WO2009092713A1 - Composés de potentialisation du récepteur ampa et ses applications médicales - Google Patents

Composés de potentialisation du récepteur ampa et ses applications médicales Download PDF

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WO2009092713A1
WO2009092713A1 PCT/EP2009/050608 EP2009050608W WO2009092713A1 WO 2009092713 A1 WO2009092713 A1 WO 2009092713A1 EP 2009050608 W EP2009050608 W EP 2009050608W WO 2009092713 A1 WO2009092713 A1 WO 2009092713A1
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disorder
compound
compounds
haloc
disease
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PCT/EP2009/050608
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English (en)
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Kevin Michael Thewlis
Simon E. Ward
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Glaxo Group Limited
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Publication of WO2009092713A1 publication Critical patent/WO2009092713A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • This invention relates to potentiation of the AMPA receptor by novel N-(2-methyl-phenyl- cyclopentyl)sulphonamide derivatives.
  • 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 1 1 : 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 D and Traynelis S (1999) Pharmacol. Rev. 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 (GluR1-4) (for review see Bettler B and Muller C (1995) Neuropharmacology 34: 123-139.). 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.
  • 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 ).
  • AMPAR depolarization removes voltage dependent Mg 2+ block of NMDA receptors which in turn leads to NMDA receptor activation, an integral stage in the induction of Long Term
  • LTP 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).
  • AMPA receptor positive allosteric modulators Compounds which act as AMPA receptor positive allosteric modulators are known, for example in international patent application WO2006/015828.
  • the invention provides a compound of formula (I), or a salt thereof:
  • R ⁇ is C-
  • RiO 1 which may be the same or different, are selected from hydrogen, halogen, C- ⁇ galkyl, haloC- ⁇ galkyl and C-
  • R 9 is halo; or phenyl or aromatic heterocyclyl, either of which is optionally substituted by one or more groups independently selected from the group consisting of: halogen, haloC- ⁇ galkyl, C-
  • R 9a and each R 9c which may be the same or different, is hydrogen or C-
  • R 9b is C-
  • R 9d is C-
  • R 9a and R 9b , R 9a and R 9c , or R 9a and R 9d together with the interconnecting atoms, may form a 5- or 6-membered ring; and
  • q is O, 1 , or 2.
  • any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
  • any alkenyl group may be straight or branched and is of 2 to 6 carbon atoms and may contain up to 3 double bonds which may be conjugated, for example vinyl, allyl and butadienyl.
  • Halo is fluoro, chloro, bromo or iodo.
  • halo is selected from fluoro and chloro.
  • aromatic heterocyclyl as used herein describes a carbocyclic group, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur and which contains at least one aromatic ring system.
  • the aromatic heterocyclyl group may, for example, be monocyclic or bicyclic. It may also be tricyclic.
  • a monocyclic aromatic heterocyclyl group may, for example, contain 5 to 7 ring atoms.
  • a bicyclic aromatic heterocyclyl group may, for example, contain 7 to 12 ring atoms. In the case of bicyclic aromatic heterocyclyl groups, one ring or both rings may be aromatic.
  • the one or more heteroatoms may be in the aromatic ring, in the non-aromatic ring or in both rings.
  • a tricyclic aromatic heterocyclyl group may, for example, contain 10 to 14 ring atoms.
  • one, two or three rings may be aromatic.
  • the one or more heteroatoms may be in an aromatic ring, or in a non-aromatic ring or in both types of rings.
  • Examples of monocyclic aromatic heterocyclyl groups are furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazinyl, oxazepinyl, thiazepinyl, and diazepinyl.
  • heterocyclyl includes fused bicyclic heterocyclyl groups in which both rings are aromatic, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl, benzodioxanyl and isoindolyl.
  • bicyclic aromatic heterocyclyl groups in which only one ring is aromatic include phenyl fused with a diazabicycloalkane group, for example ethanoquinoxalinyl.
  • tricyclic aromatic heterocyclyl groups include carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, thianthreninyl, anthraceninyl, acenaphthyleninyl, fluoreninyl and phenanthreninyl and the like.
  • R ⁇ is C-
  • Ri O 1 vvhich may be the same or different, are hydrogen, halogen or C- ⁇ g alkyl.
  • each R ⁇ which may be the same or different, is or C-
  • p is 0.
  • R 9 is phenyl or aromatic heterocyclyl, optionally substituted with one or more groups independently selected from the group consisting of: halogen, cyano, -(CH 2 ) q NR9as0 2 R 9b and -(CH 2 ) q SO 2 R 9b ; where R 9a and each R 9C 1 which may be the same or different, is hydrogen or C-
  • R 9 is a phenyl, optionally substituted with one or more groups independently selected from the group consisting of: cyano, -(CH 2 )qNR 9a SO 2 R 9b ,
  • R 9a and each R 9c which may be the same or different, is hydrogen or C- ⁇ galkyl; R9° j s C-
  • R 9 is a pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, imidazolyl, pyrroyl, oxazolyl or pyrazolyl, optionally substituted with one or more groups independently selected from the group consisting of: cyano or halogen.
  • R 9 is iodo or bromo.
  • compounds of formula (I) possess at least two chiral centres, namely the attachment points of the sulphonamide and the phenyl ring on the cyclopentyl ring.
  • the compounds may exist in four stereoisomers - a pair of diastereomers (cis and trans), each comprising a pair of enantiomers with respect to the chiral centres in the cyclopentane.
  • the level of biological activity may vary between the individual diastereoisomers of a given molecule. It is intended that the scope of the invention includes all individual stereoisomers (diastereoisomers and enantiomers) and all mixtures thereof, including but not limited to racemic mixtures, which demonstrate appropriate biological activity with reference to the procedures described herein.
  • the sulphonamide and phenyl substituents on the cyclopentyl ring are in a trans arrangement relative to each other.
  • enantiomers of various of the example compounds have been prepared. As at the date of filing, the absolute stereochemistry of the individual isomers has not been established. The individual isomers are identified by chiral HLPC retention times or by the chiral HPLC retention times of the intermediate starting materials from which they were prepared.
  • a compound that has been prepared in racemic form has the suffix "racemic”
  • a compound that has been prepared in chiral form has the suffix "enantiomer 1" or "enantiomer 2".
  • a compound of the invention in chiral form has at least 80% e.e.
  • a compound of the invention in chiral form has at least 90% e.e., for example at least 95% e.e.
  • the isomers correspond to at least 98% e.e, for example at least 99% e.e.
  • the compound according to the first aspect is of formula (Ia) or a salt thereof:
  • R 1 is C1-6 alkyl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 10 are hydrogen, halogen, or C-
  • R 9 a and each R 9 C which may be the same or different, is hydrogen or C-
  • R9d is C-
  • R 9a and R 9 ⁇ together with the interconnecting atoms, may form a 5- or 6- membered ring; and q is 0, 1 , or 2.
  • 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.
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • an appropriate compound of formula (I) may be in the form of a salt.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.
  • Other salt forms that are not pharmaceutically acceptable for example a salt that is useful as an intermediate, also form part of the present invention.
  • crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
  • solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of solvent (including water) where non- stoichiometric solvates (hydrates in the case of water) may be produced by processes such as lyophilisation).
  • pro-drugs examples include Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in "Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.
  • Preferred prodrugs for compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • compounds, their pharmaceutically acceptable salts, their solvates and prodrugs, defined in any aspect of the invention are referred to as "compounds of the invention”.
  • the compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention.
  • the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially 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%, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.
  • Compounds of general formula (I) may be prepared by coupling compounds of formula (II) where X is a leaving group such as halogen (preferably bromine) with boronic acid derivatives of formula (III) according to reaction scheme 1.
  • Typical coupling conditions comprise heating a compound of formula (II), a compound of formula (III), a base (such as cesium carbonate), triphenylphosphine, and palladium (II) acetate in a mixture of 1 ,4- dioxan and water at about 80 degC.
  • Compounds of formula (IV) may be prepared from compounds of formula (V) according to reaction scheme 3.
  • Typical reaction conditions are adding sulfonyl chloride (Vl) to an ice- cooled mixture of (V) and a base (such as diisopropylamine) in a suitable solvent (such as dichloromethane) and then warming the mixture gradually to room temperature.
  • 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 may be administered in combination with other therapeutic agents, for example an antipsychotic (such as olanzapine, risperidone, clozapine, ziprazidone and talnetant).
  • an antipsychotic such as olanzapine, risperidone, clozapine, ziprazidone and talnetant.
  • 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 by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • compositions may be formulated for administration by any route.
  • the compositions 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 is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, for example from 10-60% by weight, of the active material, depending on the method of administration.
  • each unit may, for example contain from 0.1 to 20 mg of the active ingredient.
  • such a unit may contain from 1 to 10 mg.
  • the dosage as employed for adult human treatment may, for example, range from 2 to 50 mg per day, for instance 5 to 20 mg per day depending on the route and frequency of administration (though in some instances, a dosage of 50mg to 100mg per day may be appropriate). Based on a 75kg individual, such a dosage corresponds to 0.027 to 0.667 mg/kg per day. Suitably the dosage is from 0.05 to 0.3 mg/kg per day.
  • 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. It will be appreciated that the invention includes the following further aspects.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent; ii) the use of a compound of formula (I) or a pharmaceutically acceptable salt in the manufacture of a medicament for treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iii) a compound of formula (I) or a pharmaceutically acceptable salt for use in treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iv) a compound of formula (I) or a pharmaceutically acceptable salt for use as a medicament; and v) a method of treatment or prevention of a disease or condition caused 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 pharmaceutically acceptable salt.
  • the invention also provides a combination product of a compound of formula (I) or a pharmaceutically acceptable salt with an antipsychotic.
  • the invention provides:
  • a pharmaceutical composition comprising such a combination product and at least one pharmaceutically acceptable carrier or diluent; ii) the use of such a combination in the manufacture of a medicament for treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iii) such a combination product for use in treating or preventing a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iv) such a combination product for use as a medicament; v) a method of treatment or prevention of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of such a combination product.
  • relevant diseases or conditions are: 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); 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 and
  • Relevant diseases also include some forms of epilepsy.
  • the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.
  • the term "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 (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • 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 (311 ); 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 Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23):
  • Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):
  • 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 compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone and talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • antipsychotics such as olanzapine, risperidone, clozapine, ziprazidone and talnetant
  • drugs for extrapyramidal side effects for example anticholinergics
  • the compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • the compounds of the invention may be used in combination with 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; and ii) bupropion.
  • the compounds of the invention may be used in combination with 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; and 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 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; and 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 the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon
  • barbiturates for example
  • the compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations and pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and 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 and vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil and sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion
  • alpha adrenoceptor antagonists
  • the compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition 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.
  • Mass directed preparative HPLC was carried out using a 19 mm x 100 mm or 30 mm x 100 mm, 5 ⁇ m, reversed phase Waters Atlantis column as the stationary phase and a gradient from water + 0.1% formic acid to acetonitrile + 0.1% formic acid as the eluent.
  • the eluent was monitored by a Waters 996 photodiode array and a Micromass ZQ mass spectrometer. All yields reported are of purified, isolated material.
  • NMR spectra were obtained at 298K, at the frequency stated using either a BrukerTM DPX400 or an Oxford InstrumentsTM 250 MHz machine and run as a dilute solution of CDCI 3 unless otherwise stated.
  • LC/MS (Liquid Chromatography / Mass Spectrometry) data were obtained using an AgilentTM 1100 HPLC system with a 4.6 mm x 50 mm, 3 ⁇ m, reversed phase Waters AtlantisTM column as the stationary phase.
  • a gradient elution from 97% water + 0.05% formic acid / 3% acetonitrile + 0.05% formic acid to 97% acetonitrile + 0.05% formic acid over 3 minutes plus a further minute continuing this mixture at a flow rate of 1.5 mL / min was used as the eluent. Retention time is reported as minutes (with percentage intensity for DA / ELSD for the relevant peak).
  • Spectroscopic monitoring was performed using an AgilentTM 1100 diode array (DA) detector or a SedexTM evaporative light scattering detector (ELSD). Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).
  • DA AgilentTM 1100 diode array
  • ELSD evaporative light scattering detector
  • the title compound was prepared from c/s- ⁇ /- ⁇ -2-[(4-iodophenyl)methyl]cyclopentyl ⁇ -2- propanesulfonamide as follows.
  • the reaction mixture was allowed to cool to room temperature and partitioned between ethyl acetate (6ml) and water (8ml). The organic layer was removed, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified using mass directed auto-prep to give the title compound as an oil (43mg, 56%).
  • Cis-N- ⁇ -2 [ ⁇ '-fluoro ⁇ -biphenylyljmethyllcyclopentyl ⁇ -propanesulfonamide
  • the reaction mixture was allowed to cool to room temperature and partitioned between ethyl acetate (6ml) and water (8ml). The organic layer was removed, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified using mass directed auto-prep to give the title compound as an oil (20mg, 31 %).
  • the ability of the compounds of the invention to potentiate AMPA receptor-mediated response were determined a) by using fluorescent calcium-indicator dyes such as FLUO4 and b) by measuring glutamate-evoked current recorded from human GluR2 flip unedited HEK293 cells.
  • tissue culture medium in the wells were discarded and the wells each washed three times with standard buffer (80 ⁇ l_) for the stable cell line (145 mM NaCI, 5 mM KCI, 1 mM MgCI 2 , 2 mM CaCI 2 , 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) or with a Na-free buffer for the transient transfected cells (145 mM N-methyl-glucamine instead of NaCI).
  • standard buffer 80 ⁇ l_
  • the plates were then incubated for 60 minutes in the dark with 2 ⁇ M FLUO4-AM dye (20 ⁇ l_) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which was then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well was washed three times with buffer (80 ⁇ l_) (30 ⁇ l_ of buffer remained in each well after washing).
  • DMSO dimethylsulfoxide
  • 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 30 ⁇ M to 3 pM).
  • the fluorescence was read over 5 minute period.
  • 500 ⁇ M glutamate solution (10 ⁇ l_) was added (to give a final concentration of 100 ⁇ M).
  • the fluoresecence was then read over a 4 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 cyclothiazide at their maximum response (i.e. greater than 30 ⁇ M).
  • the assay described above was 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 was generally considered to be accurate +/- 0.3. Accordingly, a compound exhibiting a pEC 5 o value within this range from such an assay may indeed have a reasonable affinity for the receptor, but equally it may also have a lower affinity, including a considerably lower affinity.
  • This assay involved the electrophysiological characterisation of AMPA receptor positive modulators using rat cultured hippocampal neurons.
  • the extracellular recording solution contained: 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), 10 mM ethylene glycol-bis(g- aminoethylether)-N,N,N',N,-tetra-acetic acid (EGTA), 14 mM MgATP, 14 mM 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 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 flowed 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.
  • fine manipulator control Liigs 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 were 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).

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Abstract

La présente invention concerne de nouveaux dérivés de N-(2-méthyl-phényl-cyclopentyl)sulfonamide de formule (I) et leurs sels, dans laquelle : R1, R2, R3, R4, R5, R6, R7, R8, p, R9 et R10 sont tels que définis dans la description. L'invention concerne également l'utilisation des dérivés dans le traitement de maladies et conditions liées à la potentialisation du récepteur du glutamate, des compositions contenant les dérivés et leurs procédés de préparation.
PCT/EP2009/050608 2008-01-23 2009-01-21 Composés de potentialisation du récepteur ampa et ses applications médicales WO2009092713A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010150192A1 (fr) * 2009-06-26 2010-12-29 Pfizer Inc. Sulfonamides hétérocycliques, utilisations et compositions pharmaceutiques associées
WO2012137982A2 (fr) 2011-04-05 2012-10-11 Takeda Pharmaceutical Company Limited Dérivé de sulfonamide et son utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6639107B1 (en) * 1999-12-08 2003-10-28 Eli Lilly And Company Cyclopentyl sulfonamide derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6639107B1 (en) * 1999-12-08 2003-10-28 Eli Lilly And Company Cyclopentyl sulfonamide derivatives

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010150192A1 (fr) * 2009-06-26 2010-12-29 Pfizer Inc. Sulfonamides hétérocycliques, utilisations et compositions pharmaceutiques associées
US8278457B2 (en) 2009-06-26 2012-10-02 Pfizer Inc. Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof
US8686043B2 (en) 2009-06-26 2014-04-01 Pfizer Inc. Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof
EA021057B1 (ru) * 2009-06-26 2015-03-31 Пфайзер Инк. Гетероциклические сульфонамиды, их применения и фармацевтические композиции
WO2012137982A2 (fr) 2011-04-05 2012-10-11 Takeda Pharmaceutical Company Limited Dérivé de sulfonamide et son utilisation
JP2014523851A (ja) * 2011-04-05 2014-09-18 武田薬品工業株式会社 スルホンアミド誘導体およびその用途
US9527807B2 (en) 2011-04-05 2016-12-27 Takeda Pharmaceutical Company Limited Sulfonamide derivative and use thereof

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