WO2010066658A1 - Composés de potentialisation du récepteur ampa et leurs utilisations en médecine - Google Patents

Composés de potentialisation du récepteur ampa et leurs utilisations en médecine Download PDF

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WO2010066658A1
WO2010066658A1 PCT/EP2009/066476 EP2009066476W WO2010066658A1 WO 2010066658 A1 WO2010066658 A1 WO 2010066658A1 EP 2009066476 W EP2009066476 W EP 2009066476W WO 2010066658 A1 WO2010066658 A1 WO 2010066658A1
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compound
disorder
propanesulfonamide
dihydro
inden
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PCT/EP2009/066476
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English (en)
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Daniel Marcus Bradley
Francesca Cardullo
Howard Marshall
Paola Marzorati
Alfonso Pozzan
Simon E Ward
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds which potentiate the glutamate receptor.
  • the invention also relates to the use of the compounds in treating diseases and conditions mediated by potentiation of the glutamate receptor, compositions containing the derivatives and processes for their preparation.
  • Glutamate receptors which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 11 : 25-33).
  • Glutamate receptors can be divided into two distinct families.
  • the G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGlu ⁇ , mGlu7, mGlu ⁇ ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237).
  • the "ionotropic" glutamate receptor family which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) 51 : 7-61 ).
  • NMDA N-methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid
  • KA kainic acid
  • AMPA receptors exist as heterotetramers consisting of combinations of four different protein subunits (GIuRI -4) (for review see Bettler B and Muller C (1995) 34:
  • Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4.
  • Such editing results in so-called 'flip' and 'flop' receptor isoforms which differ in kinetic and pharmacological properties (Sommer B, Keinanen K, Verdoon TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T,
  • GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2.
  • GluR2 is edited in this way.
  • AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198).
  • the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 ).
  • LTP Long Term Potentiation
  • AMPAR positive allosteric modulators do not activate the receptor directly.
  • AMPAR modulators increase receptor activity.
  • AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.
  • Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A, DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671 ) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559).
  • the present invention provides a compound of formula (I) or a salt thereof:
  • R is selected from the group consisting of:
  • thienyl or imidazolyl both of which are fused with a 6- or 7-membered saturated carbocyclic ring, wherein one or two of the carbon atoms in the fused ring is optionally replaced by an oxygen atom; wherein the thienyl or imidazolyl group is further optionally substituted by a halogen.
  • R is selected from the group consisting of : • pyrrolidinone
  • halogen refers to fluoro, chloro, bromo or iodo.
  • the compound is:
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable.
  • salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • salt refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts.
  • Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation.
  • Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1 S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alg
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
  • polymorphs of a compound of the invention are also included within the scope of the invention.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • a compound of the invention has at least 80% e.e. In another embodiment, a compound of the invention has at least 90% e.e., for example at least 95% e.e. In another embodiment the isomer corresponds to at least 98% e.e, for example at least 99% e.e. Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each optionally provided in substantially pure form, for example at least 60% pure, for example at least 75% pure or at least 85%, or at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, or at least 5% or from 10 to 59% of a compound of the invention
  • a compound of formula (Ib) shown below may be prepared from a compound of formula (II) by reaction with the appropriate heterocycle according to scheme 1.
  • Typical reaction conditions comprise microwaving at a suitable temperature, for example 190 degC, a mixture of a compound of formula (II) and the required heterocycle, for example 2- hydroxypyridine, in the presence of a suitable copper reagent such as copper (I) iodide, a suitable ligand such as ⁇ /, ⁇ /-dimethylglycine, and a suitable base such as caesium carbonate in a suitable solvent such as dimethylsulphoxide for the required time, for example 30 minutes.
  • a suitable copper reagent such as copper (I) iodide
  • a suitable ligand such as ⁇ /, ⁇ /-dimethylglycine
  • a suitable base such as caesium carbonate
  • a suitable solvent such as dimethylsulphoxide for the required time, for example 30 minutes.
  • the above mixture may be heated under argon using a heating block or oil bath for the appropriate time and temperature, for example 16 hours at 120 degC.
  • a heating block or oil bath for the appropriate time and temperature, for example 16 hours at 120 degC.
  • the preparation of a compound of formula (II) where X equals Br is detailed in the experimental section.
  • Compounds R 1 R 2 NH are commercially available or may be prepared by methods described in the literature.
  • a compound of formula (Ic) shown below may be prepared from a compound of formula (III) by reaction with the appropriate system R 1 X according to scheme 2.
  • Typical reaction conditions comprise heating under argon a mixture of a compound of formula (III) (where R is hydrogen, alkyl or the two R groups form a ring) and the required system R 1 X, such as 1-[(3-iodophenyl)methyl]-1 H-pyrazole, in the presence of a suitable palladium reagent such as tetrakis(triphenylphosphine)palladium(0) and a suitable base such as sodium carbonate in a suitable solvent such as a 3:1 mixture of 1 ,4-dioxane and water at a suitable temperature such as 90 degC for the required time, for example 29 hours.
  • a suitable palladium reagent such as tetrakis(triphenylphosphine)palladium(0)
  • a suitable base such as sodium carbonate
  • a suitable solvent
  • R' phenyl or heterocyclic system
  • a compound of formula (Ic) shown below may be prepared from a compound of formula (II) by reaction with the appropriate system (RO) 2 BR' according to scheme 3.
  • Typical reaction conditions comprise heating under argon a mixture of a compound of formula (II) with the appropriate boronic acid or boronate ester (RO) 2 BR' (where R is hydrogen, alkyl or the two R groups form a ring) such as 4- ⁇ [3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl ⁇ morpholine, in the presence of a suitable palladium reagent such as tetrakis(triphenylphosphine)palladium(0) and a suitable base such as sodium carbonate in a suitable solvent such as a 3:1 mixture of 1 ,4-dioxane and water at a suitable temperature such as 90 degC for the required time, for example 16 hours.
  • a suitable palladium reagent such
  • Compounds of formula (I) may be converted to other compounds of formula (I) using standard methods.
  • a compound of formula (I) wherein R is imidazolyl which is both fused with a saturated carbocyclic ring and also substituted by a halogen may be dehalogenated using standard procedures to give a compound wherein R is imidazolyl fused with a saturated carbocyclic ring.
  • the compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, for example 10 to 100 compounds.
  • Libraries of compounds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of the invention.
  • Compounds of the invention have been found to potentiate the AMPA receptor, and are thus expected to be useful in the treatment of disease states which require potentiation of such receptors, such as in the enhancement of cognition, for example in the treatment of cognition impairment brought about by various diseases.
  • the compounds are also expected to be useful in the treatment of psychotic conditions, including schizophrenia.
  • the present invention provides a compound of formula (I) or a salt thereof for use in medicine.
  • the present invention provides a compound of formula (I) or a salt thereof for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and at least one carrier, diluent or excipient.
  • the invention includes the following further aspects.
  • the embodiments described in respect of the first aspect apply equally to each of these further aspects: i) the use of a compound of formula (I) or a salt thereof in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of formula (I) or a salt thereof for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; iii) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of formula (I) or a salt thereof; iv) a combination product of a compound of formula (I) or a salt thereof with an antipsychotic; v) a pharmaceutical composition comprising a combination product as defined in iv) above and at least one carrier, diluent or excipient
  • psychosis and psychotic disorders including schizophrenia, schizo-affective disorder, schizophreniform diseases, brief reactive psychosis, child onset schizophrenia, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, acute psychosis, alcohol psychosis, drug- induced psychosis, autism, delerium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); substance related disorders (including alcohol-related disorders and nicotine-related disorders); cognitive impairment (e.g.
  • Alzheimer's disease i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment
  • cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, aging, stroke, neurodegeneration, drug- induced states, neurotoxic agents), mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, post-electroconvulsive treatment related cognitive disorders; anxiety disorders (including generalised anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neurone disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits
  • psychotic disorder includes :-
  • Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type
  • Compounds of the invention may also be of use in the treatment of the following disorders:-
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):
  • Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder,
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag
  • Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder
  • Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not
  • Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22),
  • Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and
  • cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvulsive treatment related cognitive disorders; and dyskinetic disorders
  • the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating schizophrenia or impairment of cognition.
  • the present invention provides a method of treating schizophrenia or impairment of cognition in a human, comprising administering an therapeutically effective amount of a compound of the present invention, alone or combined with a pharmaceutically acceptable carrier, dilutent or excipient.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone, talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, trihexyphenidyl), antihistamines (such as diphenhydramine), dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine,galantamine).
  • antipsychotics such as olanzapine, risperidone, clozapine, ziprazidone, talnetant
  • drugs for extrapyramidal side effects for example anticholinergics
  • the compounds of the invention may be used in combination with antidepressants to treat depression and mood disorders.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat bipolar disease: i) mood stabilisers; ii) antipsychotics; iii) antidepressants.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat anxiety disorders: i) anxiolytics; ii) antidepressants.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy, for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; ii) drugs for treating nicotine addition, for example bupropion.
  • nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches
  • drugs for treating nicotine addition for example bupropion.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; iii) Opioid receptor antagonists for example naltrexone.
  • NMDA receptor antagonists for example acamprosate
  • GABA receptor agonists for example tetrabamate
  • Opioid receptor antagonists for example naltrexone.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; Ni) vasodilatory antihypertensives for example lofexidine.
  • opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine
  • opioid receptor antagonists for example naltrexone
  • vasodilatory antihypertensives for example lofexidine.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate, chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon
  • barbiturates for
  • the compounds of the invention may be used in combination with one or more of the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; v) premenstrual agents for example pyridoxine and progesterones.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; vii) premenstrual agents.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; iv) stimulants for example methylphenidate, amphetamine formulations, pemoline.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations, pemoline; ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations, pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of the invention may be used in combination with one or more of the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; iv) anxiolytics.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine; vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil, sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion
  • the compounds of the invention may be used in combination with one or more of the following agents to treat female sexual dysfunction: i) the same agents specified for male sexual dysfunction, ii) an estrogen agonist such as estradiol.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, ziprazidone and talnetant).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperi
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, parox
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration to mammals including humans.
  • the compositions may be formulated for administration by any route.
  • the compositions may be formulated for oral, topical, or parenteral administration, and may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water.
  • a sterile vehicle for example water.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • Agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • treatment includes prophylaxis as well as alleviation of established symptoms.
  • the mammal to be treated is a human.
  • NMR spectra were obtained at 298K, 303.2K or 300K, at the frequency stated using either a BrukerTM DPX400 or AV400 machine and run as a dilute solution of CDCI 3 unless otherwise stated. All NMR spectra were referenced to tetramethylsilane (TMS ⁇ H 0, ⁇ c 0).
  • Aqueous solvent 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.
  • Aqueous solvent Water + 0.05% Formic Acid
  • the generic method used has a 2 minute runtime.
  • the above method has a flow rate of 1 ml/min.
  • the UV detection range is from 220 to 330nm
  • Stationary phase particle size 5 ⁇ m.
  • Methods There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.
  • Aqueous solvent 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.
  • UPLC/MS conditions for Example 10 AcquityTM UPLC system coupled with a ZQ single quadrupole mass spectrometer (Waters - Micromass); operated in negative electrospray ionisation (ES-) mode.
  • a reaction mixture of ⁇ /-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (5g, 15.7mmol), bis(pinacolato)diboron (4.4g, 17.3mmol), potassium acetate (4.62g, 47.1 mmol) and PdCI 2 (dppf) (642mg) in DMSO (100ml) was heated at 9O 0 C, under an atmosphere of argon, for 24 hours. The mixture was allowed to cool before being partitioned between ethyl acetate and water.
  • a reaction mixture of ⁇ /-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (100mg, 0.31 mmol, Description 1 ), 2-hydroxypyridine (31 mg, 0.32mmol), caesium carbonate (308mg, 0.94mmol), copper(l) iodide (66mg, 0.35mmol) and N, N- dimethylglycine (39mg, 0.38mmol) in DMSO (1.5ml) was heated in a microwave at 19O 0 C for 30 minutes. The mixture was then partitioned between dichloromethane and water, and the organic solution was dried and evaporated under reduced pressure to yield the crude product.
  • the crude product was purified using MDAP.
  • the resulting solution was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane.
  • the organic solution was dried (MgSO 4 ) and evaporated under reduced pressure to obtain the title compound as a white solid (40mg, 38%).
  • Example 7 ⁇ /- ⁇ (2S)-5-[3-(4-morpholinylmethyl)phenyl]-2,3-dihydro-1H-inden-2-yl ⁇ -2- propanesulfonamide
  • Example 8 ⁇ /-[(2S)-5-(2,3-dihydrothieno[3,4-fe][1 ,4]dioxin-5-yl)-2,3-dihydro-1H-inden- 2-yl]-2-propanesulfonamide
  • a reaction mixture of ⁇ /-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100mg, 0.31 mmol, Description 1 ), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3- dihydrothieno[3,4-fe][1 ,4]dioxin (102mg, 0.38mmol), tetrakis(triphenylphosphine)palladium(0) (3.6mg, 1 mol%) and sodium carbonate (67mg, 0.63mmol) in a 3:1 mixture of dioxane and water (2.0ml) was heated at 9O 0 C, under an atmosphere of argon, for 16 hours with stirring.
  • the mixture was allowed to cool before being partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution.
  • the organic solution was dried (MgSO 4 ) and evaporated under reduced pressure to yield the crude product.
  • This crude product was purified using MDAP.
  • the resulting solution was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane.
  • the organic solution was dried (MgSO 4 ) and evaporated under reduced pressure to obtain the title compound as a pale yellow solid (53mg, 45%).
  • the ability of the compounds of the invention to potentiate AMPA may be determined by the assays below.
  • the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s).
  • DMSO dimethylsulfoxide
  • DMSO dimethylsulfoxide
  • a Biomek FX Biomek FX
  • An agonist stimulus (glutamate) plate was prepared by dissolving sodium glutamate in water to give a concentration of 100 mM.
  • This solution was diluted with buffer to give a final concentration of 500 ⁇ M and dispensed into another 384-well plate (50 ⁇ l_/well) using a Multidrop (Thermolabsystems).
  • the cell plate was then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)].
  • a baseline fluorescence reading was taken over a 10 to 240 second period, and then 10 ⁇ L from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 ⁇ M to 10 pM) was added (to give a final concentration in the range
  • DMSO dimethylsulfoxide
  • the cell plate was then transferred into a fluorescence imaging plate based reader
  • a baseline fluorescence reading was taken over a 5 to 10 second period, and then 10 ⁇ L of 500 ⁇ M glutamate solution was added (to give a final concentration of 100 ⁇ M). The fluorescence was then read over a 4-5 minute period.
  • the activities of the compounds of the invention and reference compounds were determined by measuring peak fluorescence after the last addition. The activity was also expressed relative to the fluorescence increase induced by 150 ⁇ M cyclothiazide at their maximum response.
  • the assays described above are all believed to have an effective limit of detection of a pEC 50 in the region of 3.5-4.0 due to the limitations of compound solubility.
  • the pEC 50 result is generally considered to be accurate +/- 0.3.
  • Example compounds were screened more than once using at least one of the assays described above. Each compound gave a pEC 5 o of on average equal to or greater than 4.0 and/or demonstrated an activity of on average at least 10% that of the reference compound (cyclothiazide or ⁇ /-[(2/?)-2-(4'-cyano-4-biphenylyl)propyl]-2- propanesulfonamide, each at their maximal response).
  • the ability of the compounds of the invention to potentiate AMPA-subtype glutamate receptor-mediated response may also be determined by measuring AMPA-evoked current recorded from rat cultured hippocampal neurons.
  • the extracellular recording solution contains: 145 mM NaCI, 2.5 mM KCI, 1.2 mM MgCI 2 , 1.5 mM CaCI 2 , 10 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mM D-glucose, pH 7.3 with NaOH.
  • the intracellular solution contained: 80 mM CsCI, 80 mM CsF, 10 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid
  • HEPES ethylene glycol-bis(g-aminoethylether)-N,N,N',N,-tetra-acetic acid
  • EGTA ethylene glycol-bis(g-aminoethylether)-N,N,N',N,-tetra-acetic acid
  • MgATP 14 mM MgATP
  • DiTris Creatine Phosphate 50 U/ml Creatine Phosphokinase pH 7.3 with CsOH.
  • Recording electrodes were prepared from glass capillary tubes (Clark Electromedical GC120-F10) pulled into two equal lengths using a Zeitz Instruments DMZ Universal Puller, program 09, resulting in electrodes with a resistance of approximately 3-6 MOhms when measured in extracellular solution. Electrodes were back filled with internal recording solution.
  • Positive pressure was applied to the electrode to prevent mixture of internal and external solutions and to assist in formation of high resistance seal when the electrode makes contact with the cell membrane.
  • Glass coverslip fragment bearing rat cultured hippocampal neurons, was placed in the recording chamber positioned on the stage of an inverted microscope. A tube at the edge of the chamber was used to apply extracellular solution to the bath.
  • Rapid solution exchange used a fast step perfusion system (Biologic RSC160). Two outlet tubes attached together along their length were positioned close to a chosen cell so that the outflow from only one tube can pass directly over the cell surface. A motorized stepper could re-position the tubes such that the outflow from the second outlet tube flows over the cell allowing solution exchange at the cell membrane surface to occur within 10-20 ms. Excess bath solution was removed via a tube positioned at the edge of the chamber connected to a vacuum line.
  • a prospective cell was positioned in the centre of the microscope field of view.
  • Recording electrode was positioned directly above the cell membrane surface. Using fine manipulator control (Luigs and Neumann, SM-6) the electrode was lowered, while monitoring the change in electrode resistance during delivery of a 5 mV depolarizing pulse, until a high resistance seal (gigaseal) was achieved. Whole cell configuration was achieved by removing by suction a small fragment of cell membrane immediately beneath the recording electrode tip. The cell membrane potential was held at -70 mV (voltage-clamped) via the electrode (Axopatch 200B Integrating patch clamp amplifier, pClamp software, Axon Instruments). Test solutions were applied using the fast application system using the following protocol and changes in inward current are recorded and stored for off-line analysis.
  • the activity of a compound of the invention was determined by measuring the area under the curve (during 2 s period of application) for the 30 ⁇ M AMPA response in the presence of the compound of the invention and expressing it as % of potentiation of the 30 ⁇ M AMPA alone response (30 ⁇ M AMPA in the absence of the compound of the invention).
  • Examples 1 and 6 were tested in this assay.
  • the mean responses at 1OnM was respectively 135% and 129% increase of response of 30 ⁇ M AMPA alone, and at 10 ⁇ M was respectively 199% and 273% increase of response of 30 ⁇ M AMPA alone.
  • Examples 1 and 6 were tested in this assay.
  • the mean responses at 10OnM were respectively 109% and 191% potentiation of the 1 mM glutamate challenge alone, and mean reponses at 10 ⁇ M were respectively 319% and 1761 % potentiation of the 1 mM glutamate challenge alone.

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Abstract

La présente invention concerne un composé de formule (I) ou un sel de celui-ci : dans laquelle R est défini comme dans la description. La présente invention concerne en outre des procédés de préparation, des compositions pharmaceutiques, et leurs utilisations en tant que médicament, par exemple dans le traitement d’une maladie ou d’une condition médiée par une réduction ou un déséquilibre de la fonction des récepteurs du glutamate, comme dans la schizophrénie ou un trouble cognitif.
PCT/EP2009/066476 2008-12-09 2009-12-07 Composés de potentialisation du récepteur ampa et leurs utilisations en médecine WO2010066658A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013513628A (ja) * 2009-12-14 2013-04-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング スフィンゴシンキナーゼの阻害薬
WO2016176457A1 (fr) * 2015-04-29 2016-11-03 Janssen Pharmaceutica Nv Imidazopyrazines et pyrazolopyrimidines et leur utilisation comme modulateurs des récepteurs ampa
EP3008167A4 (fr) * 2013-06-13 2017-06-07 VeroScience LLC Compositions et méthodes pour le traitement des troubles métaboliques
JP2019536760A (ja) * 2016-10-26 2019-12-19 ヤンセン ファーマシューティカ エヌ．ベー． 縮合二環ピリジン化合物、及びａｍｐａ受容体調節因子としてのそれらの使用
US10604484B2 (en) 2015-04-29 2020-03-31 Janssen Pharmaceutica Nv Indolone compounds and their use as AMPA receptor modulators
US10611730B2 (en) 2015-04-29 2020-04-07 Janssen Pharmaceutica Nv Benzimidazolone and benzothiazolone compounds and their use as AMPA receptor modulators
US11312712B2 (en) 2015-04-29 2022-04-26 Janssen Pharmaceutica Nv Azabenzimidazoles and their use as AMPA receptor modulators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015828A1 (fr) * 2004-08-09 2006-02-16 Glaxo Group Limited Composés potentialisateurs de récepteur de glutamate et utilisations de ceux-ci en médecine
WO2006015829A1 (fr) * 2004-08-09 2006-02-16 Glaxo Group Limited Composés potentialisateurs de récepteur de glutamate et utilisations de ceux-ci en médecine
WO2008113795A1 (fr) * 2007-03-20 2008-09-25 Glaxo Group Limited Composés potentialisant le récepteur ampa et leurs utilisations en médecine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015828A1 (fr) * 2004-08-09 2006-02-16 Glaxo Group Limited Composés potentialisateurs de récepteur de glutamate et utilisations de ceux-ci en médecine
WO2006015829A1 (fr) * 2004-08-09 2006-02-16 Glaxo Group Limited Composés potentialisateurs de récepteur de glutamate et utilisations de ceux-ci en médecine
WO2008113795A1 (fr) * 2007-03-20 2008-09-25 Glaxo Group Limited Composés potentialisant le récepteur ampa et leurs utilisations en médecine

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013513628A (ja) * 2009-12-14 2013-04-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング スフィンゴシンキナーゼの阻害薬
EP3008167A4 (fr) * 2013-06-13 2017-06-07 VeroScience LLC Compositions et méthodes pour le traitement des troubles métaboliques
WO2016176457A1 (fr) * 2015-04-29 2016-11-03 Janssen Pharmaceutica Nv Imidazopyrazines et pyrazolopyrimidines et leur utilisation comme modulateurs des récepteurs ampa
JP2018514537A (ja) * 2015-04-29 2018-06-07 ヤンセン ファーマシューティカ エヌ．ベー． イミダゾピラジン及びピラゾロピリミジン、並びにａｍｐａ受容体調節物質としてのこれらの使用
US10513523B2 (en) 2015-04-29 2019-12-24 Janssen Pharmaceutica Nv Imidazopyrazines and pyrazolopyrimidines and their use as AMPA receptor modulators
US10604484B2 (en) 2015-04-29 2020-03-31 Janssen Pharmaceutica Nv Indolone compounds and their use as AMPA receptor modulators
US10611730B2 (en) 2015-04-29 2020-04-07 Janssen Pharmaceutica Nv Benzimidazolone and benzothiazolone compounds and their use as AMPA receptor modulators
US11312712B2 (en) 2015-04-29 2022-04-26 Janssen Pharmaceutica Nv Azabenzimidazoles and their use as AMPA receptor modulators
JP2019536760A (ja) * 2016-10-26 2019-12-19 ヤンセン ファーマシューティカ エヌ．ベー． 縮合二環ピリジン化合物、及びａｍｐａ受容体調節因子としてのそれらの使用

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