WO2018024643A1 - Dérivés de 9h-pyrrolo-dipyridine - Google Patents

Dérivés de 9h-pyrrolo-dipyridine Download PDF

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WO2018024643A1
WO2018024643A1 PCT/EP2017/069234 EP2017069234W WO2018024643A1 WO 2018024643 A1 WO2018024643 A1 WO 2018024643A1 EP 2017069234 W EP2017069234 W EP 2017069234W WO 2018024643 A1 WO2018024643 A1 WO 2018024643A1
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tau
formula
compound
pyrrolo
brain
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Joël MERCIER
Celine VERMEIREN
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UCB Biopharma SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

Definitions

  • the invention relates to 9/-/-pyrrolo-dipyridine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as radiopharmaceuticals in particular as imaging agents for the detection of Tau aggregates.
  • AD Alzheimer's disease
  • PSP progressive supranuclear palsy
  • PSP initially causes symptoms that are often misdiagnosed for Parkinson's disease, affecting balance, gait and eye movement. The disease progresses rapidly, with patients falling, being wheelchair bound and requiring nursing home care. Ultimately, PSP causes death.
  • Symptomatic treatments for AD and PSP provide limited benefit and there are currently no disease-modifying treatments available.
  • the brain pathology observed in AD includes amyloid plaques and neurofibrillary tangles. Neurofibrillary tangles are also observed in PSP.
  • the main protein component of neurofibrillary tangles is hyperphosphorylated, aggregated microtubule-associated protein tau (Tau) forming paired helical filaments (PHF).
  • Tau is a neuronal protein that is unfolded under physiological conditions, associated with microtubules, and which may play a role with their assembly and stabilization (Clavaguera et al. Brain Pathol. 2013 2013 23(3):342-9).
  • Six isoforms were described, three containing three microtubule binding regions (MTBR), three containing four MTBR; the longest form comprises 441 amino acids.
  • Tau undergoes post-translational modifications (hyper- phosphorylation, acetylation, nitrosylation, glycosylation, etc) and self-aggregates on its MTBR.
  • This aggregated post-translationally modified protein is the major component of paired helical filament (PHF) which is the building block of neurofibrillary tangles observed in a range of tauopathy diseases.
  • PHF paired helical filament
  • tauopathies have been described to contain Tau inclusions (Clavaguera et al. Brain Pathol. 2013 2013 23(3):342-9) and may be caused by Tau accumulation:
  • Alzheimer's disease Amyotrophic lateral sclerosis/parkinsonism-dementia complex; Argyrophilic grain disease; Chronic traumatic encephalopathy; Corticobasal degeneration; Diffuse neurofibrillary tangles with calcification; Down syndrome; Familial British dementia; Familial Danish dementia; Frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations; Frontotemporal lobar degeneration (caused by C90RF72 mutations); Gerstmann-Straussler-Scheinker disease; Guadeloupean parkinsonism; Myotonic dystrophy; Neurodegeneration with brain iron accumulation; Niemann-Pick disease, type C; Non- Guamanian motor neuron disease with neurofibrillary tangles; Pick disease; Post-encephalitic parkinsonism; Prion protein cerebral amyloid angiopathy; Progressive subcortical gliosis; Progressive supranuclear palsy; SLC9A6-related mental
  • An imaging agent that is selective for Tau aggregates compared to other aggregated pathological proteins would allow in-vivo visualization of Tau aggregates in patients therefore allowing a more accurate diagnosis and monitoring of treatment effects. Additionally it would better define the time course of the disease in each individual patient, and assess the efficacy of disease-modifying, tau-targeted treatments.
  • the present invention relates to 9H-pyrrolo-dipyridine derivatives, compositions, methods and use as imaging agents for the in vivo detection of Tau aggregates in the brain.
  • a further aspect of the present invention consists of novel agents that demonstrate high binding to Tau aggregates and have low non-specific binding and high selectivity compared to other unrelated proteins.
  • Potential ligands for detecting Tau aggregates in the living brain must be brain penetrant and possess high affinity for Tau aggregates and specificity, especially compared to other aggregated proteins (beta-amyloid, osynuclein, TDP-43, ...) and compared to other unrelated proteins.
  • successful neuroimaging radiotracers must have appropriate lipophilicity (logD 1-3), low non-specific brain tissue binding (Fu ⁇ 5%), low molecular weight ( ⁇ 450) and show rapid clearance from blood. (Zhang et al J Med Chem. 2013 56(1 1 ):4568-4579).
  • Potential Tau PET ligands have been described for example in Chien et al. J Alzheimers Dis.
  • the object of the present application is to identify a Tau PET ligand that will improve the identification of potential patients with excess of Tau aggregates in the brain.
  • the present invention describes compounds that may be used for binding and imaging Tau aggregates, especially for diagnostic and monitoring imaging of Tau aggregates in neurodegenerative diseases such as Progressive supranuclear palsy, Alzheimer's patients, Pick's disease, chronic traumatic encephalopathy, corticobasal degeneration, Frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations, Frontotemporal lobar degeneration, Amyotrophic lateral sclerosis/parkinsonism-dementia complex, Down syndrome and related tauopathies as listed in the background section.
  • neurodegenerative diseases such as Progressive supranuclear palsy, Alzheimer's patients, Pick's disease, chronic traumatic encephalopathy, corticobasal degeneration, Frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations, Frontotemporal lobar degeneration, Amyotrophic lateral sclerosis/parkinsonism-dementia complex, Down syndrome and related tauopathies as listed in the background section.
  • Tricyclic carboline and carbazole compounds are described for example in US-6, 177,440 as inhibitors of the human non-pancreatic secretory phospholipase A2 (SPLA2) for the treatment of septic shock and in WO 2013/176698 and US-8,491 ,869 as senile plaques and neurofibrillary tangles binders for the imaging of ⁇ -Amyloid deposits and Tau aggregates.
  • SPLA2 human non-pancreatic secretory phospholipase A2
  • WO 2009/102498 describes compounds and methods of diagnosing Alzheimer's Disease or a predisposition thereto in a mammal, the method comprising administering to the mammal a diagnostically effective amount of a radiolabeled compound, wherein the compound is selected from the group consisting of radiolabeled flavones, coumarins, carbazoles, quinolinones, chromenones, imidazoles and triazoles derivatives, allowing the compound to distribute into the brain tissue, and imaging the brain tissue, wherein an increase in binding of the compound to the brain tissue compared to a normal control level of binding indicates that the mammal is suffering from or is at risk of developing Alzheimer's Disease.
  • a radiolabeled compound wherein the compound is selected from the group consisting of radiolabeled flavones, coumarins, carbazoles, quinolinones, chromenones, imidazoles and triazoles derivatives
  • MAO-A monoamine oxidase-A enzyme
  • R is hydrogen or tritium; and F is fluoro or 18 fluoro or to a pharmaceutically acceptable acid addition salt.
  • WO 2015/052105 describes specifically 2-(6-fluoro-pyridin-3-yl)-9H-dipyrido[2,3-b;3',4'-d]pyrrole (lUPAC name : 2-(6-fluoropyridin-3-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine) ;
  • the present invention relates to compounds of formula I, or a pharmaceutically acceptable acid addition salt,
  • any H of the formula is H or its 2 H or 3 H isotope ;
  • any C of the general formula is C or its radioactive isotope 14 C, or 11 C ;
  • any F of the formula is F or its radioactive isotope 18 F
  • any H of the general formula I is H or is its 2 H or 3 H isotope.
  • C of the general formula on a benzylic methyl is C or is its radioactive isotope 14 C or 11 C.
  • any F of the general formula is F or is its radioactive isotope 18 F. Best results have been obtained with the compound 2-(6-fluoro-5-methylpyridin-3-yl)-9H- pyrrolo[2,3-b:4,5-c']dipyridine.
  • pharmaceutically acceptable salt or “pharmaceutically acceptable acid addition salt” according to the invention embraces 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, oxalic, 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
  • compounds of formula I or their pharmaceutically acceptable salts may be administered in the form of a pharmaceutical composition.
  • another embodiment of the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a detectable amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.
  • the compounds of formula I may be used for diagnostic imaging of Tau-aggregate deposits in the brain of a mammal.
  • another embodiment of the present invention is a method of imaging Tau aggregates, including introducing into a mammal a detectable quantity of a pharmaceutical composition of a compound of formula I ; allowing sufficient time for the compound of formula I to be associated with Tau aggregates in the mammal brain ; and detecting the compound of formula I associated with Tau aggregates.
  • the compounds of formula I can be used for diagnostic and monitoring imaging of Tau aggregates in the brain of human patients suffering from a tauophathy as listed above.
  • the present invention concerns a compound as listed above for use as diagnostic and monitoring imaging tool of Tau aggregates in the brain.
  • the present invention concerns a radiolabeled compound containing an isotope compound of formula I for use as diagnostic and monitoring imaging tool of tau aggregates in the brain.
  • the present invention concerns a compound as listed above for use as a medicament.
  • the present invention concerns a compound as listed above for use as a medicament in the treatment of neurodegenerative diseases.
  • the present invention concerns a pharmaceutical composition containing a compound as listed above as well as pharmaceutically acceptable excipients.
  • compounds of general formula I may be prepared by a Suzuki coupling reaction of a chloropyridine intermediate II and a boronic acid (or its corresponding boronic ester or trifluoroborate salt) III:
  • This reaction may be performed in the presence of classical palladium catalytic systems such as [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) or Pd2(dba3)2/Xantphos or other catalytic system known by the person skilled in the art, in the presence of a base such as Na2CC>3 or K3PO4 in a solvent such as dioxane or n-butanol at a temperature ranging from 80 to 120°C.
  • a base such as Na2CC>3 or K3PO4
  • a solvent such as dioxane or n-butanol
  • compounds of general formula I may be prepared by a Suzuki coupling reaction of a chloropyridine intermediate IV protected by a suitable group (PG) known from the person skilled in the art and a boronic acid (or its corresponding boronic ester or trifluoroborate salt) III, followed by protecting group removal.
  • PG suitable group
  • Protection of intermediates II may for example be performed in the presence of SEM-CI with a suitable base such as NaH in a solvent such as DMF at a temperature ranging from 0°C to 25°C.
  • the Suzuki reaction may then be performed as described above while the SEM protecting group may typically be removed in a 1 to 1 TFA/DCM mixture at room temperature or in any other conditions known by the person skilled in the art.
  • Tricyclic chloro-intermediates of formula II may be prepared by Suzuki coupling of a suitable amino-iodo-pyridine VI with the boronic acid VII, followed by intramolecular cyclization of intermediate VIII according to the equation:
  • This Suzuki coupling reaction may be performed in the presence of classical palladium catalytic systems such as Bis(triphenylphosphine)palladium(ll) dichloride or other catalytic system known by the person skilled in the art, in the presence of a base such as Na2CC>3 or K3PO4 in a solvent such as dioxane or n-butanol at a temperature ranging from 80 to 120°C.
  • classical palladium catalytic systems such as Bis(triphenylphosphine)palladium(ll) dichloride or other catalytic system known by the person skilled in the art
  • lodopyridine of formula VI is commercially available or may be prepared according to any procedure known to the person skilled in the art.
  • Intermediates of formula VIII may then be cyclized into compounds of formula II in the presence of a base such as LiHMDS or any similar base known from the person skilled in the art, in a solvent such as THF at a temperature of 90°C.
  • a base such as LiHMDS or any similar base known from the person skilled in the art
  • a solvent such as THF
  • deuterated or tritiated compounds of formula I may be prepared by direct Hydrogen isotopic Exchange (HIE) using methods know from the people skilled in the art:
  • This HIE reaction may be performed in the presence of the well known Crabtree's iridium catalyst, [(COD)lr(py)PCy3]PFe, Kerr's iridium-carbene catalysts or any similar catalyst known from the person skilled in the art, in a solvent such as THF or DMF in the presence of deuterium or tritium gas.
  • the deuterated or tritiated compounds of formula I may be prepared by reduction of the corresponding mono-, di- or tri-iodide or bromide using methods known from the people skilled in the art:
  • This reduction reaction may be performed in the presence of various palladium catalysts or any similar catalyst known from the person skilled in the art, in a solvent such as THF or DMF in the presence of deuterium or tritium gas.
  • the iodo- or bromo-substituted I may be prepared by any of the aforementioned method starting from the corresponding iodo- or bromo-substituted reagents or intermediates or by bromination/iodination using brominating agents, such as N-bromosuccinimide, known to the person skilled in the art.
  • the deuterated or tritiated compounds of formula I may be prepared by a Suzuki coupling reaction of a deuterated or tritiated chloropyridine intermediate II and a boronic acid (or its corresponding boronic ester or trifluoroborate salt) III:
  • deuterated or tritiated chloropyridine intermediates II may be prepared by any of th aforementioned methods. PREPARATION OF COMPOUNDS
  • Crude materials could be purified by normal phase chromatography, (acidic or basic) reverse phase chromatography, chiral separation or recrystallization.
  • Tritium labeling of the compounds has been performed by Asclepia MedChem Solutions through direct hydrogen-tritium exchange according to the general method described hereafter. HPLC analysis:
  • HPLC chromatograms are recorded as follows,
  • HPLC analysis is performed with Shimadzu HPLC system equipped with LC-2010 CHT module, SPD-M20A photodiode array detector (210-400 nm), by using column YMC Triart C-18 (150 X 4.6)mm 3 ⁇ . Gradient elution is done with 5 mM ammonium formate in water +0.1 % formic acid (Phase A), and Acetonitrile+5%solvent A+0.1 % formic acid (Phase B), with gradient 5-95% B in 8.0 min hold till 13.0 min, 5%B at 15.0 min hold till 18.0 min. HPLC flow rate: 1.0 ml/min, injection volume: 10 ⁇ .
  • HPLC analysis is performed with Shimadzu HPLC system equipped with LC-2010 CHT module, SPD-M20A photodiode array detector (210-400 nm), by using column YMC Triart C-18 (150 X 4.6)mm 3 ⁇ . Gradient elution is done with 5 mM ammonium formate in water +0.1 % Ammonia (Phase A), and Acetonitrile+5%solvent A+0.1 % Ammonia (Phase B), with gradient 5-95% in 8.0 min hold till 13.0 min, 5%B at 15.0 min hold till 18.0 min. HPLC flow rate.
  • LCMS Analysis :
  • Shimadzu 201 OEV single quadrupole mass spectrometer is used for LC-MS analysis.
  • This spectrometer is equipped with an ESI source and LC-20AD binary gradient pump, SPD-M20A photodiode array detector (210-400 nm). Data is acquired in a full MS scan from m/z 70 to 1200 in positive and negative mode.
  • the reverse phase analysis is carried out by using Waters XBridge C 18 (30 X 2.1 )mm 2.5 ⁇ column.
  • MS parameters Detector voltage 1.5 kV.
  • Source block temperature 200°C.
  • Desolvation temperature 240°C.
  • Shimadzu 201 OEV single quadrupole mass spectrometer is used for LC-MS analysis.
  • This spectrometer is equipped with an ESI source and LC-20AD binary gradient pump, SPD-M20A photodiode array detector (210-400 nm). Data is acquired in a full MS scan from m/z 70 to 1200 in positive and negative mode.
  • the reverse phase analysis is carried out by using Waters XBridge C 18 (30 X 2.1 )mm 2.5 ⁇ column Gradient elution is done with 5 mM ammonium formate in water +0.1 % Ammonia (solvent A), or Acetonitrile +5% solvent A+0.1 % Ammonia (solvent B), with gradient 5-95% B in 4.0 min hold till 5.0 min, 5%B at 5.1 min hold till 6.5 min. HPLC flow rate: 1.0 ml/min, injection volume: 5 ⁇ .
  • MS parameters Detector voltage 1.5 kV.
  • Source block temperature 200°C.
  • Desolvation temperature 240°C.
  • MgSCU Magnesium sulfate
  • Na2SC>4 Sodium sulfate
  • Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
  • TEA Triethyl amine
  • TFA Trifluoroacetic acid
  • This procedure exemplarily describes the preparation of [ 3 H]-labeled compounds by direct Hydrogen Isotope Exchange.
  • reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to afford a residue that was dissolved in water and extracted with ethyl acetate.
  • organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford the crude product, which was further purified by silica gel (100:200 mesh) column chromatography to afford 2',6'-dichloro-[3,3'-bipyridin]-4-amine (i1 ) (2.9 g, Yield 44%).
  • the reaction mixture was filtered, washed with H2O (20 ml_) and dried in vacuo.
  • the crude obtained was purified by triturating with CH3CN (20 ml_), pentane (20 ml_) and dried in vacuo to afford 2-(6-fluoro-5-methylpyridin-3-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine 1 (0.14 g, 89%) as off-white solid.
  • Human K18/K19 recombinant Tau fibrils were prepared as follow described. His-tagged K18 and K19 Tau containing respectively four and three repeats microtubule binding domain were cloned into a pET expression vector. Expression vectors were transformed into E.coli strain BL21 (DE3), cultured and expression induced with isopropyl ⁇ -D-thiogalactoside. Harvested E. Coli were lysed mechanically before purification of His-tagged proteins by fast protein liquid chromatography (nickel charged resin Ni-NTA superflow kit from Qiagen, Venlo, Netherlands). His-Tag was removed from K18 by cleavage with Tobacco Etch Virus protease.
  • K18 and K19 His-tagged Tau were suspended into phosphate buffered saline solution (PBS, pH 7.4), flash frozen and stored at -80°C.
  • Tau K18 and Tau K19-His were thawed and mixed (both at -300 ⁇ ). Mixture was filtered through a 0.22 ⁇ membrane. Sample was shaken in thermomixer (Eppendorf, Rotselaer, Belgium) at 750 rpm, 37°C for 96 hours. Fibril mixture was recovered, aliquotted and stored at - 80°C until use.
  • MAO monoamine oxidase
  • OFA Sprague-Dawley rats 200 to 300 g were purchased from Charles River (Saint-Germain- Nuelles, France). Animals were sacrificed by decapitation and brain was quickly removed and dissected. The reported experiments were carried out in accordance with the UCB ethical committee for animal experimentation. Crude cerebral cortex membranes were prepared as described in Gillard et al. (Eur J Pharmacol. 2003 Sep 30;478(1 ):1-9).
  • Compound selectivity for Tau protein was assessed at CEREP (Celle-l'Evescault, France) as compared to a broad panel of receptors, enzymes and ion channels. Compound was tested at 10 ⁇ in radioligand competitive binding assays for most of the targets except for MAO-A, MAO-B, COMT, COX1 and 2, AChE, GABA transaminase, LCK, cNOS, PDE3A, 4D2 and 7A and PLA2 in which case functional enzyme assays were performed.
  • Compound affinity was measured using radioligand in vitro binding assays as described above.
  • the Brain free faction was carried out in duplicate at a single concentration of 1 ⁇ after 4h of equilibrium dialysis.
  • mice Male Sprague-Dawley Rat (Harlan, Bresso, Italy) brain homogenate were prepared in PBS, pH 7.4 at 25% w/vy using a Precellys 24-dual tissue homogenizer (BERTIN technologies, Montigny-le- Bretonneux, France). 200 [it brain homogenate was incubated with 1 ⁇ test compound or reference compound (propranolol, Sigma, St Louis, United states) (1 % DMSO final) for at least 30 min at 37°C under agitation before loading in a retentate chamber of a RED Device insert (8K MWCO, Thermo ScientificTM PierceTM RED Device, Waltham, United states). 350 ⁇ _ PBS pH 7.4 was loaded in the other chamber of the insert. The Red device reusable base counting insert containing insert with both samples and buffer was sealed and incubated during 4h at 37°C, 300 rpm, on an orbital shaker.
  • BERTIN technologies Montigny-le- Bretonneux, France. 200
  • the LC system used was an Agilent 1290 (Agilent, Santa Clara, United states) coupled with a API5000 mass spectrometer (ABSciex, Framingham, United states) .
  • the software was analyst 1.5.2. (Agilent, Santa Clara, United states), the analytical column was an Aquity UPLC HSS T3 (30x2.1 mm, 1.8 ⁇ , Waters, Saint- Quentin , France) operated at 40°C. Analysis were performed in the gradient described below. Gradient used for LC MS/MS :
  • eluent A was 0.1 % formic acid in H2O (Biosolve, Dieuze, France)
  • eluent B was 0.1 % formic acid in acetonitrile (Biosolve, Dieuze, France).
  • the flow was directly injected into the electrospray source.
  • the Fu brain (%) was calculated using the following equation :
  • Fu brain (%) (1/ (1 +((1/((fu homogenate )-1 )xD))) x100

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Abstract

L'invention concerne des dérivés de 9H-pyrrolo-dipyridine de formule (I), des procédés pour leur préparation, des compositions pharmaceutiques les contenant et leur utilisation en tant que produits radiopharmaceutiques, en particulier en tant qu'agents d'imagerie pour la détection d'agrégats de Tau.
PCT/EP2017/069234 2016-08-02 2017-07-28 Dérivés de 9h-pyrrolo-dipyridine Ceased WO2018024643A1 (fr)

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WO2020037004A1 (fr) * 2018-08-14 2020-02-20 Osteoqc Inc. Composés pyrrolo-dipyridine
US11267814B2 (en) 2013-03-14 2022-03-08 OsteoQC, Inc. Compounds for bone growth
US11903949B2 (en) 2018-08-14 2024-02-20 Ossifi Therapeutics Llc Fluoro beta-carboline compounds

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WO2013176698A1 (fr) 2012-05-22 2013-11-28 Eli Lilly And Company Agents d'imagerie à base de carboline et de carbazole pour la détection de dysfonction neurologique
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WO2020037004A1 (fr) * 2018-08-14 2020-02-20 Osteoqc Inc. Composés pyrrolo-dipyridine
US10947236B2 (en) 2018-08-14 2021-03-16 Osteoqc Inc. Pyrrolo-dipyridine compounds
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