1 N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3- 2 H 4 )-1-benzofuran-4- yl]cyclopropyl]methyl]( 2 H5)propanamide: To a solution of [(1R,2R)-2-[2,3-dihydro(2,2,3,3- 2 H 4 )-1-benzofuran-4-yl]cyclopropyl] methanamine, obtained, for example, as the product of step 10 of Example 4, (500 mg, 2.59 mmol, 1.00 equiv), BOP (1.72 g, 1.50 equiv) and TEA (785 mg, 7.76 mmol, 3.00 equiv) in DCM (8 mL) was added ( 2 H 5 )propan( 2 H)oic acid (249 mg, 3.11 mmol, 1.20 equiv). The resulting solution was stirred overnight at room
  • the crude product was purified by Prep-SFC with the following conditions following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO2(75%), ethanol (25%); Detector, UV 220 nm to afford 160 mg of N-[[(1R,2R)-2-[2,3-dihydro(2,2,3,3- 2 H 4 ) -1-benzofuran-4- yl]cyclopropyl]methyl]( 2 H5)propanamide as a white solid.
  • the crude product was purified by Prep-SFC with the following conditions: Column, Chiralpak AS-H, 2*25cm, 20um; mobile phase, CO 2 (75%), ethanol (25%); Detector, UV 220 nm to afford 180 mg of N-[[(1R,2R)-2- [2,3-dihydro(3,3- 2 H2)-1-benzofuran -4-yl]cyclopropyl]methyl]( 2 H5)propanamide as a white solid.
  • Human liver microsomal stability assays are conducted at 0.5 mg per mL liver microsome protein with NADPH (2mM, pH 7.4).
  • Test compounds are typically prepared as solutions in acetonitrile with 5% DMSO and added to the assay mixture (1uM, final concentration in incubation) to be incubated at 37 oC.
  • Reactions are initiated with the addition of NADPH cofactor and are stopped at 0, 15, 30, 45 or 60 min after cofactor addition with stop reagent, acetonitrile. After quenching, plates containing samples are vibrated for 10 min (600 rpm/min) and then centrifuged at 5594 g for 15 min. Supernatant fractions are analyzed by LC-MS/MS to determine the percent remaining and estimate the degradation half-life of the test compounds. Results are given below.
  • Recombinant CYP1A2 stability assays are conducted at an enzyme concentration of 40 pmol per mL with NADPH (2mM, pH 7.4).
  • Test compounds are typically prepared as acetonitrile with 5% DMSO and added to the assay mixture (1uM, final concentration in incubation) to be incubated at 37 oC.
  • Reactions are initiated with the addition of NADPH cofactor and are stopped at 0, 30, 60, 90 or 120 min after cofactor addition with stop reagent, acetonitrile. After quenching, plates containing samples are vibrated for 10 min (600 rpm/min) and then centrifuged at 5594 g for 15 min. Supernatant fractions are analyzed by LC-MS/MS to determine the percent remaining and estimate the degradation half-life of the test compounds. Results are given below.
  • Compounds disclosed herein may be tested in variations of the assay above, for metabolic activity by other CYP enzymes. Alternatively, the compounds may be tested as follows. Cytochrome P450 enzymes may be expressed from the corresponding human cDNA using a baculovirus expression system (BD Biosciences, San Jose, CA).
  • a 0.25 milliliter reaction mixture containing 0.8 milligrams per milliliter protein, 1.3 millimolar NADP + , 3.3 millimolar glucose-6-phosphate, 0.4 U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound of Formula I, the corresponding non-isotopically enriched compound or standard or control in 100 millimolar potassium phosphate (pH 7.4) may be incubated at 37 °C for 20 min.
  • the major metabolites of the example compounds in terms of the UV absorbance and mass spectrometry response were identified by comparison of the LC-UV and LC-MS total ion chromatograms (TIC) of T 0 , T 60-w/o , T 60 samples in full scan mode using MassLynx and MetaboLynx.
  • TIC total ion chromatograms
  • the tandem mass spectra or MSMS data of the parent compounds and the metabolites were obtained by using product ion scanning during positive and negative ion electrospray.
  • the possible chemical structures of the metabolites were deduced based on their MSMS spectra.

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Abstract

La présente invention concerne de nouveaux modulateurs de récepteurs de la mélatonine à base de cyclopropyl dihydrobenzofurane, des compositions pharmaceutiques à base de ceux-ci, et sur leurs procédés d'utilisation.
PCT/US2015/067541 2014-12-29 2015-12-27 Modulateurs de récepteurs de la mélatonine à base de cyclopropyl dihydrobenzofurane Ceased WO2016109359A1 (fr)

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WO2017193662A1 (fr) * 2016-05-12 2017-11-16 浙江京新药业股份有限公司 Forme cristalline du tasimelteon
CN108395370A (zh) * 2017-02-08 2018-08-14 中国石化扬子石油化工有限公司 一种氧化苯乙烯制备苯甲醛的方法
CN108663460A (zh) * 2018-08-03 2018-10-16 安徽省金楠医疗科技有限公司 一种盐酸达泊西汀异构体检测方法
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
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