WO2012143116A1 - Dérivés de 4-oxo-1-imidazolidinyl imidazothiadiazole - Google Patents

Dérivés de 4-oxo-1-imidazolidinyl imidazothiadiazole Download PDF

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WO2012143116A1
WO2012143116A1 PCT/EP2012/001657 EP2012001657W WO2012143116A1 WO 2012143116 A1 WO2012143116 A1 WO 2012143116A1 EP 2012001657 W EP2012001657 W EP 2012001657W WO 2012143116 A1 WO2012143116 A1 WO 2012143116A1
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methyl
methoxymethyl
thiadiazol
imidazo
chloro
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Laurent Provins
Yannick Quesnel
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UCB SA
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UCB SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to 4-oxo-1 -imidazolidinyl imidazothiadiazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
  • European Patent No. 0 162 036 B1 discloses compound (S)-a-ethyl-2-oxo-1 -pyrrolidine acetamide, which is known under the International Nonproprietary Name (INN) levetiracetam.
  • Levetiracetam a laevorotary compound, is disclosed as a protective agent for the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system.
  • This compound is also effective in the treatment of epilepsy (seizure control), a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-a-ethyl-2-oxo-1 -pyrrolidine acetamide, also known from European Patent No. 0 165 919 B1 , completely lacks activity (Gower A.J. et al., Eur. J. Pharmacol. (1992), 222, 193-203).
  • a persistent problem in seizure control arises with those patients who do not at all or only insufficiently respond to currently available treatments. Those patients are viewed as being refractory to treatment and represent a considerable challenge for the medical community. It is estimated that about 30% of epilepsy patients are to be classified as being refractory. Hence, there is a need to develop new medications that specifically target this population of patients.
  • WO 01/62726 discloses pyrrolidinone compounds having the following formula:
  • the imidazole or benzimidazole is attached by a nitrogen to the methylene linker of the pyrrolidinone.
  • WO 2006/128693 discloses pyrrolidinone compounds of the following formula B:
  • R 1 is hydrogen, substituted or unsubstituted C-
  • R 2 is hydrogen.
  • R 1 and R 2 may be linked together in such a way to form a C3.6 cycloalkyl.
  • R3 is either
  • 2-chloro-1 H-benzimidazol-1 -yl. in formula (I) is selected from the group comprising or consisting of hydrogen; C-
  • the compounds of WO 2006/128693 are said to be useful in the treatment of epilepsy, epileptogenesis, seizure disorders, convulsions, Parkinson's disease, dyskinesia induced by dopamine replacement therapy, tardive dyskinesia induced by administration of neuroleptic drugs, Huntington Chorea, and other neurological disorders including bipolar disorders, mania, depression, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, tremor, essential tremor, simple or complex tics, Tourette syndrome, restless legs syndrome and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity and degenerative diseases, bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and va
  • Y is O or S
  • R 1 is hydrogen or C-
  • R2 is hydrogen
  • R3 is -CO R5R6, -COR 7 , an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;
  • R5, R6 are the same or different and are independently selected from hydrogen and C-i-6 alkyl;
  • R 7 is Ci_6 alkyl
  • A is a monocyclic or bicyclic heterocyclic moiety selected from the group consisting of imidazolidin-1-yl, 1 ,3-oxazolidin-3-yl, 2,5-dihydro-1 H-pyrrol-1-yl, 1 ,3-thiazol-3(2H)-yl, 1 ,3-thiazolidin-3-yl, piperidin-1-yl, azepan-1-yl, 5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl, hexahydro-4H-thieno[3,2-b]pyrrol-4-yl, 2,3-dihydro-1 H-thieno[3,4-b]pyrrol-1-yl, 1 ,3- benzothiazol-3(2H)-yl, 1 ,3-benzoxazol-3(2H)-yl, pyrazolo[1 ,5-a]pyridin-1 (2H)-yl, 3,4- di
  • the invention provides new 4-oxo-1-imidazolidinyl imidazothiadiazole derivatives having the formula (I), their geometrical isomers, enantiomers, diastereoisomers and mixtures, or a pharmaceutically acceptable salt thereof,
  • the present invention relates to 4-oxo-1-imidazolidinyl imidazothiadiazole derivatives according to formula (I),
  • R 1 is a C-
  • R2 is either a halogen (chlorine, bromine, iodine) or a C-
  • R 3 is a C-
  • _4 alkyl e.g. a methyl or ethyl
  • OH hydroxy
  • an alkoxy e.g. methoxy or ethoxy or propoxy
  • R 1 is a n-propyl, an isobutyl, a 2,2-difluoropropyl, a 2-chloro- 2,2-difluoroethyl, a 2,2-difluoroethyl, a 2,2,2-trifluoroethyl, a 3,3,3-trifluoropropyl, a 2,2,3,3,3-pentafiuoropropyl, 2-phenylethyl, a cyclopropylmethyl, or a 2-fluoroethyl moiety, preferably a n-propyl, an isobutyl, a 2,2-difluoropropyl, a 2,2,2-trifluoroethyl, a 3,3,3-trifluoropropyl, a 2,2,3,3,3-pentafiuoropropyl, 2-phenylethyl or a cyclopropylmethyl group.
  • R 2 is a chloro, a difluoromethyl or a trifluoromethyl moiety, preferably a chloro or a trifluoromethyl moiety.
  • R 3 is either a hydroxymethyl, a methoxymethyl, a [( 2 H3)methyloxy]methyl, a methoxy( 2 H2)methyl, a (2,2,2-trifluoroethoxy)methyl or a 2- methoxyethyl moiety, preferably a methoxymethyl moiety.
  • compounds of formula (I) are those wherein: ⁇ R 1 is a n-propyl, an isobutyl, a 2,2-difluoropropyl, a 2,2,2-trifluoroethyl, a 3,3,3- trifluoropropyl, a 2,2,3,3,3-pentafluoropropyl, a 2-phenylethyl or a cyclopropylmethyl group;
  • R 2 is a chloro or a trif luoromethyl moiety
  • R3 is a methoxymethyl moiety.
  • Specific compounds of the present invention are those selected from the group consisting of:
  • _4 alkyl refers to alkyl groups having 1 to 4 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, fert-butyl. "C-
  • Any moiety "H” in formula (I) may be the isotope hydrogen, deuterium or tritium.
  • Haldroxy represents a group of formula -OH.
  • Alkoxy refers to the group -O-R where R includes "C1.4 alkyl”.
  • Halogen refers to fluoro, chloro, bromo and iodo atoms, preferably fluoro and chloro.
  • compositions of formula (I) include therapeutically active, non-toxic acid or base salt forms which the compounds of formula (I) are able to form.
  • the acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p- toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like.
  • an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or
  • the compounds of formula (I) containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • salt forms can be converted into the free forms by treatment with an appropriate base or acid.
  • solvates include for example hydrates, alcoholates and the like.
  • Compounds of formula (I) and/or their intermediates may have at least one stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem., 45 (1976) 11-30.
  • the invention thus also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of formula (I) or mixtures thereof (including all possible mixtures of stereoisomers).
  • reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, unless the particular isomeric form is referred to specifically.
  • the expression “enantiomerically pure” as used herein refers to compounds which have enantiomeric excess (ee) greater than 95%.
  • compounds having the general formula (I) may be prepared by cyclization of a compound of formula (II) according to the equation:
  • This reaction may be performed using a formylating agent such as formaldehyde in acetonitrile at 70°C, or according to any method known to the person skilled in the art.
  • a formylating agent such as formaldehyde in acetonitrile at 70°C, or according to any method known to the person skilled in the art.
  • Compounds of formula II may be prepared by reaction of a compound of formula III wherein X is a halogen atom, preferably a chlorine atom, with an amine RI-NH2 according to the equation:
  • R1 , R2 and R ⁇ have the same definitions as defined above for compounds of formula I.
  • This reaction may be performed using an excess of amine IV in the presence of a base such as ⁇ , ⁇ -diisopropylethylamine in a classical organic solvent such as acetonitrile at 60°C, or according to any method known to the person skilled in the art.
  • a base such as ⁇ , ⁇ -diisopropylethylamine
  • a classical organic solvent such as acetonitrile at 60°C
  • This reaction may be performed using a halogeno alkyl halide such as chloroacetyl chloride in the presence of a tertiary amine such as triethylamine in a classical organic solvent such as dichloromethane at room temperature.
  • a halogeno alkyl halide such as chloroacetyl chloride
  • a tertiary amine such as triethylamine
  • a classical organic solvent such as dichloromethane at room temperature.
  • This reaction may be performed using a reducing agent such as triphenylphosphine in in a THF/water mixture at room temperature or according to any method known to the person skilled in the art.
  • a reducing agent such as triphenylphosphine in in a THF/water mixture at room temperature or according to any method known to the person skilled in the art.
  • This reaction may be performed in a two-steps sequence by treatment of compounds VII with a sulfonyl chloride such as methanesulfonyl chloride in the presence of a base such as ⁇ , ⁇ -diisopropylethylamine in dichloromethane at 0°C, or according to any other method known to the person skilled in the art, followed by treatment of the intermediate with an azide derivative such as sodium azide in DMF at 0°C.
  • compounds VII may be directly treated with diphenylphosphorylazide in the presence of a base such as DBU in THF, or according to any other method known to the person skilled in the art.
  • This reaction may be performed using a formylating agent such as formaldehyde in acidic conditions in a polar solvent such as sulfolane at 1 10°C, or according to any other method known to the person skilled in the art.
  • a formylating agent such as formaldehyde in acidic conditions in a polar solvent such as sulfolane at 1 10°C, or according to any other method known to the person skilled in the art.
  • R 2 is C1.4 alkyl and R ⁇ has the same definition as described above for compounds of formula I.
  • This reaction can be performed using procedures described in the literature or known to the person skilled in the art.
  • This reaction can be performed by treatment of a compound of formula XII with a halogenating agent such as phosphorus oxychloride with a tertiary amine such as triethylamine in classical organic solvent such as acetonitrile, or according to any other method known by the person skilled in the art.
  • a halogenating agent such as phosphorus oxychloride
  • a tertiary amine such as triethylamine
  • organic solvent such as acetonitrile
  • Compound of formula XII can be prepared from a compound of formula X, by protection of its amino group by a Boc group, then by reaction of the resulting intermediate with a bromo derivative of formula XI wherein is OH, according to the equation:
  • This reaction may be performed using procedures described in the literature or known to the person skilled in the art.
  • the present invention includes the synthesis of the following intermediates:
  • the compounds of the present invention are for use as a medicament, in the treatment of epilepsy, epileptogenesis, seizure disorders, convulsions, in particular for refractory seizures.
  • Seizures can be classified as refractory when a patient fails to achieve seizure freedom for 12 months or more of state of the art treatment with two or more anti-epileptic drugs at maximal tolerated doses.
  • the methods of the invention comprise administration to a mammal (preferably a human) suffering from above mentioned conditions or disorders, of a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 1 to 2000 mg, preferably 1 to 1000 mg, more preferably 1 to 500 mg of active ingredient per unit dosage form.
  • treatment includes curative treatment and prophylactic treatment.
  • curative is meant efficacy in treating a current symptomatic episode of a disorder or condition.
  • prophylactic is meant prevention of the occurrence or recurrence of a disorder or condition.
  • epileptic seizure refers to a chronic neurologic condition characterised by unprovoked, recurrent epileptic seizures.
  • An epileptic seizure is the manisfestation of an abnormal and excessive synchronised discharge of a set of cerebral neurons; its clinical manifestations are sudden and transient.
  • epilepsy as used herein can also refer to a disorder of brain function characterised by the periodic occurrence of seizures. Seizures can be "nonepileptic" when evoked in a normal brain by conditions such as high fever or exposure to toxins or "epileptic” when evoked without evident provocation.
  • seizure refers to a transient alteration of behaviour due to the disordered, synchronous, and rhythmic firing of populations of brain neurones.
  • a further aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable diluent or carrier.
  • Activity in any of the above-mentioned indications can of course be determined by carrying out suitable clinical trials in a manner known to a person skilled in the relevant art for the particular indication and/or in the design of clinical trials in general.
  • compounds of formula (I) or their pharmaceutically acceptable salts may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition.
  • another embodiment of the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition according to the invention one or more of the compounds of formula (I) or a pharmaceutically acceptable salt thereof is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.
  • Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, parenteral or intranasal.
  • compositions comprising compounds according to the invention can, for example, be administered orally, parenterally, i.e., intravenously, intramuscularly or subcutaneously, intrathecally, transdermal ⁇ (patch), by inhalation or intranasally.
  • compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing-gums and the like.
  • the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose.
  • these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatine
  • a disintegrant such as alginic acid
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetener such as sucrose or saccharin
  • colouring agents or a flavouring agent such as peppermint or methyl salicylate.
  • compositions which can release the active substance in a controlled manner are contemplated.
  • compositions which can be used for parenteral administration are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.
  • these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrate
  • the amount of active ingredient in the pharmaceutical compositions can fall within a wide range of concentrations and depends on a variety of factors such as the patient's sex, age, weight and medical condition, as well as on the method of administration.
  • the quantity of compound of formula (I) in compositions for oral administration is at least 0.5 % by weight and can be up to 80 % by weight with respect to the total weight of the composition.
  • the compounds of formula (I) or the pharmaceutically acceptable salts thereof can be administered alone or in combination with other pharmaceutically active ingredients.
  • additional compounds which can be cited for use in combination with the compounds according to the invention are antivirals, antispastics (e.g. baclofen), antiemetics, antimanic mood stabilizing agents, analgesics (e.g. aspirin, ibuprofen, paracetamol), narcotic analgesics, topical anesthetics, opioid analgesics, lithium salts, antidepressants (e.g. mianserin, fluoxetine, trazodone), tricyclic antidepressants (e.g.
  • anticonvulsants e.g. valproic acid, carbamazepine, phenytoin
  • antipsychotics e.g. risperidone, haloperidol
  • neuroleptics e.g. benzodiazepines (e.g. diazepam, clonazepam), phenothiazines (e.g. chlorpromazine), calcium channel blockers, amphetamine, clonidine, lidocaine, mexiletine, capsaicin, caffeine, quetiapine, serotonin antagonists, ⁇ -blockers, antiarrhythmics, triptans, ergot derivatives and amantadine.
  • anticonvulsants e.g. valproic acid, carbamazepine, phenytoin
  • antipsychotics e.g. risperidone, haloperidol
  • neuroleptics e.g. benzodiazepines (e.g. di
  • the daily dosage is in the range 1 mg to 2000 mg of compounds of formula I.
  • the dosage unit is in the range 1 mg to 1000 mg of compounds of formula I, preferably 1 mg to 500 mg.
  • the quantity of compound of formula (I) present is at least 0.5 % by weight and can be up to 33 % by weight with respect to the total weight of the composition.
  • the dosage unit is in the range 1 mg to 2000 mg of compounds of formula I.
  • the daily dose can fall within a wide range of dosage units of compound of formula (I) and is generally in the range 1 to 2000 mg, preferably 1 to 1000 mg. However, it should be understood that the specific doses can be adapted to particular cases depending on the individual requirements, at the physician's discretion.
  • the SV2 proteins binding compounds provided by this invention and labeled derivatives thereof may be useful as standards and reagents in determining the ability of tested compounds (e.g., a potential pharmaceutical) to bind to the SV2 proteins.
  • Labeled derivatives of SV2 proteins' ligands provided by this invention may also be useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon emission computerized tomography
  • the present invention therefore further provides labelled ligands as tools to screen chemical libraries for the discovery of potential pharmaceutical agents, in particular for treatment and prevention of the conditions set forth herein, on the basis of more potent binding to SV2 proteins, for localizing SV2 proteins in tissues, and for characterizing purified SV2 proteins.
  • SV2 proteins include SV2A, SV2B, and SV2C whereby SV2A is the binding site for the anti-seizure drug levetiracetam and its analogs.
  • the SV2 isoforms SV2A, SV2B, or SV2C can be derived from tissues, especially brain, from any mammal species, including human, rat or mice.
  • the isoforms may be cloned versions of any mammalian species, including human, rat, and mice, heterologously expressed and used for assays.
  • the screening method comprises exposing brain membranes, such as mammalian or human brain membranes, or cell lines expressing SV2 proteins or fragments thereof, especially SV2A and SV2C, but including SV2B, to a putative agent and incubating the membranes or proteins or fragments and the agent with labelled compound of formula I.
  • the method further comprises determining if the binding of the compound of formula (I) to the protein is inhibited by the putative agent, thereby identifying binding partners for the protein.
  • the screening assays enable the identification of new drugs or compounds that interact with SV2 proteins.
  • the present invention also provides photoactivable ligands of SV2 proteins.
  • the labelled-ligands can also be used as tools to assess the conformation state of SV2 proteins after solubilization, purification and chromatography.
  • the labelled-ligands may be directly or indirectly labeled. Examples of suitable labels include a radiolabel, such as 3
  • Labelled compounds of formula (I) are useful in the methods as probes in assays to screen for new compounds or agents that bind to the SV2 proteins (SV2A, SV2B and SV2C).
  • ligands can be used without modification or can be modified in a variety of ways; for example, by labelling, such as covalently or non- covalently joining a moiety which directly or indirectly provides a detectable signal.
  • the materials can be labelled either directly or indirectly.
  • Possibilities for direct labelling include label groups such as: radiolabels including, but not limited to, [ 3 H], [ 14 C], [ 32 P], [ 35 S] or [ 25 I], enzymes such as peroxidase and alkaline phosphatase, and fluorescent labels capable of monitoring the change in fluorescence intensity, wavelength shift, or fluorescence polarization, including, but not limited to, fluorescein or rhodamine.
  • Possibilities for indirect labelling include biotinylation of one constituent followed by binding to avidin coupled to one of the above label groups or the use of anti-ligand antibodies.
  • the compounds may also include spacers or linkers in cases where the compounds are to be attached to a solid support.
  • SV2 proteins especially SV2A and SV2C
  • intact cells, cellular or membrane fragments containing SV2A or SV2C or the entire SV2 protein or a fragment thereof can be used.
  • the agent or compound may be incubated with the cells, membranes, SV2 protein or fragment prior to, at the same time as, or after incubation with labelled levetiracetam or an analog or derivative thereof.
  • Assays may be modified or prepared in any available format, including high-throughput screening (HTS) assays that monitor the binding of levetiracetam or the binding of derivatives or analogs thereof to SV2 proteins or fragments thereof.
  • HTS high-throughput screening
  • screening assays may use intact cells, cellular or membrane fragments containing SV2 as well as cell-free or membrane-free systems, such as may be derived with purified or semi-purified proteins.
  • the advantage of the assay with membrane fragment containing SV2 or purified SV2 proteins and peptides is that the effects of cellular toxicity and/or bioavailability of the test compound can be generally ignored, the assay instead being focused primarily on the effect of the drug on the molecular target as may be manifest in an inhibition of, for instance, binding between two molecules.
  • the assay can be formulated to detect the ability of a test agent or compound to inhibit binding of labeled ligand according to the invention to SV2 or a fragment of SV2 or of labelled levetiracetam, or derivatives or analogs thereof, to SV2 or a fragment of SV2 protein.
  • the inhibition of complex formation may be detected by a variety of techniques such as filtration assays, Flashplates (Perkin Elmer), scintillation proximity assays (SPA, GE).
  • SPA scintillation proximity assays
  • HTS high-throughput screenings
  • scintillation proximity assay which uses microspheres coated with biological membranes or flashplates coated with biological membranes arepowerful methods that do not require separation or washing steps.
  • NMR spectra are recorded on a BRUKER AVANCE 400 NMR Spectrometer fitted with a Linux workstation running XWIN NMR 3.5 software and a 5 mm inverse 1 H/BB probehead, or BRUKER DRX 400 NMR fitted with a SG Fuel running XWIN NMR 2.6 software and a 5 mm inverse geometry 1 H/ 1 3C/19F triple probehead.
  • the compound is studied in dg-dimethylsulfoxide (or d3-chloroform) solution at a probe temperature of 313 K or 300 K and at a concentration of 10 mg/ml.
  • the instrument is locked on the deuterium signal of de-dimethylsulfoxide (or d3-chloroform). Chemical shifts are given in ppm downfield from TMS (tetramethylsilane) taken as internal standard.
  • HPLC analyses are performed using one of the following systems:
  • the gradient runs from 100 % solvent A (acetonitrile, water, trifluoroacetic acid (10/90/0.1 , v/v/v)) to 100 % solvent B (acetonitrile, water, trifluoroacetic acid (90/10/0.1 , v/v/v)) in 7 min with a hold at 100 % B of 4 min.
  • the flow rate is set at 2.5 ml/min and a split of 1/25 is used just before API source.
  • API spectra (+ or -) are performed using a FINNIGAN LCQ ion trap mass spectrometer.
  • APCI source operated at 450°C and the capillary heater at 160°C.
  • ESI source operated at 3.5 kV and the capillary heater at 210°C.
  • Mass spectrometric measurements in DIP/EI mode are performed as follows: samples are vaporized by heating the probe from 50°C to 250°C in 5 min. El (Electron Impact) spectra are recorded using a FINNIGAN TSQ 700 tandem quadrupole mass spectrometer. The source temperature is set at 150°C.
  • Mass spectrometric measurements on a TSQ 700 tandem quadrupole mass spectrometer (Finnigan MAT) in GC/MS mode are performed with a gas chromatograph model 3400 (Varian) fitted with a split splitless injector and a DB-5MS fused-silica column (15 m x 0.25 mm I.D., 1 ⁇ ) from J&W Scientific. Helium (purity 99.999 %) is used as carrier gas.
  • the injector (CTC A200S autosampler) and the transfer line operate at 290 and 250°C, respectively.
  • Sample (1 ⁇ ) is injected in splitless mode and the oven temperature is programmed as follows: 50°C for 5 min., increasing to 280°C (23°C/min) and holding for 10 min.
  • the TSQ 700 spectrometer operates in electron impact (El) or chemical ionization (CI/CH4) mode (mass range 33 - 800, scan time 1.00 sec).
  • the source temperature is set at 150°C.
  • High resolution mass spectrometry measurements are run on a Waters LCT Time of flight mass spectrometer equipped with an ESI source and a Waters Acquity UPLC (column: BEH C18 (1.7 ⁇ , 2.1 x 50 mm)) with diode array detector.
  • the gradient runs from 98 % solvent A (aqueous ammonium formate (63 mg/l), 30% aqueous ammonia (50 ⁇ / ⁇ )) to 95 % acetonitrile and back in 6 min.
  • the source parameters are as follows: ESI capillary voltage 2.5 kV, cone voltage 135 V, source block temperature 35°C, desolvation temperature 350°C, cone gas flow 20 L Hr (Nitrogen), desolvation Gas flow 800 L/Hr.
  • the detector is set with a flight tube at 7.2 KV and an MCP detector at 2,500 V.Specific rotation is recorded on a Perkin-Elmer 341 polarimeter. The angle of rotation is recorded at 25°C on 1 % solutions in methanol, at 589 nm.
  • Preparative chromatographic separations are performed on silicagei 60 Merck, particle size 15-40 ⁇ , reference 1.151 1 1.9025, using Novasep axial compression columns (80 mm i.d.), flow rates between 70 and 150 ml/min. Amount of silicagei and solvent mixtures as described in individual procedures. Reverse phase separations are carried out using 500 g of either romasil C18 10 ⁇ silicagel (acidic or neutral conditions) or Phenomenex Gemini C18 10 ⁇ (basic conditions) in 8-cm ID columns with a flow rate of 150 ml/min. Products are detected at 215 nm unless otherwise specified.
  • Preparative Chiral Chromatographic separations are performed on a DAICEL Chiralpak AD 20 ⁇ , 100 * 500 mm column using an in-house build instrument with various mixtures of lower alcohols and C5 to C8 linear, branched or cyclic alkanes at ⁇ 350 ml/min. Solvent mixtures as described in individual procedures.
  • Bromotrifluoroacetone (478 g, 2.5 mol, 1.05 eq) is added on a suspension of 5- (methoxymethyl)-1 ,3,4-thiadiazol-2-amine a1 (346 g, 2.4 mol, 1 eq) in 1 ,2- dimethoxyethane (6 I) at 20°C.
  • the reaction mixture is heated to 80°C until maximum conversion ( ⁇ 24 h).
  • Water (4 I) is added to the reaction mixture at 32°C and the expected compound crystallized out of the reaction mixture.
  • 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1 ,3,4]thiadiazole a2 (10 g, 42.2 mmol, 1 eq), formaldehyde (16 g, 421.6 mmol, 10 eq) and hydrochloric acid (37 %, 8.2 ml, 2 eq) are diluted in sulfolane (250 ml). The reaction mixture is heated at 1 10°C overnight. Water (500 ml) is added and the mixture is heated at 50°C for 2h. The solvent is then removed under reduced pressure.
  • lodoacetic acid (409.3 g, 2.2 mol, 1.5 eq) is added in one portion to a solution of tert- butyl [5-(methoxymethyl)-1 ,3,4-thiadiazol-2-yl]carbamate a4 (360 g, 1.47 mol, 1 eq) in tetrahydrofurane (3 I) at room temperature.
  • Sodium hydride (52.8 g, 2.2 mol, 1.5 eq) is then added portionwise, in 30 minutes, at room temperature.
  • [5-[(benzyloxy)methyl]-2-[(tert-butoxycarbonyl)imino]-1 ,3,4-thiadiazol-3(2H)-yl]acetic acid a7 may be synthesized according to the same method.
  • reaction mixture is extracted with dichloromethane (2 x 1.2 I), the combined organic layers are washed by a NaOH/NaCI aqueous solution (1.4 I of saturated NaCI solution + 400 ml 2N NaOH), dried over MgSC>4, filtered and condensed under reduced pressure. The residue is recrystallized from acetonitrile/water (1/1 ) to afford 99.8 g of pure 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1 ,3,4]thiadiazole a8. Yield: 36 %.
  • 2-[(benzyloxy)methyl]-6-chloroimidazo[2,1 -b][1 ,3,4]thiadiazole a9 may be synthesized according to the same method.
  • Phosphorus oxychloride (2.75 ml, 3 eq) is added very slowly to dimethyl formamide (5 ml) cooled at 0°C. The temperature rises to 50°C.
  • the reaction mixture is heated at 60°C, then 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1 ,3,4]thiadiazole a8 (2 g, 9.82 mmol, 1 eq) is added portionwise for 2.5 h.
  • the reaction mixture is poured on an ice/water mixture. The precipitate is filtered and washed with water.
  • 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1 ,3,4]thiadiazole-5-carbaldehyde a10 (2.97 g, 12.94 mmol, 1 eq) is dissolved in ethanol (80 ml), cooled at 0°C and sodium borohydride (578 mg, 15.53 mmol, 1.2 eq) is added portionwise at 0°C. The reaction mixture is stirred overnight at room temperature, then cooled at 0°C and a satured NH4CI aqueous solution (100 ml) is added.
  • N,N-Diisopropylethylamine (9.13 g, 70.6 mmol, 5 eq) and methanesulfonyl chloride (2.42 g, 21.2 mmol, 1.5 eq) are successively and slowly added to [6-chloro-2- (methoxymethyl)imidazo[2,1-b][1 ,3,4]thiadiazol-5-yl]methanol a12 (3.3 g, 14.1 mmol, 1 eq) in dichloromethane (80 ml) at 0°C.
  • Triphenylphosphine (3.47 g, 13.2 mmol, 1 eq) is added at room temperature to a suspension of 5-(azidomethyl)-6-chloro-2-(methoxymethyl)imidazo[2,1-b][1 ,3,4]thia- diazole a14 (3.42 g, 13.2 mmol, 1 eq) in THF/H2O (18 ml/2 ml).
  • the reaction mixture is stirred at room temperature for 16 h.
  • the solvent is evaporated under reduced pressure, water is added to the residue, the solution is acidified to pH 2 with aqueous 5N HCI, then extracted with Et20 (1 x 50 ml).
  • the aqueous layer is basified (pH 8) by addition of a Na2CC-3 aqueous solution, and extracted with dichloromethane (3 x 200 ml), the cumulated organic layers are dried over MgS04, filtered and evaporated under reduced pressure to afford 2.2 g of 1 -[6-chloro-2-(methoxymethyl)imidazo[2,1 -b][1 ,3,4]thiadiazol- 5-yl]methanamine a17 .
  • Triethylamine (1.23 ml, 8.85 mmol, 1 eq) and chloroacetyl chloride (0.99 g, 8.85 mmol, 1 eq, 0.705 ml) are added to a solution of 1-[6-chloro-2-(methoxymethyl)imidazo[2,1- b][1 ,3,4]thiadiazol-5-yl]methanamine a11 (2.06 g, 8.88 mmol, 1 eq) in dichloromethane (60 ml). The mixture is stirred at room temperature for 16 h.
  • reaction mixture is extracted with dichloromethane (2 x 100 ml), the cumulated organic layers are dried over MgS04, filtered and condensed under reduced pressure to afford 2.58 g of 2- chloro-N- ⁇ [6-chloro-2-(methoxymethyl)imidazo[2,1-b][1 ,3,4]thiadiazol-5- yl]methyl ⁇ acetamide a20 .
  • Trifluoropropylamine (2.78 g, 24.65 mmol, 3 eq) and N,N-diisopropylethylamine (1.27 g, 9.86 mmol, 1.2 eq, 1.72 ml) are added to a solution of 2-chloro-N- ⁇ [6-chloro-2- (methoxymethyl)imidazo[2,1 -b][1 ,3,4]thiadiazol-5-yl]methyl ⁇ acetamide a20 (2.54 g, 8.22 mmol, 1 eq) in acetonitrile (80 ml). The mixture is heated at 60°C for 16 hours.
  • Formaldehyde (35% in water, 3.52 ml, 41.08 mmol, 5 eq) is added to N- ⁇ [6-chloro-2- (methoxymethyl)imidazo[2, 1 -b][1 ,3,4]thiadiazol-5-yl]methyl ⁇ -2-[(3,3,3-trif luoropropyl)- amino]acetamide a23 (3.17 g, 8.22 mmol, 1 eq) in acetonitrile (70 ml) and the mixture is heated overnight at 70°C. The reaction mixture is evaporated. The residue is dissolved in water and this mixture is extracted with dichloromethane (2 x 150 ml).
  • the combined organic layers are dried over MgSC>4, filtered and condensed under reduced pressure.
  • the residue is purified by chromatography over silicagel (eluent: CI- ⁇ C ⁇ /MeOH 99.5/0.5). After evaporation of the solvents, the residue is recristallized from dichloromethane/n-hexane.
  • Compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 13 may be synthesized according to the same method.
  • N-( ⁇ 2-[(benzyloxy)methyl]-6-chloroimidazo[2,1-b][1 ,3,4]thiadiazol-5-yl ⁇ methyl)-2-[(3,3,3- trifluoropropyl)amino]acetamide a34 (650 mg, 1.41 mmol, 1 eq) is dissolved in triiluoroacetic acid (20 ml) and the mixture is heated at 60°C for 16 h. The reaction is not completed, the mixture reaction is still heated at 70°C for 5 h.
  • 3- ⁇ [6-chloro-2-(hydroxymethyl)imidazo[2,1-b][1 ,3,4]thiadiazol-5-yl]methyl ⁇ -1 -(3,3,3- trifluoropropyl)imidazolidin-4-one 12 may be prepared from N- ⁇ [6-chloro-2- (hydroxymethy imidazo ⁇ .l-bltl .S ⁇ lthiadiazol-S-ynmethylJ ⁇ - ⁇ S.S.S- trifluoropropyl)amino]acetamide a35 according to the method described in example 2.10.
  • Table (I) indicates the lUPAC name of the compound, the ion peak observed in mass spectroscopy, the H NMR description, the melting point or onset on DSC.
  • the inhibition constant (Ki) of a compound is determined in competitive binding experiments by measuring the binding of a single concentration of a radioactive ligand at equilibrium with various concentrations of the unlabeled test substance.
  • the concentration of the test substance inhibiting 50 % of the specific binding of the radioligand is called the ⁇ C ⁇ Q.
  • Ki is proportional to the IC50 and is calculated using the equation of Cheng and Prusoff (Cheng Y. et al., Biochem. Pharmacol. (1972), 22, 3099-3108).
  • the concentration range usually encompasses 6 log units with variable steps (0.3 to 0.5 log). Assays are performed in mono- or duplicate, each Ki determination is performed on two different samples of test substance.
  • Cerebral cortex from 200-250g male Sprague-Dawley rats are homogenised using a Potter S homogeniser (10 strokes at 1 ,000 rpm; Braun, Germany) in 20 mmol/l Tris-HCI (pH 7.4), 250 mmol/l sucrose (buffer A); all operations are performed at 4°C.
  • the homogenate is centrifuged at 30,000 g for 15 min.
  • the crude membrane pellet obtained is resuspended in 50 mmol/l Tris-HCI (pH 7.4), (buffer B) and incubated 15 min at 37°C, centrifuged at 30,000 g for 15 min and washed twice with the same buffer.
  • the final pellet is resuspended in buffer A at a protein concentration ranging from 15 to 25 mg/ml and stored in liquid nitrogen.
  • Membranes (150-200 ⁇ g of protein / assay) are incubated at 4°C for 120 min in 0.5 ml of a 50 mmol/l Tris-HCI buffer (pH 7.4) containing 2 mmol/l MgCI 2 , 1 to 2 10 ⁇ 9 mol/l of [3H]-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide and increasing concentrations of the test compound of formula I.
  • the non specific binding (NSB) is defined as the residual binding observed in the presence of a concentration of reference substance (e.g. 10" 3 mol/l levetiracetam) that binds essentially all the receptors.
  • Membrane-bound and free radioligands are separated by rapid filtration through glass fiber filters (equivalent to Whatman GF/C or GF/B; VEL, Belgium) pre-soaked in 0.1 % polyethyleneimine and 10 ⁇ 3 mol/l levetiracetam to reduce non specific binding.
  • Samples and filters are rinsed by at least 6 ml of 50 mmol/l Tris-HCI (pH 7.4) buffer. The entire filtration procedure does not exceed 10 seconds per sample.
  • the radioactivity trapped onto the filters is counted by liquid scintillation in a ⁇ -counter (Tri-Carb 1900 or TopCount 9206, Camberra Packard, Belgium, or any other equivalent counter).
  • Data analysis is performed by a computerized non linear curve fitting method using a set of equations describing several binding models assuming populations of independent non- interacting receptors, which obey the law of mass.
  • SV2C expressed in COS-7 cells are used under standard conditions.
  • t ⁇ H]-(+)-4-(3-azido-2,4-difluorophenyl)-1-(1 H-imidazol-1-ylmethyl) pyrrolidin-2-one is the used as the radio ligand that binds selectively to SV2C whereby the differential binding of the test compounds is measured, the IC5 Q S of the test compounds are calculated under conditions known to a person skilled in the art.
  • the following 3 seizure models are viewed to be predictive in the assessment of compounds that are potentially useful in the control of seizures in patients with epilepsy.
  • the 6 Hz seizure model has been proposed to be useful for identification of compounds possessing clinical activity in patients with refractory seizures (Barton et al., Epilepsy Res. (2001 ), 47, 217-27).
  • the objective of this test is to evaluate the anticonvulsant potency of a compound in sound-susceptible mice, a genetic animal model with reflex seizures.
  • seizures are evoked without electrical or chemical stimulation and the seizure types are, at least in part, similar in their clinical phenomenology to seizures occurring in man (Loscher W. & Schmidt D., Epilepsy Res. (1998), 2, 145-181 ; Buchhalter J.R., Epilepsia (1993), 34, S31 -S41 ).
  • the experimental design consisted of several groups, one group receiving the vehicle control and the other groups different doses of the test-compound.
  • the compounds are administered intraperitoneally 60 minutes before the induction of audiogenic seizures.
  • the range of the doses administered had a logarithmic progression, generally between 1.0 x 10-5 mol/kg and 1.0 x 10-3 mol/kg, but lower or higher doses are tested if necessary.
  • mice For testing, the animals are placed in small cages, one mouse per cage, in a sound- attenuated chamber. After a period of orientation of 30 seconds, the acoustic stimulus (90 dB, 10-20 kHz) is delivered for 30 seconds via loudspeakers positioned above each cage. During this interval, the mice are observed and the presence of the 3 phases of the seizure activity namely wild running, clonic and tonic convulsions, is recorded. The proportion of mice protected against wild running, clonic and tonic convulsions, respectively, is calculated.
  • the acoustic stimulus 90 dB, 10-20 kHz
  • an ED50 value i.e. the dose producing 50 % protection relative to the control group, together with 95 % confidence limits, is calculated using a Probit Analysis (SAS/STAT® Software, version 6.09, PROBIT procedure) of the proportions of protected mice for each of the 3 phases of the seizure activity.
  • SAS/STAT® Software version 6.09, PROBIT procedure
  • mice Male NMRI mice (Charles River, France) weighing 20-30 g are used in all experiments. The animals are kept on a 12/12-h light/dark cycle with lights on at 0600 h and are housed at a temperature maintained at 20-21 °C and at humidity of about 40%. The mice are housed in groups of 10 per cage (38 x 26 x 14 cm). All animals have free access to standard pellet food and water before random assignment to experimental groups consisting of 10 mice each. All animal experiments are done according to the Helsinki declaration and conducted in accordance with the guidelines of the European Community Council directive 86/609/EEC. A local ethical committee approved the experimental protocol.
  • the 6 Hz model is carried out according to a previously described protocol (Kaminski et al., Epilepsia (2004), 45, 864-867). Briefly, corneal stimulation (44 mA, 0.2 ms-duration monopolar rectangular pulses at 6 Hz for 3 s) is delivered by a constant-current device (ECT Unit 57800; Ugo Basile, Comerio, Italy). A drop of 0.4% oxybuprocaine hydrochloride (Unicaine, Thea, France) is placed on the eyes before electrical stimulation. During the stimulation, mice are manually restrained and released into the observation cage (38 x 26 x 14 cm) immediately after the current application.
  • the seizures are often preceded by a brief period (-2-3 s) of intense locomotor agitation (wild running and jumping).
  • the animals then exhibit a "stunned" posture associated with rearing, forelimb automatic movements and clonus, twitching of the vibrissae, and Strub-tail.
  • animals resume their normal exploratory behavior.
  • the experimental endpoint is protection against the seizure.
  • the animal is considered to be protected if it resumes its normal exploratory behavior within 7 s from the stimulation.
  • In vivo activities determined for test compounds are typically comprised between 0.05 mg/kg and 10 mg/kg.
  • Pentylenetetrazol is used at the previously established CD97 dose of 89 mg/kg; a convulsive dose inducing clonic convulsions of all four extremities in 97% of mice (Klitgaard et al., Eur. J. Pharmacol. (1998), 353, 191-206). Immediately following pentylenetetrazol injection the mice are placed individually in Perspex cages and observed for the presence of clonic convulsions in all four extremities and tonic hindlimb extension during 60 min period.

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Abstract

La présente invention concerne des dérivés de 4-oxo-1-imidazolidinyl imidazothiadiazole, leurs procédés de préparation, des compositions pharmaceutiques en contenant et leur utilisation en tant que médicaments.
PCT/EP2012/001657 2011-04-18 2012-04-17 Dérivés de 4-oxo-1-imidazolidinyl imidazothiadiazole Ceased WO2012143116A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015110435A1 (fr) 2014-01-21 2015-07-30 Janssen Pharmaceutica Nv Combinaisons comprenant des modulateurs allostériques positifs ou des agonistes orthostériques de sous-type 2 de récepteur glutamatergique métabotrope, et leur utilisation
CN106279129A (zh) * 2015-05-21 2017-01-04 广西师范大学 合成咪唑烷及其衍生物的杂环结构的简易方法
WO2019011770A1 (fr) 2017-07-10 2019-01-17 Ucb Biopharma Sprl Dérivés de 2-oxo-1,3-oxazolidinyle imidazothiadiazole
WO2019011767A1 (fr) 2017-07-10 2019-01-17 Ucb Biopharma Sprl Dérivés de 2-oxo-1-imidazolidinyl imidazothiadiazole
JP2021505639A (ja) * 2017-12-12 2021-02-18 ユーシービー バイオファルマ エスアールエル ２−オキソ−１−ピロリジニルイミダゾチアジアゾール誘導体
JP2021522290A (ja) * 2018-05-08 2021-08-30 ユーシービー バイオファルマ エスアールエル １−イミダゾチアジアゾロ−２ｈ−ピロール−５−オン誘導体
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

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WO2006128692A2 (fr) * 2005-06-01 2006-12-07 Ucb Pharma, S.A. Derives de 2-oxo-1-pyrrolidine
WO2008132142A2 (fr) * 2007-04-27 2008-11-06 Ucb Pharma S.A. Nouveaux dérivés hétérocycliques utiles pour le traitement des troubles du système nerveux central

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WO2006128692A2 (fr) * 2005-06-01 2006-12-07 Ucb Pharma, S.A. Derives de 2-oxo-1-pyrrolidine
WO2008132142A2 (fr) * 2007-04-27 2008-11-06 Ucb Pharma S.A. Nouveaux dérivés hétérocycliques utiles pour le traitement des troubles du système nerveux central

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EP3827830A1 (fr) 2014-01-21 2021-06-02 Janssen Pharmaceutica NV Combinaisons comprenant des modulateurs allostériques positifs ou des agonistes orthostériques de récepteurs glutamatergiques métabotropes de sous-type 2 et leur utilisation
US12048696B2 (en) 2014-01-21 2024-07-30 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
WO2015110435A1 (fr) 2014-01-21 2015-07-30 Janssen Pharmaceutica Nv Combinaisons comprenant des modulateurs allostériques positifs ou des agonistes orthostériques de sous-type 2 de récepteur glutamatergique métabotrope, et leur utilisation
CN106279129A (zh) * 2015-05-21 2017-01-04 广西师范大学 合成咪唑烷及其衍生物的杂环结构的简易方法
US11155565B2 (en) 2017-07-10 2021-10-26 UCB Biopharma SRL 2-oxo-1,3-oxazolidinyl imidazothiadiazole derivatives
JP2020526532A (ja) * 2017-07-10 2020-08-31 ユーシービー バイオファルマ エスアールエル ２−オキソ−１，３−オキサゾリジニルイミダゾチアジアゾール誘導体
CN110869374A (zh) * 2017-07-10 2020-03-06 Ucb生物制药有限责任公司 2-氧代-1,3-噁唑烷基咪唑并噻二唑衍生物
WO2019011767A1 (fr) 2017-07-10 2019-01-17 Ucb Biopharma Sprl Dérivés de 2-oxo-1-imidazolidinyl imidazothiadiazole
JP7126545B2 (ja) 2017-07-10 2022-08-26 ユーシービー バイオファルマ エスアールエル ２－オキソ－１，３－オキサゾリジニルイミダゾチアジアゾール誘導体
WO2019011770A1 (fr) 2017-07-10 2019-01-17 Ucb Biopharma Sprl Dérivés de 2-oxo-1,3-oxazolidinyle imidazothiadiazole
JP2021505639A (ja) * 2017-12-12 2021-02-18 ユーシービー バイオファルマ エスアールエル ２−オキソ−１−ピロリジニルイミダゾチアジアゾール誘導体
JP7126547B2 (ja) 2017-12-12 2022-08-26 ユーシービー バイオファルマ エスアールエル ２－オキソ－１－ピロリジニルイミダゾチアジアゾール誘導体
JP2021522290A (ja) * 2018-05-08 2021-08-30 ユーシービー バイオファルマ エスアールエル １−イミダゾチアジアゾロ−２ｈ−ピロール−５−オン誘導体
JP7340542B2 (ja) 2018-05-08 2023-09-07 ユーシービー バイオファルマ エスアールエル １－イミダゾチアジアゾロ－２ｈ－ピロール－５－オン誘導体

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