WO2014001280A1 - Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa - Google Patents

Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa Download PDF

Info

Publication number
WO2014001280A1
WO2014001280A1 PCT/EP2013/063191 EP2013063191W WO2014001280A1 WO 2014001280 A1 WO2014001280 A1 WO 2014001280A1 EP 2013063191 W EP2013063191 W EP 2013063191W WO 2014001280 A1 WO2014001280 A1 WO 2014001280A1
Authority
WO
WIPO (PCT)
Prior art keywords
pain
disorder
disorders
disease
condition
Prior art date
Application number
PCT/EP2013/063191
Other languages
English (en)
Inventor
Janus Schreiber LARSEN
Magnus Gustafsson
Carsten Jessen
Original Assignee
Aniona Aps
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aniona Aps filed Critical Aniona Aps
Publication of WO2014001280A1 publication Critical patent/WO2014001280A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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

Definitions

  • This invention relates to a novel phenyl triazole derivative, pharmaceutical compositions containing this compound, and methods of treatment therewith.
  • the compound of the invention is in particular considered useful for the treatment of central nervous system diseases and disorders which are responsive to modulation of GABA A receptors containing the a5 subunit.
  • the GABA A receptor protein complex is the molecular target of a number of ligands, including the benzodiazepine class of tranquilizer drugs. Multiple isoforms of the GABAA receptor exist; each receptor is a pentameric complex comprising subunits drawn from ⁇ - ⁇ -6 , ⁇ - ⁇ -3, ⁇ - ⁇ -3, ⁇ , ⁇ , and ⁇ subunit isoforms.
  • the classical benzodiazepines show no subtype selectivity.
  • benzodiazepanes (such as sedation, dependency and cognitive impairment) has to do with the a1 subunit of the GABA A receptors.
  • the GABA A a5 subunit represents a therapeutic target for treatment of various diseases and disorders of the central nervous system
  • literature has establish a nexus between the GABA A a5 subunit as therapeutic target, and various acute and chronic neurological discorders, chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis, dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression,
  • neuropsychiatric conditions psychosis, attention-deficit hyperactivity disorder, neuropathic pain, stroke, attentional disorders, eating disorders, anorexia, anorexia 5 nervosa, cachexia, weight loss, muscle atrophy, pain conditions, chronic pain, nociceptive pain, post-operative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, ocular pain, pain due to inflammation, pain due to bone fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, post-stroke pain, post-ischemia pain,
  • neuropathic pain phantom limb pain, visceral pain and cutaneous pain
  • compounds capable of modulating GABA A receptors containing the a5 subunit are in particular expected to be useful candidates for the treatment of i.a. cognitive disorders, Alzheimer's disease, schizophrenia, positive, negative and/or cognitive
  • Isoxazole derivatives capable of modulating the GABA A receptor complex are known from e.g. WO 2007/039389, WO 2007/042420, WO 2007/054444, WO 2007/071598, WO 2007/074078, WO 2007/074089, WO 2007/137954, WO
  • the invention provides a phenyl triazole derivative of the following structure (I):
  • the invention provides a pharmaceutical composition, comprising a therapeutically effective amount of the phenyl triazole derivative of formula (I) of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient or diluent.
  • the invention relates to the use of the phenyl triazole derivative of formula (I) of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to
  • the invention provides a method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of GABA A receptors containing the a5 subunit, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of the phenyl triazole derivative of the invention, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a phenyl triazole derivative of formula (I) of the following structure:
  • the phenyl triazole derivative of formula (I) of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts of the compound of the invention.
  • Examples of pharmaceutically acceptable salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the fumarate derived from fumaric
  • the phenyl triazole derivative of formula (I) of the invention may exist in the form of a polymorph, or the compound may be provided in dissoluble or indissoluble forms together with a pharmaceutically acceptable solvent such as water, ethanol, and the like.
  • Dissoluble forms may also include hydrated forms such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate, and the like. In general, the dissoluble forms are considered equivalent to indissoluble forms for the purposes of this invention.
  • the phenyl triazole derivative of formula (I) of the invention may be used in its labelled or unlabelled form.
  • a labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The labelling will allow easy quantitative detection of said compound.
  • the labelled compounds of the invention may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo receptor imaging.
  • the labelled isomer of the invention preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this invention the radionuclide is preferably selected from 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 131 l, 125 l, 123 l and 18 F.
  • the physical method for detecting the labelled isomer of the present invention may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance
  • MRS Magnetic Resonance Imaging
  • CAT Computed Axial X-ray Tomography
  • the phenyl triazole derivative of formula (I) of the invention may be provided in the form of their deuterated analogs.
  • Deuterium forms bonds with carbon that vibrate at a lower frequency and are thus stronger than C-H bonds. Therefore "heavy hydrogen" (deuterium) versions of drugs may be more stable towards degradation and last longer in the organism.
  • the phenyl triazole derivative of formula (I) of the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples.
  • the starting materials for the process described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
  • the end product of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation,
  • the phenyl triazole derivative of formula (I) of the invention are capable of modulating GABA A receptors containing the a5 subunit.
  • the phenyl triazole derivative of formula (I) of the invention is considered useful for the treatment, prevention or alleviation of a disease, disorder or condition responsive to modulation of GABA A receptors containing the a5 subunit, in particular in the central nervous system.
  • the phenyl t azole derivative of formula (I) of the invention is considered useful for the treatment, prevention or alleviation of a disease, disorder or condition which is selected from the group of acute
  • neurological discorders chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorder, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive compulsive disorders, acute stress disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric conditions, psychosis, attention-deficit hyperactivity disorder, neuropathic pain, stroke, attentional disorders, and for use as cognitive enhancers.
  • ALS amyotrophic lateral sclerosis
  • the phenyl thazole derivative of formula (I) of the invention is considered useful for the treatment, prevention or alleviation of a disease, disorder or condition which is selected from the group of eating disorders, anorexia, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain
  • the phenyl thazole derivative of formula (I) of the invention is considered useful for the treatment, prevention or alleviation of a disease, disorder or condition selected from the group of cognitive disorders,
  • the phenyl triazole derivative of formula (I) of the invention is considered useful for the treatment, prevention or alleviation of a disease, disorder or condition selected from the group of Alzheimer's disease, schizophrenia and Down syndrome.
  • the phenyl triazole derivative of formula (I) of the invention is considered useful as a cognitive enhancer.
  • phenyl triazole derivative of formula (I) of the invention may be useful as a radioligand in assays for detecting compounds capable of modulating GABA A receptors containing the a5 subunit.
  • compositions are within the range of from about 0.1 to about 1000 mg API per day, more preferred of from about 10 to about 500 mg API per day, most preferred of from about 30 to about 100 mg API per day, dependent, however, upon the exact mode of administration, the form in which it is administered, the indication considered, the subject and in particular the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
  • the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the phenyl triazole derivative of formula (I) of the invention.
  • phenyl triazole derivative of formula (I) of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a
  • physiologically acceptable salt in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • the invention provides pharmaceutical compositions comprising the phenyl triazole derivative of formula (I) of the invention, or a pharmaceutically acceptable salt or derivative of formula (I) thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and/or prophylactic ingredients, known and used in the art.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, pulmonal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous,
  • intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration or those in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems.
  • sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compound of the invention, which matrices may be in form of shaped articles, e.g. films or microcapsules.
  • the phenyl triazole derivative of formula (I) of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
  • Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in
  • unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the phenyl triazole derivative of formula (I) of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, cellulose, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the
  • composition of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by
  • lyophilization from solution for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen-free water
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations intended for conversion shortly before use to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • preparations may comprise colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the compound of the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micron ization.
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the invention provides tablets or capsules for oral administration.
  • the invention provides liquids for intravenous administration and continuous infusion. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).
  • the dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
  • compositions containing of from about 0.1 to about 500 mg of active ingredient of formula (I) per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
  • the active ingredient of formula (I) may be administered in one or several doses per day. A satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 ⁇ g kg i.v. and 1 ⁇ g kg p.o.
  • the upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o.
  • Preferred ranges are from about 0.1 ⁇ g kg to about 10 mg/kg/day i.v., and from about 1 ⁇ g/kg to about 100 mg/kg/day p.o.
  • the invention provides a method for the treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to modulation of GABA A receptors containing the a5 subunit, and which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of the phenyl triazole derivative of formula (I) of the invention, or a pharmaceutically acceptable salt thereof.
  • suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
  • reaction mixture was slowly quenched with ice cold water (1000 ml) and the aqueous layer was extracted with ethyl acetate (5 X 1000 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude mass (50 g, 84.66% mass balance). It was purified by gravity column using 20% ethyl acetate in pet ether as an eluent to afford desired product 4-(2- Fluorophenyl)-1 -methyl-1 H-1 ,2,3-triazole-5-carbaldehyde (40 g, 67.72%) as reddish solid.
  • reaction mixture was quenched with NaHCO3 solution (40 ml) at 0°C, diluted with dichloromethane, washed with water (10 ml), brine (10 ml), dried over Na 2 SO and concentrated under reduced pressure to afford crude mass 3-Chloro-6-(4-difluoromethyl- imidazol-1 -yl)-pyridazine (0.43 g, 65%) and used directly.
  • reaction mixture was quenched with ice-water, extracted with ethylacetate (50 ml), washed with brine (10 ml), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford crude mass (0.7g, 97% mass balance). It was purified by silica gel (230-400 mesh) column chromatography using 70% ethylacetate in hexane as mobile phase to furnish desired compound (0.145 g, 20.25%) as off white solid.
  • the benzodiazepine modulator unit can selectively be labelled with the antagonist 3 H-flumazenil.
  • the pharmacology of the mutated o ⁇ 3*Y2s GABA a receptor is similar to that of the wild type receptor with respect 3 H-flumazenil binding.
  • GABAA O ⁇ 3*Y2S receptors (plasmid H46/E9/B10) are seeded in T175 polystyrene flasks or roller bottles (1700 cm 2 , Fisher Scientific CCI-431 191 ), and cultured (37°C, 5% CO 2 ) in Dulbecco's Modified Eagle Medium (DMEM) with GlutaMAXTM supplemented with 10% fetal bovine serum and one or both of the following antibiotics: hygromycin B (50 pg/ml; ⁇ 2 subunit) or G418 (0.5 mg/ml; a 5 subunit).
  • DMEM Dulbecco's Modified Eagle Medium
  • GlutaMAXTM supplemented with 10% fetal bovine serum and one or both of the following antibiotics: hygromycin B (50 pg/ml; ⁇ 2 subunit) or G418 (0.5 mg/ml; a 5 subunit).
  • the DMEM is removed and the cells are washed (10 ml for T175 flasks; 50 ml for roller bottles) once in Dulbecco's Phosphate Buffered Saline (DPBS).
  • DPBS Dulbecco's Phosphate Buffered Saline
  • the pellet is washed once in 15 ml Tris-citrate buffer (50 mM, pH 7.1 ) using an Ultra-Turrax homogenizer and centrifuged at 2°C for 10 min at 27,000 x g.
  • the washed pellet is re-suspended in 15 ml Tris-citrate buffer and frozen at -80°C until the day of the binding experiment.
  • the cell membrane preparation On the day of the experiment the cell membrane preparation is thawed and centrifuged at 2°C for 10 min at 27,000 x g. The pellet is re-suspended, using an Ultra-Turrax homogenizer in Tris-citrate buffer, to 15-50 g protein per assay and then used for binding assays.
  • test compounds All dilutions of test compounds and incubation of assay are performed in glass vials / 96-vial plates. Solutions of test compounds and 3 H-flumazenil are prepared 22x the desired final concentration. Compounds are dissolved in 100% DMSO (10 mM stock), diluted in 48% ethanol-water, and tested in triplicate in serial 1 :3 or 1 :10 dilutions. When screening large numbers of compounds only one concentration of each compound is tested in single wells. Reference compounds are not included routinely, but for each experiment performed total and nonspecific binding is compared to data obtained during validation of the assay.
  • Binding is either terminated by rapid filtration onto
  • the amount of radioactivity on the filters is determined by conventional liquid scintillation counting using a
  • Tri-CarbTM counter PerkinElmer Life and Analytical Sciences
  • Topcount counter PerkinElmer Life and Analytical Sciences
  • IC 50 the concentration ( ⁇ ) of the test compound which inhibits the specific binding of 3 H-flumazenil by 50%.
  • the IC50 value for a test compound is determined based on the equation:
  • n is set to 1 .
  • the IC50 value is calculated from the concentration response curves by the non-linear regression method using the curve-fitting program GraphPad Prism.
  • the Ki value for a test compound can be calculated from the IC50 value using the equation by Cheng and Prusoff:
  • compositions The phenyl t azole derivative of formula (I) of the invention may be put on any desirable form of composition, and may be dosed in any desired amount.
  • This example shows the preparation of a standard capsule formulation. Standard Capsule Formulation
  • Capsules containing 1 mg active pharmaceutical ingredient (API) of formula (I) per capsule are obtained using the following composition:
  • Figure 1 shows modulation of 0 ⁇ 272 GABA A receptor currents by the compound of formula (I) in Xenopus laevis oocytes.
  • Modulatory efficacy of compound (1 ) was determined by techniques similar to those described in Mirza et al. ⁇ J Pharmacol Exp Ther. 2008; 327:954-68).
  • oocytes were injected with cRNA for human GABA A receptor subunits ⁇ 5 , ⁇ 2 and ⁇ 2 in a 1 :1 :2 ratio and modulatory efficacy was evaluated by co-applications with a submaximal ECs-2o GABA concentration (0.5 ⁇ ) termed GABAcontrol.
  • the compound was tested in five concentrations (3.16, 0.316, 0.0316, 0.00316 and

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau dérivé de phényle triazole, des compositions pharmaceutiques contenant ce composé, et des méthodes de traitement associées. Le composé de l'invention est notamment considéré utile pour le traitement de maladies et troubles du système nerveux central, qui sont sensibles à la modulation des récepteurs GABAA contenant la sous-unité α5.
PCT/EP2013/063191 2012-06-26 2013-06-25 Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa WO2014001280A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201261664283P 2012-06-26 2012-06-26
DKPA201270366 2012-06-26
US61/664,283 2012-06-26
DKPA201270366 2012-06-26

Publications (1)

Publication Number Publication Date
WO2014001280A1 true WO2014001280A1 (fr) 2014-01-03

Family

ID=49782298

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/063191 WO2014001280A1 (fr) 2012-06-26 2013-06-25 Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa

Country Status (1)

Country Link
WO (1) WO2014001280A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021531291A (ja) * 2018-07-20 2021-11-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｇａｂａ受容体モジュレーターとしてのジフルオロメチル−フェニルトリアゾール
WO2021228795A1 (fr) 2020-05-13 2021-11-18 F. Hoffmann-La Roche Ag Nouveaux dérivés triazolyles utilisés en tant que gaba a alpha5 pam
EP3971179A1 (fr) * 2020-09-22 2022-03-23 Boehringer Ingelheim International GmbH Triazoles difluorométhyl-pyridin-2-yl
WO2023016521A1 (fr) * 2021-08-12 2023-02-16 上海赛默罗生物科技有限公司 Dérivé de triazole substitué, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039389A1 (fr) 2005-09-19 2007-04-12 F. Hoffmann-La Roche Ag Derives d'isoxazolo utilises en tant qu'agonistes inverses de gaba a $g(a)5
WO2007042420A1 (fr) 2005-10-11 2007-04-19 F. Hoffmann-La Roche Ag Derives d'isoxazole
WO2007054444A2 (fr) 2005-11-09 2007-05-18 F. Hoffmann-La Roche Ag Derives du 3-aryl-isoxazole-4-carbonyl-benzofurane
WO2007071598A1 (fr) 2005-12-23 2007-06-28 F. Hoffmann-La Roche Ag Derives d'aryl-isoxazolo-4-yl-oxadiazole
WO2007074078A2 (fr) 2005-12-27 2007-07-05 F. Hoffmann-La Roche Ag Derives aryl-isoxazol-4-yl-imidazo[1,5-a] pyridine
WO2007074089A1 (fr) 2005-12-27 2007-07-05 F. Hoffmann-La Roche Ag Derives aryl-isoxazol-4-yl-imidazo[1, 5-a]pyridine
WO2007137954A1 (fr) 2006-05-31 2007-12-06 F. Hoffmann-La Roche Ag Dérivés d'aryl-4-éthynyl-isoxazole
WO2008025539A1 (fr) 2006-08-29 2008-03-06 Phenex Pharmaceuticals Ag Composés de liaison au fxr hétérocycliques
WO2008025540A1 (fr) 2006-08-29 2008-03-06 Phenex Pharmaceuticals Ag Composés hétérocycliques se liant au fxr
WO2009000662A1 (fr) 2007-06-22 2008-12-31 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-imidazole
WO2009071464A1 (fr) 2007-12-04 2009-06-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazolo-pyrazine
WO2009071477A1 (fr) 2007-12-04 2009-06-11 F. Hoffmann-La Roche Ag Dérivés isoxazolo-pyridazine
WO2009071476A1 (fr) 2007-12-04 2009-06-11 F. Hoffmann-La Roche Ag Dérivés isoxazolo-pyridine
WO2009149795A2 (fr) 2008-05-26 2009-12-17 Phenex Pharmaceuticals Ag Composés de liaison à fxr substitués par cyclopropyle, hétérocycliques
WO2010097368A1 (fr) 2009-02-25 2010-09-02 F. Hoffmann-La Roche Ag Dérivés isoxazole / o-pyridine avec séquence de liaison éthyle et éthényle
WO2010112475A1 (fr) 2009-04-02 2010-10-07 F. Hoffmann-La Roche Ag Dérivés d'hydroxyméthylisoxazole en tant que modulateurs des gaba a
WO2010125042A1 (fr) 2009-04-30 2010-11-04 F. Hoffmann-La Roche Ag Dérivés d'isoxazole
WO2010127974A1 (fr) 2009-05-05 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-thiazole comme agonistes inverses du récepteur gaba a, utiles dans le traitement de troubles cognitifs
WO2010127968A1 (fr) 2009-05-05 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-pyridazine
WO2010127976A1 (fr) 2009-05-05 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-pyridine
WO2010127975A1 (fr) 2009-05-05 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-pyrazole
WO2010127978A1 (fr) 2009-05-07 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-pyridine en tant que modulateurs de gaba
WO2011020615A1 (fr) 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité
WO2012062687A1 (fr) 2010-11-09 2012-05-18 F. Hoffmann-La Roche Ag Dérivés de triazole et leur utilisation pour des troubles neurologiques
WO2012062623A1 (fr) * 2010-11-09 2012-05-18 F. Hoffmann-La Roche Ag Dérivés de triazole en tant que ligands pour les récepteurs gaba

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039389A1 (fr) 2005-09-19 2007-04-12 F. Hoffmann-La Roche Ag Derives d'isoxazolo utilises en tant qu'agonistes inverses de gaba a $g(a)5
WO2007042420A1 (fr) 2005-10-11 2007-04-19 F. Hoffmann-La Roche Ag Derives d'isoxazole
WO2007054444A2 (fr) 2005-11-09 2007-05-18 F. Hoffmann-La Roche Ag Derives du 3-aryl-isoxazole-4-carbonyl-benzofurane
WO2007071598A1 (fr) 2005-12-23 2007-06-28 F. Hoffmann-La Roche Ag Derives d'aryl-isoxazolo-4-yl-oxadiazole
WO2007074078A2 (fr) 2005-12-27 2007-07-05 F. Hoffmann-La Roche Ag Derives aryl-isoxazol-4-yl-imidazo[1,5-a] pyridine
WO2007074089A1 (fr) 2005-12-27 2007-07-05 F. Hoffmann-La Roche Ag Derives aryl-isoxazol-4-yl-imidazo[1, 5-a]pyridine
WO2007137954A1 (fr) 2006-05-31 2007-12-06 F. Hoffmann-La Roche Ag Dérivés d'aryl-4-éthynyl-isoxazole
WO2008025539A1 (fr) 2006-08-29 2008-03-06 Phenex Pharmaceuticals Ag Composés de liaison au fxr hétérocycliques
WO2008025540A1 (fr) 2006-08-29 2008-03-06 Phenex Pharmaceuticals Ag Composés hétérocycliques se liant au fxr
WO2009000662A1 (fr) 2007-06-22 2008-12-31 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-imidazole
WO2009071464A1 (fr) 2007-12-04 2009-06-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazolo-pyrazine
WO2009071477A1 (fr) 2007-12-04 2009-06-11 F. Hoffmann-La Roche Ag Dérivés isoxazolo-pyridazine
WO2009071476A1 (fr) 2007-12-04 2009-06-11 F. Hoffmann-La Roche Ag Dérivés isoxazolo-pyridine
WO2009149795A2 (fr) 2008-05-26 2009-12-17 Phenex Pharmaceuticals Ag Composés de liaison à fxr substitués par cyclopropyle, hétérocycliques
WO2010097368A1 (fr) 2009-02-25 2010-09-02 F. Hoffmann-La Roche Ag Dérivés isoxazole / o-pyridine avec séquence de liaison éthyle et éthényle
WO2010112475A1 (fr) 2009-04-02 2010-10-07 F. Hoffmann-La Roche Ag Dérivés d'hydroxyméthylisoxazole en tant que modulateurs des gaba a
WO2010125042A1 (fr) 2009-04-30 2010-11-04 F. Hoffmann-La Roche Ag Dérivés d'isoxazole
WO2010127974A1 (fr) 2009-05-05 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-thiazole comme agonistes inverses du récepteur gaba a, utiles dans le traitement de troubles cognitifs
WO2010127968A1 (fr) 2009-05-05 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-pyridazine
WO2010127976A1 (fr) 2009-05-05 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-pyridine
WO2010127975A1 (fr) 2009-05-05 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-pyrazole
WO2010127978A1 (fr) 2009-05-07 2010-11-11 F. Hoffmann-La Roche Ag Dérivés d'isoxazole-pyridine en tant que modulateurs de gaba
WO2011020615A1 (fr) 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité
WO2012062687A1 (fr) 2010-11-09 2012-05-18 F. Hoffmann-La Roche Ag Dérivés de triazole et leur utilisation pour des troubles neurologiques
WO2012062623A1 (fr) * 2010-11-09 2012-05-18 F. Hoffmann-La Roche Ag Dérivés de triazole en tant que ligands pour les récepteurs gaba

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", MAACK PUBLISHING CO.
MIRZA ET AL., J PHARMACOL EXP THER, vol. 327, 2008, pages 954 - 68
SIEGHART, PHARMACOL. REV., vol. 47, 1995, pages 181 - 234
STAHL P ET AL.: "Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021531291A (ja) * 2018-07-20 2021-11-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｇａｂａ受容体モジュレーターとしてのジフルオロメチル−フェニルトリアゾール
JP7311583B2 (ja) 2018-07-20 2023-07-19 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｇａｂａ受容体モジュレーターとしてのジフルオロメチル－フェニルトリアゾール
WO2021228795A1 (fr) 2020-05-13 2021-11-18 F. Hoffmann-La Roche Ag Nouveaux dérivés triazolyles utilisés en tant que gaba a alpha5 pam
EP3971179A1 (fr) * 2020-09-22 2022-03-23 Boehringer Ingelheim International GmbH Triazoles difluorométhyl-pyridin-2-yl
WO2023016521A1 (fr) * 2021-08-12 2023-02-16 上海赛默罗生物科技有限公司 Dérivé de triazole substitué, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée
CN115703765A (zh) * 2021-08-12 2023-02-17 上海赛默罗生物科技有限公司 取代三唑类衍生物、其制备方法、药物组合物和用途

Similar Documents

Publication Publication Date Title
US9931329B2 (en) Phenyl triazole derivative and its use for modulating the GABAA receptor complex
US6218547B1 (en) 1-phenyl-benzimidazole compounds and their use as GABA-a receptor modulators
JP4211394B2 (ja) プロパン−１，３−ジオン誘導体
WO2014001279A1 (fr) Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa
TW200413317A (en) Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions
JPH11501321A (ja) ベンズイミダゾール化合物、およびｇａｂａ▲下ａ▼レセプター複合体モジュレーターとしてのその使用
US9884848B2 (en) Phenyl triazole derivative and its use for modulating the GABAA receptor complex
CZ20021812A3 (cs) Nové cyklopropany jako antagonisté CGRP, farmaceutické prostředky obsahující tyto sloučeniny a způsob jejich výroby
WO2014001278A1 (fr) Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa
WO2014001280A1 (fr) Dérivé de phényle triazole et son utilisation pour moduler le complexe du récepteur gabaa
JP2006522070A (ja) ベンズイミダゾール誘導体及びこれをｇａｂａａ受容体複合体をモジュレートするために使用する方法
US7335777B2 (en) Benzimidazole derivatives and their use for modulating the GABAA receptor complex
US20080306044A1 (en) Spirobenzoazepanes as vasopressin antagonists
JP5712135B2 (ja) ベンゾイミダゾール誘導体及びｇａｂａａレセプター複合体を調節するためのそれらの使用
MX2011004736A (es) Derivados de benzimidazol y su uso para modular el complejo del receptor gaba a.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13731139

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13731139

Country of ref document: EP

Kind code of ref document: A1