WO2024163546A1 - Nouveaux composés pour l'imagerie tau - Google Patents

Nouveaux composés pour l'imagerie tau Download PDF

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WO2024163546A1
WO2024163546A1 PCT/US2024/013667 US2024013667W WO2024163546A1 WO 2024163546 A1 WO2024163546 A1 WO 2024163546A1 US 2024013667 W US2024013667 W US 2024013667W WO 2024163546 A1 WO2024163546 A1 WO 2024163546A1
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compound
alkyl
pharmaceutically acceptable
tau
acceptable salt
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PCT/US2024/013667
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English (en)
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Giorgio Giovanni ATTARDO
Jennifer Williford Clemens
Carey Horchler
Adam Thomas HOYE
Ximin LI
Junichi Kent OGIKUBO
Kristen Marie TERRANOVA
Tho Van THIEU
Hui Xiong
Shyamali Ghosh
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Eli Lilly And Company
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Publication of WO2024163546A1 publication Critical patent/WO2024163546A1/fr

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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
    • C07D471/02—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 two hetero rings
    • C07D471/04—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
    • A61K51/0455—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
    • 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

  • 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.
  • 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
  • tau imaging tau in the brain with improved imaging agents There are several potential benefits of imaging tau in the brain with improved imaging agents. Enhanced tau imaging will improve diagnosis by identifying potential patients, those having high levels of tau in the brain, who may have increased chance of developing AD. Imaging with an improved tau imaging agent will also be useful to monitor tau accumulation and localization, and or progression of AD and or other tauopathies via PET, and when anti-tau drug treatments become available, tau imaging may provide an essential tool for monitoring treatment.
  • the present disclosure provides novel compounds, compositions, formulations and methods for tau imaging. Improved technology advancing the capacity to image tau in patients is also needed to expand the clinical benefits and impact of diagnostic tau imaging. An improved imaging agent may provide better PET images with better clarity due to better tau selectivity. Improved tau imagining agents may also increase our understanding 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.
  • FIG. 1 depicts autoradiography on AD brain sections for Kd determination for Example 3 following the protocol described in Assay Example 32.
  • FIG. 2 depicts autoradiography on AD brain sections for selectivity determination for Example 3 following the protocol described in Assay Example 33.
  • FIG. 3 depicts autoradiography on PSP brain sections for Example 4 for the determination of binding following the protocol described in Assay Example 34.
  • FIG. 4 depicts autoradiography on CBD brain sections for Example 4 for the determination of binding following the protocol described in Assay Example 34. DETAILED DESCRIPTION
  • n 0, 1, or 2;
  • R 1 is H, halo, C1-C3 alkyl, or C3-C6 cycloalkyl
  • R 2 is H, halo, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, -O-(Ci-C 4 alkyl), C1-C4 alkylhalo, C2-C4 alkenylhalo,
  • R 3 is H or F
  • R 4 is F, 18 F, Ci-C 4 -alkylF, Ci-C 4 -alkyl 18 F, -O-(Ci-C 4 -alkyl)F, or -O-(Ci-C 4 - alkyl) 18 F;
  • R 5 is H, halo, or C1-C4 alkyl; provided when n is 0, R 1 is methyl, and R 2 , R 3 , and R 5 are each H, then R 4 is not F or 18 F positioned at the 3 position of the 4-membered ring.
  • n may be 0, 1, or 2. If n is 0, then the ring will be a 4-membered azetidin-l-yl. If n is 1, then the ring will be a 5-membered, pyrrolidin-l-yl ring. If n is 2, then the ring will be a piperidin-l-yl. In each of these ring systems, conventional naming systems identify the nitrogen atom in the 1 position of the ring. In selected embodiments, the R 4 substituent is attached to the 3-position on the ring. In other embodiments, when n is 2 for the piperidin-l-yl ring system R 4 can be positioned at the 3- or 4-position on the ring.
  • R 5 is H, halo, or C1-C4 alkyl.
  • the present disclosure provides a compound of Formula I above, or a pharmaceutically acceptable salt thereof wherein n is 0 or 1; R 1 is H, halo, C1-C2 alkyl, or cyclopropane; R 2 is H, halo, -CH 3 , -OCH 3 , each at the 3-position of the cycloalkyl ring; and R 5 is H, halo, or -CH 3 .
  • R 3 is H or F
  • R 4 is F or 18 F each at the 3-position of the cycloalkyl ring
  • R 5 is H, halo, or -CH 3 .
  • the present disclosure provides a compound of Formula I above, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 ; R 2 is H; R 3 is H; R 4 is F or 18 F positioned at the 3-position of the cycloalkyl ring; and R5 is Cl.
  • the present disclosure provides a compound of Formula I above, or a pharmaceutically acceptable salt thereof, wherein n is 0; R 1 , R 2 , R 3 , and R 5 are each H; and R 4 is F or 18 F.
  • the present disclosure provides a compound of Formula I above, or a pharmaceutically acceptable salt thereof, wherein n is 0; R 1 is H; R 2 is Cl, F or I; R 3 is H; R 4 is F or 18 F; and R 5 is H.
  • the present disclosure provides a compound of Formula I above, or a pharmaceutically acceptable salt thereof, wherein n is 0; R 1 is -CH3 or -CH2CH3; R 2 , R 3 and R 5 are each H; and R 4 is F or 18 F positioned at the 3-position of the 4-membered ring.
  • the present disclosure provides a compound of Formula I above, or a pharmaceutically acceptable salt thereof, where n is 2; R 1 is H; R 2 is H or -CH ; R3 is H; R4 is F, 18 F, -C1-C3 alkylF, or -C1-C3 alkyl 18 F; and R 5 is H.
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is:
  • 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.
  • the buffer may comprise sodium chloride, sodium phosphate, or sodium ascorbate.
  • 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 are preferably formulated as pharmaceutical compositions that are administered for intravenous use in a patient, preferably 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, a or pharmaceutically acceptable salt thereof, for imaging tau.
  • the tau imaging formulation is preferably formulated for use in 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 preferred method for detecting the radiolabeled compound uses PET.
  • 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, preferably humans.
  • the present disclosure provides a process of making a compound according to Formula 1 with a 18F radiolabel.
  • the present disclosure provides methods of preparing a compound of Formula 1, 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 , C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C 4 , C5 or Ce branched saturated aliphatic hydrocarbon groups.
  • Ci-Ce alkyl is intended to include Ci, C 2 , C 3 , C 4 , C5 and Ce alkyl groups.
  • alkyl examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl.
  • a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
  • the halogen or F( 18 F) atom replaces any one of the hydrogen atoms on the carbon chain.
  • the F or 18 F atom is attached to the terminal carbon atom of the chain.
  • the term “-O-(Ci-C 4 alkyl)” refers to an alkoxyl group that includes from 1 to 4 carbon atoms. Said alkyl group can be a straight or branched alkyl chain. When the term is used with the term halogen or specifically an F atom or 18 F atom; the halogen or F( 18 F) can be attached replacing one of the hydrogen atoms attached to the carbon backbone of the chain. In some embodiments, the F atom or 18 F atom is attached to the terminal carbon in a straight chain alkyl group.
  • alkylhalo includes saturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but where at least halogen atom replaces any one of the hydrogen atoms on the carbon chain.
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.
  • a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 -Ce for straight chain, C3-C6 for branched chain).
  • C 2 -C 4 includes alkenyl groups containing two to four carbon atoms.
  • C 2 -Ce includes alkenyl groups containing two to six carbon atoms.
  • Cs-Ce includes alkenyl groups containing three to six carbon atoms.
  • the geometry about the double bond can be described in as either a cis or trans double bond.
  • the term is used with a halogen or specifically an F atom or an 18 F atom, the halogen or F( 18 F) atom can be attached replacing one of the hydrogen atoms attached to the carbon backbone of the alkenyl chain.
  • C2-C6 alkenylene linker is intended to include C2, C3, C4, C5 or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups.
  • alkenylhalo includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but where at least halogen atom replaces any one of the hydrogen atoms on the carbon chain.
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight chain alkynyl groups (e.g, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g, C2-C6 for straight chain, C3-C6 for branched chain).
  • C2-C6 includes alkynyl groups containing two to six carbon atoms.
  • C2-C4 includes alkynyl groups containing two to four carbon atoms.
  • Cs-Ce includes alkynyl groups containing three to six carbon atoms.
  • C2-C6 alkynylene linker is intended to include C2, C3, C4, C5 or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups.
  • C2-C6 alkenylene linker is intended to include C2, C3, C4, C5 and Ce alkenylene linker groups.
  • cycloalkyl refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or Cs-Cs).
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • polycyclic cycloalkyl only one of the rings in the cycloalkyl needs to be non-aromatic
  • LG refers to -NO2, a trialkyl amine, alkyl 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, Methanesulfonate (mesylate) and ethanesulfonate are preferred alkyl sulfonates.
  • Benzenesulfonate, 4- methylbenzenesulfonate (tosylate), 4-bromobenzenesulfonate and 4- nitrobenzenesulfonate are preferred aryl sulfonates.
  • 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.
  • a treating physician, veterinarian, or other medical person will be able to determine an effective amount of the compound for treatment of a patient in need.
  • Preferred pharmaceutical compositions can be 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.
  • Novel compounds of Formula I have been discovered to be advantageous for tau imaging, preferably including human clinical imaging. Some of the preferred compounds of Formula I possess a combination of particularly useful properties for tau imaging, including high affinity for tau. In vivo, some of the preferred compounds demonstrate advantageous tissue distribution and pharmacokinetics. Ex vivo and/or in vitro, 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 electrospray ionization
  • 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 chemes 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.
  • the 5H-pyrido[l,2-a]benzimidazole (IV) can be prepared by reacting an appropriately substituted bromoaniline (II), a bromopyridine (III), a base such as cesium carbonate, a catalytic amount of a copper(I) iodide, and 1,10-phenanthroline in a nonpolar solvent such as a mixture of xylenes. When the reaction is complete, cool the mixture to room temperature and filter to remove any solids. Isolate the desired material using standard procedures. In some of the preparations below, X is a halogen, such as bromine or chlorine. In other preparations, X is a cyclic amine.
  • the cyclic amine can be substituted with linker “L”, which can be a bond or alkyl or O-alkyl.
  • linker “L” can be a bond or alkyl or O-alkyl.
  • R4 can be attached to the cyclic amine via L
  • reaction is cooled to room temperature and added dropwise to water.
  • the solids are isolated by filtration and washed with water.
  • the solids are re-dissolved in 10% methanol in dichloromethane, and adsorbed onto silica gel.
  • the crude product is purified by column chromatography on silica gel using a gradient of 5 to 65% ethyl acetate in hexanes.
  • the mixture was heated at 90 °C for 24 hours.
  • the reaction mixture was cooled to room temperature and water (1000 mL) was slowly added with vigorous stirring.
  • the precipitated solids were isolated by vacuum filtration and dissolved in 10% methanol in methylene chloride (500 mL).
  • the aqueous filtrate was extracted with 10% methanol in methylene chloride (3 x 250 mL).
  • the organic extracts were combined with the solution of isolated solids from the initial aqueous filtration, and dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 1 preparation of l-(7-Vinylbenzo[4,5]imidazo[l,2-a]pyridin-3-yl)azetidin-3- ol
  • Amixture of dimethoxyethane:ethanol:water (7:2: 1 v/v, 5.0 mL) was added to 1- (7-bromobenzo[4,5]imidazo[l,2-a]pyridin-3-yl)azetidin-3-ol (165 mg, 0.516 mmol, 1.0 eq) and potassium carbonate (213 mg, 1.55 mmol, 3.0 eq) in a screw-capped vial.
  • Step 2 preparation of 3-(3-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethoxy)azetidin-l- yl)-7-vinylbenzo[4,5]imidazo[l,2-a]pyridine
  • Step 3 preparation of 2-((l-(7-Vinylbenzo[4,5]imidazo[l,2-a]pyridin-3- yl)azeti din-3 -yl)oxy)ethanol
  • reaction mixture was concentrated, re-suspended in methylene chloride (175 mL), and treated with 1 N aqueous sodium hydroxide solution (150 mL).
  • the biphasic mixture stirred vigorously for 90 minutes, transfered to a separatory funnel and the layers were separated.
  • the organic layer was shaken vigorously with 1 N aqueous sodium hydroxide solution (2 x 100 mL, 1 x 150 mL), dried over magnesium sulfate, filtered, concentrated, and placed under high vacuum.
  • a solution of the isolated solid in 10% methanol in methylene chloride was concentrated over silica gel (24 g) under reduced pressure.
  • Step 2 preparation of 3-(3-((terLButyldimethylsilyl)oxy)azetidin-l-yl)-7- iodobenzo[4,5]imidazo[l,2-a]pyridine
  • Step 1 preparation of 3-(3-((terLButyldimethylsilyl)oxy)azetidin-l-yl)-7- ((trimethylsilyl)ethynyl)benzo[4,5]imidazo[l,2-a]pyridine
  • Step 3 preparation of l-(7-Ethynylbenzo[4,5]imidazo[l,2-a]pyridin-3-yl)azetidin- 3-yl 4-methylbenzenesulfonate
  • the mixture was diluted with aqueous sodium bicarbonate and extracted with 10% methanol in di chloromethane. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure.
  • the crude product was purified by column chromatography on silica (0-6% methanol in dichloromethane).
  • potassium hydroxide IN in water, 0.5 mL
  • methanol :tetrahydrofuran (1 : 1, 2 mL) were added.
  • the mixture was stirred at room temperature for 1 hour until all di-tosylate was converted to the desired compound.
  • Aqueous hydrochloric acid (IN) was added slowly to adjust the pH of the mixture and washed with aqueous sodium bicarbonate.
  • Precursor 26 was prepared from l-(4-Chloro-8-methylbenzo[4,5]imidazo[l,2- a]pyri din-3 -yl)azeti din-3 -yl 4-methylbenzenesulfonate in 81% yield by following essentially the procedure for Precursor 25.
  • 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 6 for details).
  • the isolated fraction from the HPLC column contained the radiolabeled Example as identified in Table 6.
  • the substance was eluted off the cartridge using dehydrated alcohol, USP (0.4 to 1 mL) and combined with a solution of 0.5% sodium ascorbate (w/v) in 0.9% Sodium Chloride Injection, USP, furnishing the product (substance in 10% ethanol (v/v) 0.45% (w/v) sodium ascorbate in 0.9% Sodium Chloride Injection, USP; 4-10 mL total volume).
  • a product sample was removed and analyzed by HPLC to determine radiochemical purity, radiochemical identity, chemical purity and specific activity.
  • the peak(s) from the UV chromatograms and radiochromatogram were integrated for the determination of radiochemical purity (% RCP), radiochemical identity, chemical purity and specific activity.
  • the range of RCP was 92-100%. Stability data for select Examples is provided in Table 7 below.
  • Step 1 preparation of 3-(3-Fluoroazetidin-l-yl)-7-(tributylstannyl)benzo [109] The title compound was prepared from 7-bromo-3-(3-fluoroazetidin-l- yl)benzo[4,5]imidazo[l,2-a]pyridinein 46% yield using substantially the same procedure as Precursor 21, Step 1.
  • Step 2 preparation of 3-(3-Fluoroazetidin-l-yl)-7-iodobenzo[4,5]imidazo[l,2-a]pyridine
  • Ki and Kd Determination of the compound of Example 3 using tau from Alzheimer’s disease human donors.
  • Soluble PHF tau was isolated from the supernatant by affinity chromatography over an Affigel-10 column on which the tau antibody MCI, which recognizes a pathological conformation of tau, has been immobilized (G. A. Jicha, R. Bowser, I. G. Kazam (1997), “Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau” J Neurosci Res. 48(2): 12.)
  • the IC50 is the molar concentration of competing ligand, which reduces the specific binding of a radioligand by 50%.
  • the competing ligand was the un-radiolab eled, compound of Example 3 and the radiolabeled compound or radioligand is 7-[6-(F)fluoropyridin-3-YL]-5H-pyrido[4,3-B]indole (also known as [18F]AV-1451 or T807)
  • the binding of [18F]AV-1451 to PHF tau was determined against the un-radiolabel ed compound of Example 3 at various concentrations.
  • the reaction mixture (200 pl) contained PHF tau (0.12 ug), [18F]AV-1451 at 0.1-0.5 nM, and the un-radiolabeled compound of Example 3 serially diluted from 316 nM to 0.01 nM; assays were performed in PBS, pH 7.4 containing 0.01% bovine serum albumin in 96 well polypropylene microplates.
  • Nonspecific binding is defined as the binding of the radioligand in the presence of 2-[4-(2-fluoranylethyl)-l-piperidyl]pyrimido[l,2- a]benzimidazole T808/AV-680 (5 pM), a known PHF tau ligand (Zhang, J.
  • the bound radioactivity was harvested onto Millipore Multi Screen HTS 96-well glass fiber FB filter plates using a Millipore Multi Screen HTS Vacuum Manifold, followed by five washes with PBS, pH 7.4. Filters containing bound [18F]AV-1451 were assayed for radioactivity in a Wizard 2480 automatic gamma-counter [Perkin Elmer], Using these assay conditions, the total bound fraction is typically less than 10% of the added radioligand [18F]AV-1451.
  • the Ki i.e. the equilibrium dissociation constant for binding of the unradiolabeled compound
  • the Ki is calculated from the IC50 value using the Cheng-Prusoff equation (Cheng Y., Prusoff W.H. (1973), "Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction” Biochem Pharmacol 22 (23):3099-3108):
  • Ki IC50/(l + [L]/Kd)
  • [L] the concentration of [18F]AV-1451 (typically ⁇ 0.5 nM)
  • Ka the dissociation constant for [18F]AV-1451 (0.57 nM).
  • the dissociation constant [Kd] for the radiolabeled compound of Example 3(18F) was determined by saturation binding, in which the total and nonspecific binding of the radioligand were measured at various radioligand concentrations.
  • the reaction mixture (250 pl) contained PHF tau (0.15 pg), and the compound of Example 3, serially diluted from 25 nM to 0.3 nM in PBS; assays were performed in PBS containing 0.01% bovine serum albumin in 96 well polypropylene microplates.
  • Nonspecific binding is defined as the binding of the radioligand in the presence of 2-[4-(2-fluoranylethyl)-l- piperidyl]pyrimido[l,2-a]benzimidazole (also known as T808/AV-680) (10 pM); the radioligand in this assay was the compound of Example 3. After incubation for 1.5 h at 37°C, the bound radioactivity was harvested by vacuum filtration onto Millipore
  • Multi ScreenHTS 96-well glass fiber FB filter plates using a Millipore Multi ScreenHTS Vacuum Manifold, followed by five washes with PBS.
  • Filters containing the bound compound of Example 3 were assayed for radioactivity in a Wizard 2480 automatic gamma-counter [Perkin Elmer], Using these assay conditions, the total bound fraction is typically less than 10% of the added radioligand.
  • the total binding and nonspecific binding data were analyzed by nonlinear regression analysis using Graphpad Prism to determine the Kd for the radioligand.
  • the Kd of the compound of Example 3 is 1.5 ⁇ 0.2 nM on PHF tau that was obtained from donors with Alzheimer’s disease, indicating that this compound binds PHF tau with high affinity. Therefore, PET imaging with this compound and examination of the imaging pattern would be useful to detect the presence of tau in patients and could confirm a diagnosis of AD or non-AD tauopathies.
  • the experiment uses 15 adjacent frontal lobe sections from each of two AD brains: a tau-rich and amyloid-rich (Tau+A0+) brain as well as tau-poor and amyloid-rich (Tau-A0+) brain to define nonspecific binding. Sections were covered with 0.5 ml of 3-(3-[18F]-fluoroazetidin-l- yl)-7-methylbenzo[4,5]imidazo[l,2-a]pyridine, serially diluted from -250 nM in binding buffer (2.5% dimethylsulfoxide + 2.5% ethanol in IX PBS, pH 7.4).
  • Group A are pathologic tau-rich AD brain slices (labeled as Tau+Ap+)
  • Group B are pathologic tau-poor AD brain slices (marked as Tau-Ap+)
  • Group Cl are Tau-AP- normal brain slices.
  • Group A human AD brain sections used are #0185, #28770, #30121, #30311, and #30461.
  • the human AD brain sections in Group B are #33562, #32656, #33998, #35682, and #33563.
  • the normal human brain sections in group C are #29092 and #32566. Tissue slices from the same donors were used to calculate selectivity. Autoradiography is performed for each of these three groups of brains on adjacent 10 pm sections with the amyloid tracer [18F]W372 (2- (6-fluoro-3-pyridyl)-6-methoxy-imidazo[l,2]thiazolo[2,3-c]pyridine) to quantify the P- amyloid burden.
  • [18F]W372 is a selective amyloid binding tracer discovered by Siemens and evaluated under IND 105173 see also (US9,023,316).
  • Sections were covered with 0.5 ml containing the compound of Example 3 in binding buffer: 2.5% dimethylsulfoxide + 2.5% ethanol in IX PBS, pH 7.4, about 20 pCi/slide and incubated for 60 minutes. Then successive washing cycles (2 min PBS, 2 min 30% EtOH/PBS, 2 min 70% EtOH/PBS, 2 min PBS) were employed to remove any unbound tracer.
  • the sections were air dried, placed on a phosphorimaging plate (Fuji IP plate), and exposed overnight.
  • the IP plate is read using a GE Healthcare Life Sciences Typhoon FLA 7000 Phosphorimager.
  • the signal intensity of the grey matter is measured using Fujifilm Multi Gauge software.
  • the signal of individual sections of Group A and B were normalized with corresponding signal from autoradiography of the respective adjacent sections with [18F]W372.
  • the calculations were based on Group B brain sections #32656 and #33998, which have undetectable tau pathology by immunohistochemistry.
  • the normalized signal in Group B brain sections is the relative signal level of the compound of Example 3 to [18F]W372 resulting from binding to native P-amyloid aggregates.
  • the binding level to native tau-aggregates in Group A sections was estimated by subtracting the amount of the total signal attributable to binding to P-amyloid (calculated by multiplying the total signal from [18F]W372 binding to P-amyloid in the adjacent section by the relative signal of the compound of Example 3 to [18F]W372 determined from the Group B sections). The resulting difference was then divided by the signal attributable to binding to P-amyloid to estimate the selectivity. [129] Strong signal on grey matter (cortex region) of sections in Group A (Tau+A
  • the normalized autoradiography signal on the cortex region of these AD brain sections is derived from the binding of the compound of Example 3 to native P-amyloid aggregates.
  • the selectivity of the compound of Example 3 binding to native tau aggregates vs. binding native P-amyloid aggregates is reflected by the ratio of Group A (Tau+Ap+) signal to the average signal of the brain sections #32656 and #33998.
  • the compound of Example 3 exhibits a selectivity ratio for Tau: Ap of approximately 31.4, based on 5 Tau + Ap + brain specimens, and 2 Tau-Ap+ brain specimens and exhibits grey matter to white matter (GM/WM) signal ratio of approximately 18.9.
  • the autoradiography signal of the compound of Example 3 on normal brain sections is weak and even, showing little difference between grey matter and white matter, indicative of low non-specific binding.
  • Example Assay 34 The results provided in the biological assays above support the use of the compound of Example 3 as a radiolabeled Example can be used with a PET imaging probe for detecting levels of aggregated tau protein in AD patients and/or other neurodegenerative disorders, such as CTE. The results also suggest that the use of the compounds of the other Examples are useful as PET imaging probes for aggregated tau proteins to help diagnose and monitor patients with AD and other neurodegenative disorders associated with aggregated tau proteins.
  • the experiment used 10 um adjacent sections from cases clinically diagnosed with AD, PSP, or CBD confirmed as tau positive by IHC employing AT8 or AT100 antibody using standard techniques or control tissue defined as amyloid and tau negative by IHC. Sections were covered with Example 4[ 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 was 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 were exposed overnight to a phosphorimaging screen.
  • the autoradiography signal recorded on the phosphorimaging screen was read using an Amersham Typhoon Bio-Imaging System. Individual tissue samples were compared to adjacent slices with either AT8 or AT 100. A positive correlation with tau antibody indicates binding to the non-AD tau being studied (PSP or CBD).
  • FIG. 4 Autoradiography from the compound of Example 4( 18 F) on CBD brain sections (5 cases, 3-6 regions per case) for determination of binding is shown in FIG. 4. Strong signal was observed in tau positive tissue from CBD patients. Note the binding in the white matter regions of the CBD patients reported to have abundant tau deposits and hence a region enriched in tau aggregates. The presence of ARG signal for the compound of Example 3, which correlates to tau positive regions of PSP and CBD human tissues indicates this compound binds non-AD tau. Both FIGs. 3 and 4 include the binding of the compound of Example 4( 18 F) to human AD tissue indicating strong binding to AD tau. Therefore, PET imaging with the compound of Example 4( 18 F) and examination of the imaging pattern, would be useful to detect the presence of AD and non-AD tau in patients, and could confirm a diagnosis of AD or non-AD tauopathies.

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Abstract

La présente invention concerne de nouveaux composés de formule : (I) dans laquelle R1, R2, R3, R4, et R5 sont tels que décrits dans la description, des procédés de préparation de ceux-ci, des compositions pharmaceutiques les comprenant, des formules d'imagerie tau et des procédés d'utilisation des composés pour l'imagerie tau.
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