WO2011073299A1 - Composés pyridinyloxadiazole et leur utilisation en tant que modulateurs des récepteurs nicotiniques de l'acétylcholine - Google Patents

Composés pyridinyloxadiazole et leur utilisation en tant que modulateurs des récepteurs nicotiniques de l'acétylcholine Download PDF

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WO2011073299A1
WO2011073299A1 PCT/EP2010/069857 EP2010069857W WO2011073299A1 WO 2011073299 A1 WO2011073299 A1 WO 2011073299A1 EP 2010069857 W EP2010069857 W EP 2010069857W WO 2011073299 A1 WO2011073299 A1 WO 2011073299A1
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pyridyl
pyridinyl
disorders
oxadiazol
pain
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PCT/EP2010/069857
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English (en)
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Dan Peters
Morten Grunnet
Birgitte L. Eriksen
Daniel B. Timmermann
Tino Dyhring
Philip K. Ahring
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Neurosearch A/S
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Publication of WO2011073299A1 publication Critical patent/WO2011073299A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to pyridinyl oxadiazolyl derivatives, which are found to be modulators of the nicotinic acetylcholine receptors. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
  • CNS central nervous system
  • PNS peripheral nervous system
  • acetylcholine exerts its biological effect via two types of cholinergic receptors, the muscarinic Acetyl Choline Receptors (mAChR) and the nicotinic Acetyl Choline Receptors (nAChR).
  • mAChR muscarinic Acetyl Choline Receptors
  • nAChR nicotinic Acetyl Choline Receptors
  • Nicotinic acetylcholine receptors are pentameric ligand gated ion channels and widely distributed throughout the central (CNS) and peripheral (PNS) nervous systems. At least 12 subunit proteins, i.e. cc2-a10 and ⁇ 2- ⁇ 4, have been identified in neuronal tissue. These subunits provide for a great variety of homomeric and heteromeric combinations that account for the diverse receptor subtypes. For example, the predominant receptor that is responsible for high affinity binding of nicotine in brain tissue has composition ⁇ 4 ⁇ 2, while another major population of receptors is comprised of the homomeric cc7.
  • WO 2008/049864 describes oxadiazole and thiadiazole compounds and their use as nicotinic acetylcholine receptor modulators.
  • the present invention is devoted to the provision modulators of the nicotinic receptors, which modulators are useful for the treatment of diseases or disorders related to the nicotinic acetylcholine receptor (nAChR).
  • nAChR nicotinic acetylcholine receptor
  • the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and abuse liability and withdrawal symptoms caused by the termination of abuse of chemical substances, in particular nicotine.
  • CNS central nervous system
  • PNS peripheral nervous system
  • diseases or disorders related to smooth muscle contraction endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and abuse liability and withdrawal symptoms caused by the termination of abuse of chemical substances, in particular nicotine.
  • the compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.
  • the invention provides a pyridinyl oxadiazole derivative represented by Formula I
  • Ar 1 and Ar 2 represents a pyridinyl group, optionally substituted with alkyl, halo, hydroxy or alkoxy;
  • Ar 1 and Ar 2 represents a furanyl, thienyl or selenophenyl group, which furanyl, thienyl and selenophenyl are optionally substituted with one or two substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy and cyano.
  • compositions comprising a therapeutically effective amount of the pyridinyl oxadiazole derivative of the invention, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
  • the invention relates to the use of the pyridinyl oxadiazole derivative of the invention, or a pharmaceutically acceptable addition salt thereof, for the manufacture of pharmaceutical compositions/medicaments 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 modulation of cholinergic receptors.
  • the invention provides a method for treatment, prevention or alleviation of diseases, disorders or conditions of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of cholinergic receptors, and which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of the pyridinyl oxadiazole derivative of the invention.
  • the invention provides a pyridinyl oxadiazole derivative represented by Formula I
  • Ar 1 and Ar 2 represents a pyridinyl group, optionally substituted with alkyl, halo, hydroxy or alkoxy;
  • Ar 1 and Ar 2 represents a furanyl, thienyl or selenophenyl group, which furanyl, thienyl and selenophenyl are optionally substituted with one or two substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy and cyano.
  • Ar 1 and Ar 2 represent a unsubstituted heterocyclic group.
  • neither of Ar 1 and Ar 2 represents 5-halo-thien- 2-yl. In a still further embodiment neither of Ar 1 and Ar 2 represents 3-chloro-thien- 2-yl.
  • neither of Ar 1 and Ar 2 represents 5-bromo- furan-2-yl.
  • neither of Ar 1 and Ar 2 represents 2-fluoro- pyridin-3-yl.
  • the pyridinyl oxadiazole derivative of the invention is a compound of Formula I, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof,
  • Ar 1 and Ar 2 represents a pyridinyl group, optionally substituted with alkyl, halo, hydroxy or alkoxy;
  • Ar 1 and Ar 2 represents a furanyl, thienyl or selenophenyl group, which furanyl, thienyl and selenophenyl are optionally substituted with one or two substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy and cyano; and
  • the pyridinyl oxadiazole derivative of the invention is a compound of Formula I, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein Ar 1 represents a pyridinyl group, optionally substituted with alkyl, halo, hydroxy or alkoxy.
  • Ar 1 represents a pyridinyl group, optionally substituted with alkyl, halo or alkoxy.
  • Ar 1 represents a pyridinyl group substituted with alkyl, and in particular methyl.
  • Ar 1 represents a pyridinyl group substituted with halo, and in particular fluoro.
  • Ar 1 represents a pyridinyl group substituted with alkoxy, and in particular methoxy.
  • Ar 1 represents a pyridinyl group.
  • Ar 1 represents pyridyl (such as 3-pyridyl), methyl-pyridyl (such as 5-methyl-3-pyridyl or 6-methyl-3-pyridyl), fluoro-pyridyl (such as 5-fluoro-3-pyridyl or 6-fluoro-3-pyridyl), or methoxy-pyridyl (such as 6- methoxy-3-pyridyl).
  • the pyridinyl oxadiazole derivative of the invention is a compound of Formula I, a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable addition salt thereof, wherein Ar 2 represents a furanyl, thienyl or selenophenyl group, which furanyl, thienyl and selenophenyl are optionally substituted with one or two substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy and cyano. In a more preferred embodiment Ar 2 represents a furanyl group optionally substituted with one or two substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy and cyano.
  • Ar 2 represents a furanyl group optionally substituted with halo, trifluoromethyl, trifluoromethoxy or cyano.
  • Ar 2 represents a furanyl group optionally substituted with cyano.
  • Ar 2 represents a furanyl group.
  • Ar 2 represents a thienyl group optionally substituted with one or two substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy and cyano.
  • Ar 2 represents a thienyl group optionally substituted once or twice with halo, trifluoromethyl, trifluoromethoxy and/or cyano.
  • Ar 2 represents a thienyl group optionally substituted with halo, trifluoromethyl, trifluoromethoxy and/or cyano.
  • Ar 2 represents a thienyl group optionally substituted once or twice with cyano.
  • Ar 2 represents a thienyl group optionally substituted with cyano.
  • Ar 2 represents a thienyl group. In an eleventh more preferred embodiment Ar 2 represents a selenophenyl group optionally substituted with one or two substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy and cyano.
  • Ar 2 represents a selenophenyl group optionally substituted with halo, trifluoromethyl, trifluoromethoxy or cyano.
  • Ar 2 represents a selenophenyl group optionally substituted with cyano. In a further embodiment Ar 2 represents a selenophenyl group optionally substituted with halo.
  • Ar 2 represents a selenophenyl group.
  • Ar 2 represents cyano-thienyl (such as 3-cyano- thien-5-yl, 2-cyano-thien-4-yl, 2-cyano-thien-5-yl), bromo-thienyl (such as 5-bromo- thien-3-yl), dicyano-thienyl (such as 2,3-di-cyano-thien-5-yl), cyano-furanyl (such as 2-cyano-furan-4-yl), or bromo-selenophenyl (such as 5-bromo-selenopheny-2- yi)
  • the pyridinyl oxadiazole derivative of the invention is 5-[5-(3-Pyridyl)-1 ,3,4-oxadiazol-2-yl]thiophene-3-carbonitrile;
  • halo represents fluoro, chloro, bromo or iodo.
  • an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
  • the hydrocarbon chain preferably contain of from one to eighteen carbon atoms (Ci-is-alkyl), more preferred of from one to six carbon atoms (Ci-6-alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • alkyl represents a Ci -4 -alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
  • alkyl represents a Ci-3-alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
  • alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above.
  • alkyl is as defined above.
  • preferred alkoxy groups of the invention include methoxy and ethoxy.
  • the pyridinyl oxadiazole derivative of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the compound of the invention.
  • Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate derived, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like.
  • Such salts may be formed by procedures well known and described in the art.
  • acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
  • Metal salts of a compound of the invention include alkali metal salts, such as the sodium salt of a compound of the invention containing a carboxy group.
  • Examples of pharmaceutically acceptable cationic salts of a chemical compound of the invention include, without limitation, the sodium, the potassium, the calcium, the magnesium, the zinc, the aluminium, the lithium, the choline, the lysinium, and the ammonium salt, and the like, of a chemical compound of the invention containing an anionic group.
  • Such cationic salts may be formed by procedures well known and described in the art.
  • the chemical compound of the invention 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.
  • onium salts of N-containing compounds may also be contemplated as pharmaceutically acceptable salts.
  • Preferred “onium salts” include the alkyl-onium salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.
  • the compounds of the present invention may exist in different stereoisomeric forms, including enantiomers, diastereomers, as well as geometric isomers (cis-trans isomers).
  • the invention includes all such stereoisomers and any mixtures thereof including racemic mixtures.
  • Racemic forms can be resolved into the optical antipodes by known methods and techniques.
  • One way of separating the enantiomeric compounds (including enantiomeric intermediates) is by use of an optically active amine, and liberating the diastereomeric, resolved salt by treatment with an acid.
  • Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix.
  • Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of D- or L- (tartrates, mandelates or camphorsulphonate) salts for example.
  • Optical active compounds can also be prepared from optical active starting materials or intermediates.
  • the compounds of the invention may be used in their labelled or unlabelled form.
  • the 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 Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof.
  • PET Position Emission Tomography
  • SPECT Single Photon Imaging Computed Tomography
  • MRS Magnetic Resonance Spectroscopy
  • MRI Magnetic Resonance Imaging
  • CAT Computed Axial X-ray Tomography
  • the pyridinyl oxadiazole derivative 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 processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
  • one compound of the invention can be converted to another compound of the invention using conventional methods.
  • the end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
  • the present invention is devoted to the provision modulators of the nicotinic receptors, which modulators are useful for the treatment of diseases or disorders related to the nicotinic acetylcholine receptor (nAChR).
  • Preferred compounds of the invention show a positive allosteric modulation of the nicotinic acetylcholine ⁇ 4 ⁇ 2 receptor subtypes.
  • the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and abuse liability and withdrawal symptoms caused by the termination of abuse of chemical substances, in particular nicotine.
  • CNS central nervous system
  • PNS peripheral nervous system
  • diseases or disorders related to smooth muscle contraction endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and abuse liability and withdrawal symptoms caused by the termination of abuse of chemical substances, in particular nicotine.
  • the disease, disorder or condition relates to the central nervous system.
  • the compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.
  • the disease, disorder or condition is a cognitive disorder, learning deficit, memory deficits and dysfunction, Down's syndrome, Alzheimer's disease, attention deficit, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, psychosis, depression, bipolar disorder, mania, manic depression, schizophrenia, cognitive or attention deficits related to schizophrenia, obsessive compulsive disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, autism, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), anxiety, non-OCD anxiety disorders, convulsive disorders, convulsions, epilepsy, neurodegenerative disorders, transient anoxia, induced neuro-degeneration, neuropathy, diabetic neuropathy, periferic dyslexia, tardive dyskinesia, hyperkinesia, pain, mild pain, moderate or severe pain, pain of
  • the compounds of the invention are used for the treatment, prevention or alleviation of pain, mild or moderate or severe pain, pain of acute, chronic or recurrent character, pain caused by migraine, postoperative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, to postherpetic neuralgia, or to peripheral nerve injury.
  • the compounds of the invention are used for the treatment, prevention or alleviation of smooth muscle contractions, convulsive disorders, angina pectoris, premature labour, convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, or erectile difficulty.
  • the compounds of the invention are used for the treatment, prevention or alleviation of a neurodegenerative disorder, transient anoxia, or induced neuro-degeneration.
  • the compounds of the invention are used for the treatment, prevention or alleviation of an inflammatory disorder, inflammatory skin disorder, acne, rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, or diarrhoea.
  • the compounds of the invention are used for the treatment, prevention or alleviation of diabetic neuropathy, schizophrenia, cognitive or attentional deficits related to schizophrenia, or depression.
  • the compounds of the invention are used for the treatment, prevention or alleviation of pain, in particular neuropathic pain, diabetic neuropathy, schizophrenia and cognitive or attentional deficits related to schizophrenia, depression, and for assisting in obtaining smoking cessation.
  • the compounds of the invention are used the treatment of abuse liability and withdrawal symptoms caused by termination of use of addictive substances, in particular nicotine containing products such as tobacco, opioids such as heroin, cocaine and morphine, cannabis, benzodiazepines, benzodiazepine-like drugs, and alcohol.
  • addictive substances in particular nicotine containing products such as tobacco, opioids such as heroin, cocaine and morphine, cannabis, benzodiazepines, benzodiazepine-like drugs, and alcohol.
  • the compounds of the invention are used for the treatment of anxiety, cognitive disorders, learning deficit, memory deficits and dysfunction, Down's syndrome, Alzheimer's disease, attention deficit, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles de la Tourette's syndrome, psychosis, depression, mania, manic depression, schizophrenia, obsessive compulsive disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, sleeping disorders, pseudodementia, Ganser's syndrome, pre-menstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania, and jet-lag.
  • ADHD attention
  • the compounds of the invention are used for the treatment of cognitive disorders, psychosis, schizophrenia and/or depression.
  • the compounds of the invention are used for the treatment of endocrine disorders, such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.
  • endocrine disorders such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.
  • the compounds of the invention are used for the treatment of inflammatory diseases, disorders, or conditions, including inflammatory skin disorders such as acne and rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and diarrhoea.
  • the compounds of the invention may be useful for the treatment of cognition, schizophrenia, attention deficit hyperactivity disorder (ADHD) and neuropathic pain.
  • ADHD attention deficit hyperactivity disorder
  • treatment covers treatment, prevention, prophylactics and alleviation of abuse liability and withdrawal symptoms and abstinence as well as treatment resulting in a voluntary diminished intake of the addictive substance.
  • the compounds of the invention are used as diagnostic agents, e.g. for the identification and localisation of nicotinic receptors in various tissues.
  • the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a pyridinyl oxadiazole derivative of the invention.
  • a compound of the invention for use in therapy may be administered in the form of the raw 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 pyridinyl oxadiazole derivative of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and/or prophylactic ingredients, know 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.
  • the pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy.
  • Preferred routes of administration include oral administration, in particular in tablet, in capsule, in drage, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection.
  • the pharmaceutical composition of the invention can be manufactured by the skilled person by use of standard methods and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.
  • 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.
  • compositions and unit dosages thereof may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
  • 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 conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the chemical compound 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 chemical compound of the invention or a pharmaceutically acceptable salt of a chemical 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, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation 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.
  • 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 chemical 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.
  • 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.
  • 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 chemical 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 metered valve.
  • 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 hydroxypropyl methyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropyl methyl 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.
  • Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
  • compositions of the invention when the pharmaceutical composition of the invention is intended for treating patients with abuse liability and withdrawal symptoms caused by nicotine addiction, formulations such as gums, patches, sprays, inhalers, aerosols, etc., are contemplated.
  • a therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition.
  • Therapeutic efficacy and toxicity e.g. ED 5 o and LD 5 o, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LD 5 o/ED 5 o. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.
  • 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 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 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 pyridinyl oxadiazole derivatives of the present invention are valuable nicotinic receptor modulators, and therefore useful for the treatment of a range of ailments involving cholinergic dysfunction as well as a range of disorders responsive to the action of nAChR modulators.
  • 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 cholinergic receptors, and which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of a pyridinyl oxadiazole derivative of the invention.
  • treatment covers treatment, prevention, prophylaxis or alleviation
  • disease covers illnesses, diseases, disorders and conditions related to the disease in question.
  • 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.
  • a satisfactory result can, in certain instances, be obtained at a dosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o.
  • the upper limit of the dosage range is about 10 mg/kg i.v. and 100 mg/kg p.o.
  • Preferred ranges are from about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about 10 mg/kg p.o.
  • Tributyltin chloride (19 mg, 0.058 mmol) was added, after five minutes, followed by Pd2(dba)3 (0.089 g, 0.097 mmol) and after another 5 minutes, stirred and evacuated and refilled with nitrogen three times followed by 1 ,1 ' -Bis(diphenylphosphino)ferrocene (0.054 g, 0.097 mmol).
  • the mixture was stirred and evacuated and refilled with nitrogen three times.
  • the mixture was stirred at room-temperature for 30 minutes followed by stirring at 80°C for four days.
  • the mixture was evaporated and purified by silica gel column chromatography, using dichloromethane, methanol and aqueous ammonia as eluent. Yield 12 mg (5%).
  • LC-ESI-HRMS of [M+H]+ shows 255.03338 Da. Calc. 255.033512 Da, dev. -0.5 ppm.
  • This experiment shows the modulating activity of compounds of the invention by the ability to positively modulate the response induced by a range of concentrations of nicotine (0.1 nM-100 mM) in a HEK-293 cell line stably expressing the human nicotinic acetylcholine receptor subtype a4b2.
  • the modulator activity is determined as a fluorescence-based assay using a Fluorometric Imaging Plate Reader (FLIPR) as described below in more detail.
  • FLIPR Fluorometric Imaging Plate Reader
  • ⁇ - ⁇ 4 ⁇ 2 cells were seeded on poly-D-lysin-coated 384 well microtiter plates and allowed to proliferate for 24 h.
  • Dye loading was performed by incubating cells with 2 ⁇ fluo-4/AM for 1 .5 h at room temperature.
  • Dye not taken up by the cells was removed by aspiration, followed by three washing cycles with NMDG Ringer buffer (containing in mM: 140 NMDG, 5 KCI, 1 MgCI 2 , 10 CaCI 2 , 10 HEPES, pH 7.4).
  • the microtiter plates were then placed in the FLIPR and subjected to test solutions.

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Abstract

La présente invention a pour objet des dérivés pyridinyloxadiazolyle, dont on a découvert qu'ils étaient des modulateurs des récepteurs nicotiniques de l'acétylcholine. En raison de leur profil pharmacologique, les composés selon l'invention peuvent être utiles pour le traitement de maladies ou de troubles aussi divers que ceux associés au système cholinergique du système nerveux central (SNC), du système nerveux périphérique (SNP), de maladies ou de troubles associés à la contraction des muscles lisses, de maladies ou de troubles endocriniens, de maladies ou de troubles associés à une neurodégénérescence, de maladies ou de troubles associés à une inflammation, une douleur, et pour la suppression des symptômes provoqués par la fin d'un abus de substances chimiques.
PCT/EP2010/069857 2009-12-18 2010-12-16 Composés pyridinyloxadiazole et leur utilisation en tant que modulateurs des récepteurs nicotiniques de l'acétylcholine WO2011073299A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP4025211A4 (fr) * 2019-09-05 2023-09-06 Trevena, Inc. Procédés de traitement de l'épilepsie à l'aide de ceux-ci

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