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WO2025155625A1 - Nouveaux composés pour l'imagerie tau - Google Patents

Nouveaux composés pour l'imagerie tau

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Publication number
WO2025155625A1
WO2025155625A1 PCT/US2025/011716 US2025011716W WO2025155625A1 WO 2025155625 A1 WO2025155625 A1 WO 2025155625A1 US 2025011716 W US2025011716 W US 2025011716W WO 2025155625 A1 WO2025155625 A1 WO 2025155625A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
membered heterocycloalkyl
tau
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/011716
Other languages
English (en)
Inventor
Giorgio Giovanni ATTARDO
Jennifer Williford Clemens
Derek Dunn
Carey Horchler
Adam Thomas HOYE
Ximin LI
Hui Xiong
Shyamali Ghosh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of WO2025155625A1 publication Critical patent/WO2025155625A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present disclosure relates to novel compounds; intermediates for preparation of these compounds; methods of using these compounds for tau imaging; compositions and formulations of these compounds for diagnostic imaging; and methods of imaging using these compounds, compositions, and formulations.
  • AD Alzheimer’s disease
  • NFT neurofibrillary tangles
  • AD hyperphosphorylated tau
  • tau aggregates appear in particular brain regions and patterns that are linked to disease risk, onset, and or progression, and these regions and patterns are known to skilled artisans.
  • tau-containing tangles first appear in brain regions that are very closely linked to memory, and pathologic studies show that tangles may correlate even more strongly with cognition than plaques.
  • Signals arising from a tau imaging agent in these regions and patterns can be used by skilled artisans to better monitor and diagnose the risk, onset and progression of the particular disease state.
  • Non-AD tauopathies such as progressive supranuclear palsy (PSP), cortical basal degeneration (CBD), Pick’s disease (PiD), argyrophilic grains disease (AGD), atypical Alzheimer’s disease, primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE) and frontotemporal dementia (FTD).
  • PSP progressive supranuclear palsy
  • CBD cortical basal degeneration
  • PiD cortical basal degeneration
  • ATD argyrophilic grains disease
  • APD argyrophilic grains disease
  • PART primary age-related tauopathy
  • CTE chronic traumatic encephalopathy
  • FTD frontotemporal dementia
  • Detection of early tau accumulation could provide an endpoint for evaluation of therapeutic efficacy in early stage AD patients while identification of a PET ligand for a non-AD tauopathy (e.g.-PSP, CBD, or PiD) would be valuable for disease differentiation and staging in patients and for quantification of therapeutic efficacy.
  • a PET ligand for a non-AD tauopathy e.g.-PSP, CBD, or PiD
  • Improved tau imagining agents may also increase our understanding of the onset and progression of dementia in general and AD and non-AD tauopathies, in particular, which in turn may lead to provide better treatment. [07] There is clinical need for improved tau imaging agents at least for the reasons described above. Moreover, there is a need for tau imaging agents that are selective for AD or non-AD taupathies.
  • the present disclosure provides compounds, compositions, formulations and methods for tau imaging.
  • FIG. 1 depicts autoradiography on PSP brain sections for Compound No. 8( 18 F) for the determination of binding following the protocol described in Example 23.
  • ARG positivity is seen in regions rich in AT8 positive tufted astrocytes, a classical neuropathological hallmark observed in PSP.
  • FIG. 2 depicts autoradiography on CBD brain sections for Compound No. 8( 18 F) for the determination of binding following the protocol described in Example 23.
  • the binding in the white matter (WM) regions of the CBD patients reported to have abundant tau threads and hence a region enriched in tau aggregates.
  • R 2 is H, halogen, or C2-C6 alkenyl
  • R 3 is Ce-Cio aryl or 3- to 6-membered heterocycloalkyl, wherein the Ce-Cio aryl or 3- to 6-membered heterocycloalkyl is substituted with one or more R 3a ; and each R 3a independently is F, 18 F, Ci-Ce alkyl, or 3- to 6-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 3- to 6-membered heterocycloalkyl is substituted with a leaving group, F, or 18 F; provided that the compound is not
  • R 1 is H, halogen, -OH, or Ci-Ce alkoxyl
  • R 3 is Ce-Cio aryl or 3- to 5-membered heterocycloalkyl, wherein the Ce-Cio aryl or 3- to 6-membered heterocycloalkyl is substituted with one or more R 3a ; and each R 3a independently is F, 18 F, Ci-Ce alkyl, or 3- to 6-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 3- to 6-membered heterocycloalkyl is substituted with F or 18 F.
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula la:
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula lb:
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula Id:
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula le:
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is H, iodine, -OH, or -OCH3;
  • R 3 is phenyl, pyrrolidyl, or piperidyl, wherein the phenyl, pyrrolidyl, or piperidyl is substituted with one or more R 3a ; and each R 3a independently is F, 18 F, Ci alkyl, C2 alkyl, C3 alkyl, or azetidinyl, wherein the Ci alkyl, C2 alkyl, C3 alkyl, or azetidinyl is substituted with F or 18 F; provided that the compound is not [18] In some embodiments, R 1 is H.
  • R 1 is -OH.
  • R 2 is H.
  • R 2 is halogen
  • R 2 is bromine or iodine. In some embodiments, R 2 is bromine. In some embodiments, R 2 is iodine.
  • R 3 is phenyl substituted with one or more R 3a . In some embodiments, R 3 is phenyl substituted with one R 3a .
  • R 3a is Ci alkyl, C2 alkyl, or C3 alkyl, wherein the Ci alkyl, C2 alkyl, or C3 alkyl is substituted with F or 18 F. In some embodiments, R 3a is Ci alkyl substituted with F or 18 F. In some embodiments, R 3a is C2 alkyl substituted with F or 18 F. In some embodiments, R 3a is C3 alkyl substituted with F or 18 F.
  • R 2 is H
  • R 3 is Ce-Cio aryl or 3- to 6-membered heterocycloalkyl, wherein the Ce-Cio aryl or 3- to 6-membered heterocycloalkyl is substituted with one or more R 3a ; and each R 3a independently is a leaving group, Ci-Ce alkyl, or 3- to 6-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 3- to 6-membered heterocycloalkyl is substituted with a leaving group.
  • the compound of Formula (II) is a precursor compound for making radiolabeled compounds.
  • the precursor compound may be useful for imagin.
  • the compound, or pharmaceutically acceptable salt thereof, of the compound of formula (II) is: [42]
  • the compounds of the present disclosure were prepared in radiolabeled and nonradiolabeled forms.
  • each of Compound Nos. 1-15, as represented in Table 1, were prepared with a naturally occurring F and a radiolabeled 18 F.
  • the notation “F( 18 F)” is understood to disclose the compound with naturally occurring F, and with the 18 F radioisotope.
  • any reference to a compound by number (e.g., Compound No. 1, Compound No. 2, etc. or Comp. No. 1, Comp. No. 2, etc.) or by structure, encompasses both its naturally occurring isotope (e.g., Comp. No. 1(F)) and its radiolabeled isotope (e.g., Compound No. 1( 18 F)).
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof according to Formula I above as described in the various forms above and one or more of a pharmaceutically acceptable carrier, diluent, or stabilizer.
  • a pharmaceutically acceptable carrier diluent, or stabilizer.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, as described in the various forms above wherein the carrier comprises ethanol, water, and a buffer suitable for injection into a patient.
  • the composition includes sodium chloride in an amount to provide a formulation suitable for injection into a patient.
  • Examples of diluents includes water for injection and saline.
  • the diluent can be included in the pharmaceutical composition in an amount sufficient to provide a concentration of the radiolabeled embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, suitable to facilitate the diagnosis of a patient at risk for or suffering from dementia or AD.
  • stabilizers in particular radiolytic stabilizers, include ethanol, ascorbic acid, monothioglycerol, vitamin E, and cysteine.
  • the compounds of the present disclosure may be formulated as pharmaceutical compositions that are administered for intravenous use in a patient (e.g., in humans). Such pharmaceutical compositions and processes for preparing the compositions are known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (P.P. Gerbino, 21st ed., Lippincott Williams & Wilkins, 2006). Methods of using tau imaging agents for PET imaging of tau are known to those of skill in the art. See e.g.
  • [(18)F]T807 a novel tau positron emission tomography imaging agent for Alzheimer's disease. Xia CF, et al., Alzheimer’s Dement. 2013 Nov; 9(6):666-76.). [(18)F]T807 is also known as [18F]AV- 1451.
  • the invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for imaging tau.
  • the tau imaging formulation may be formulated for use in mammals (e.g., humans).
  • the tau imaging formulation includes a compound according to Formula I, or a pharmaceutically acceptable salt thereof, formulated in 10% EtOH (v/v), 0.45% (w/v) sodium ascorbate in 0.9% sodium chloride.
  • the present disclosure also provides methods of imaging tau comprising introducing into a patient a detectable quantity of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of imaging tau comprising introducing into a patient a pharmaceutical composition comprising a detectable quantity of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of imaging tau comprising introducing into a mammal a detectable quantity of a pharmaceutical composition as described according to the embodiments herein and allowing sufficient time for said pharmaceutical composition to become associated with tau; and detecting the radiolabeled compound.
  • the method for detecting the radiolabeled compound may be PET.
  • the present disclosure provides a method of imaging aggregated tau in a mammal, the method comprising: introducing into a mammal a detectable quantity of a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable excipient; wherein said compound or pharmaceutical composition has an 18 F substituent; allowing sufficient time for said compound or said pharmaceutical composition to become associated with aggregated tau; and detecting said compound or said pharmaceutical composition.
  • the present disclosure provides a method of imaging aggregated tau in a mammal, wherein the mammal is a human.
  • the present disclosure provides a method of imaging aggregated tau in a mammal, wherein the mammal is a human and is suspected of having a neurological disease or disorder.
  • the neurological disease or disorder is Alzheimer’s Disease.
  • the neurological disease or disorder is progressive supranuclear palsy (PSP), cortical basal degeneration (CBD), Pick’s disease (PiD), atypical Alzheimer’s disease, chronic traumatic encephalopathy (CTE), or frontotemporal dementia (FTD).
  • PSP progressive supranuclear palsy
  • CBD cortical basal degeneration
  • PiD Pick’s disease
  • atypical Alzheimer’s disease chronic traumatic encephalopathy
  • FTD frontotemporal dementia
  • the human is suspected of having early Alzheimer’s disease tau.
  • the human is suspected of having non- Alzheimer’s disease tau.
  • the present disclosure provides the use of compounds of Formula I or pharmaceutically acceptable salts thereof. Further, the present disclosure also provides that the compounds (or pharmaceutically acceptable salts) of Formula I may be used, for the manufacture of a radiopharmaceutical agent for imaging tau in a patient (e.g., humans).
  • the present disclosure provides a process of making a compound according to Formula I with a 18 F radiolabel.
  • the present disclosure provides methods of preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, from a precursor compound outlined herein.
  • alkyl As used herein, “alkyl”, “Ci, C 2 , C 3 , C 4 , C 5 or C 6 alkyl” or “Ci-C 6 alkyl” is intended to include Ci, C 2 , C 3 , C 4 , Cs or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C 3 , C 4 , C> or Ce branched saturated aliphatic hydrocarbon groups.
  • Ci-Ce alkyl is intended to include Ci, C 2 , C 3 , C 4 , Cs and Ce alkyl groups.
  • LG refers to a halogen (e.g., Cl, Br, or I), a trialkyl ammonium, alkyl sulfonate, trifluoroalkyl sulfonate, or aryl sulfonate.
  • Alkyl sulfonates of the present disclosure include C1-C4 alkyl sulfonate.
  • Aryl sulfonates of the present disclosure include phenyl sulfonate, wherein the phenyl group is optionally substituted once with C1-C4 alkyl, halogen or nitro.
  • the leaving group is an alkyl sulfonate (e.g., methanesulfonate (mesylate) or ethanesulfonate).
  • the leaving group is an aryl sulfonate (e.g., benzenesulfonate, 4- methylbenzenesulfonate (tosylate), 4-bromobenzenesulfonate, or 4- nitrobenzenesulfonate).
  • radiolabeled compound refers to one of the compounds described below that includes an 18 F atom.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention considered to be acceptable for clinical and/or veterinary use.
  • pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et al., "Pharmaceutical Salts” , Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
  • the term “effective amount” refers to an amount that is a dosage, which is effective in imaging tau.
  • the attending physician can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • determining an effective amount or dose of a compound a number of factors are considered, including, but not limited to whether the compound or its salt, will be administered; the co-administration of other agents, if used; the species of mammal; its size, age, and general health; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances.
  • the term "patient” refers to a mammal.
  • the patient is a human or companion mammal, such as, a dog or cat; or other domesticated mammal, such as, a cow, pig, horse, sheep, rabbit, mouse, rat, and goat.
  • compositions are formulated as an injectable solution.
  • the solution can include a compound of the present disclosure in an amount effective for treating a patient in need of treatment.
  • the compounds of Formula I have been discovered to be advantageous for tau imaging, including, for example, in human clinical imaging.
  • the compounds of Formula I possess a combination of useful properties for tau imaging, including high affinity for tau.
  • some of the compounds of Formula I demonstrate advantageous tissue distribution and pharmacokinetics.
  • some of the compounds demonstrate high affinity binding to tau, and label tau containing tissue samples from AD brain with high selectivity with respect to A
  • AD Alzheimer’s disease
  • Boc or “BOC” refers to tert-butoxy carbonyl
  • cat amt refers to catalytic amount
  • CT or “CAT” refers to computer tomography
  • DMAP 4- (dimethylamino)pyridine
  • DMF dimethylformamide
  • DMPAO 2,6-Dimethylanilino)(oxo)acetic acid
  • DMSO dimethylsulfoxide
  • EOS refers to end of synthesis
  • EESI electrospray ionization
  • EtOH refers to ethanol
  • HPLC refers to
  • the compounds of the present disclosure, or salts thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the schemes, preparations, precursors, and examples below.
  • the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds or salts of the present disclosure.
  • the products of each step in the schemes below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • all substituents unless otherwise indicated, are as previously defined.
  • the reagents and starting materials are readily available to one of ordinary skill in the art.
  • Radiolabeling synthesis was performed using a GE TRACERlab FXF-N automated radiosynthesizer with starting activity in the range of 0.1 Ci - 2.4 Ci.
  • the range of averaged synthesis time was 60 ⁇ 10 minutes and the range of averaged decay- corrected yield was 12-54%.
  • the diluted crude reaction was loaded onto a semi -preparative HPLC column for purification using isocratic elution (Agilent ZORBAX Eclipse XDB-C18 9.4 x 250 mm; flow rate of 4 mL/minutes, see Table 4 for details).
  • the isolated fraction from the HPLC column contained the radiolabeled compound as identified in Table 4.
  • Step 1 Synthesis of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine.
  • Step 2 Synthesis of 2-(4-(3-fluoropropyl)piperidin-l-yl)-8- methoxybenzo[4,5]imidazo[l,2-a]pyrimidine.
  • Step 1 Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2- y 1 )py rrol i di n-3 -yl)methanol .
  • Step 2 Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2- yl)pyrrolidin-3-yl)methyl 4-methylbenzenesulfonate.
  • Step 3 Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2- yl)pyrrolidin-3-yl)methyl 4-methylbenzenesulfonate.
  • the organic layer was washed with water (2 x 5 mL), dried over sodium sulfate, filtered, and concentrated.
  • the residue was purified on silica gel using a gradient of 0 to 4% methanol in dichoromethane as eluent.
  • the fractions containing the product were combined, concentrated and redissolved in 1 mL of 4:1 acetonitrile methanol, and purified on a 5.5 g C18 reverse phase column using a gradient of 95% to 85% water in acetonitrile with 0.1% trifluoroacetic acid as the gradient.
  • the purification was repeated using 4: 1 water: acetonitrile as the loading solvent.
  • the fractions containing product were combined and concentrated to remove acetonitrile.
  • Step 1 Synthesis of 2-[4-(2-fluoroethyl)piperi din- l-yl]pyrimido[ 1,2- A]benzimidazole.
  • Step 2 Synthesis of 7-bromo-2-(4-(2-fluoroethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2- a]pyrimidine.
  • Step 1 Synthesis of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidin-8-ol.
  • Step 2 Synthesis of 2-(4-(2-fluoroethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2- a]pyrimidin-7-ol.
  • the reaction was heated at 100 °C for 6 hours, determined to be complete by LCMS, and cooled to room temperature.
  • the reaction mixture was diluted with 10 mL methylene chloride/methanol, adhered to 3 g silica gel, and concentrated.
  • the crude product was purified on silica gel using a gradient of 0 to 5% methanol in dichoromethane as eluent to afford the title compound as a yellow solid (10 mg, 39%).
  • Step 1 Synthesis of l-(4-bromophenyl)-3 -fluoroazetidine.
  • Step 3 Synthesis of 2-(4-(3-fluoroazetidin-l-yl)phenyl)benzo[4,5]imidazo[l,2- a]pyrimidine.
  • the reaction was determined to be complete by LCMS.
  • the reaction mixture was concentrated over silica gel, dried under high vac, and then purified by column chromatography using a gradient of 0 to 10% methanol in methylene chloride as eluent to afford 2-(4-(3-fluoroazetidin-l-yl)phenyl)benzo[4,5]imidazo[l,2-a]pyrimidine (84 mg, 77 %) as a light brown solid.
  • Step 1 Synthesis of tert-butyl 4-(2-fluoroethyl)piperidine-l -carboxylate.
  • Step 2 Synthesis of 4-(3-fluoropropyl)piperidine.
  • LCMS showed conversion to the di-tosylate.
  • the reaction mixture was treated with 2 mL of IM KOH (aq) and stirred vigorously for 2 hours.
  • LCMS showed conversion to the mono-tosylate.
  • the reaction mixture was diluted with water and extracted with methylene chloride (x3). The combined organics were dried over sodium sulfate, filtered, and concentrated over silica gel.
  • Step 1 Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2- yl)piperidin-4-yl)methanol.
  • Step 2 Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2- yl)piperidin-4-yl)methyl methanesulfonate.
  • Step 1 Synthesis of 2-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3- yl)ethan-l-ol.
  • Step 2 Synthesis of 2-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3- yl)ethyl methanesulfonate.
  • Step 1 Synthesis of (R)-l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3- ol.
  • Step 2 Synthesis of (R)-l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3- yl methanesulfonate.
  • Step 1 Synthesis of 3-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4- yl)propan-l-ol.
  • Step 2 Synthesis of 3-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4- yl)propyl methanesulfonate.
  • Step 1 Synthesis of (l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4- yl)methanol.
  • Step 2 Synthesis of (l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4- yl)methyl methanesulfonate.
  • the experiment uses 10 um adjacent sections from cases clinically diagnosed with AD, PSP or CBD confirmed as tau positive by IHC employing AT8 or AT 100 antibody using standard techniques or control tissue defined as amyloid and tau negative by IHC. Sections are covered with Compound No. 8( 18 F) (40 pCi/ml in binding buffer (2.5% dimethylsulfoxide + 2.5% ethanol in IX PBS, pH 7.4). After a 60 min incubation at room temperature, unbound ligand is removed through successive wash cycles (2 minutes in IX PBS, 2 minutes 30% ethanol in IX PBS, 2 minutes in 70% ethanol in IX PBS, 2 minutes in IX PBS). After drying under the hood, the sections are exposed overnight to a phosphorimaging screen.
  • the autoradiography signal recorded on the phosphorimaging screen is read using an Amersham Typhoon Bio-Imaging System. Individual tissue samples are compared to adjacent slices which have been stained with either AT8 or AT 100. A positive correlation with tau antibody indicates binding to the non-AD tau being studied (PSP or CBD).

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Abstract

La présente invention concerne de nouveaux composés de formule : dans laquelle R1, R2, et R3 sont tels que décrits dans la description, des procédés de préparation de ceux-ci, des compositions pharmaceutiques les comprenant, des formulations d'imagerie tau, et des procédés d'utilisation des composés pour l'imagerie tau.
PCT/US2025/011716 2024-01-16 2025-01-15 Nouveaux composés pour l'imagerie tau Pending WO2025155625A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
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