WO2016033190A1 - Composés radiotraceurs - Google Patents

Composés radiotraceurs Download PDF

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WO2016033190A1
WO2016033190A1 PCT/US2015/046962 US2015046962W WO2016033190A1 WO 2016033190 A1 WO2016033190 A1 WO 2016033190A1 US 2015046962 W US2015046962 W US 2015046962W WO 2016033190 A1 WO2016033190 A1 WO 2016033190A1
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compound
mmol
mixture
solution
reaction
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PCT/US2015/046962
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Zizhong Li
Stephen Krause
Michiyuki Suzuki
Takeo Sasaki
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Eisai, Inc.
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Publication of WO2016033190A1 publication Critical patent/WO2016033190A1/fr

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    • 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
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • Embodiments may relate to radiolabeled compounds including tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivatives that may be suitable for use as Positron Emission Tomography (PET) radiotracers. Embodiments may also relate to methods of making those compounds.
  • PET Positron Emission Tomography
  • Glutamic acid is known as one of principal excitatory neurotransmitters working for adjusting advanced functions of memory, learning and the like in a central nervous system of a mammal. Glutamate receptors are roughly classified into two types, that is, ionotropic glutamate receptors (iGlu receptors) and metabotropic glutamate receptors (mGlu receptors) coupled with G protein (see Science, 258, 597-603, 1992).
  • iGlu receptors ionotropic glutamate receptors
  • mGlu receptors metabotropic glutamate receptors
  • the iGlu receptors are classified, on the basis of types of their agonists, into three types, that is, N-methyl-D-aspartate (NMDA) receptors, cc-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors.
  • NMDA N-methyl-D-aspartate
  • AMPA cc-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid
  • kainate receptors On the other hand, the mGlu receptors have 8 subtypes (mGluRl to 8) and are classified, on the basis of a signaling system to be conjugated and pharmacological characteristics, into group I (mGluRl , mGluR5), group II (mGluR2, mGluR3) and group III (mGluR4, mGluR6, mGluR7 and mGluR8).
  • the group II and group III mGluRs are expressed as an autoreceptor or a heteroreceptor mainly at the nerve terminal, so as to suppress adenylate cyclase via Gi protein and regulate a specific K + or Ca 2+ channel activity (see Trends Pharmacol. Sci., 14, 13 ( 1993)).
  • Antagonists against group II mGluRs among these glutamate receptors, show an action to improve the cognitive function in animal models and also show an antidepressant action and an antianxiety action, and therefore, it is suggested that group II mGluR antagonists are effective as a novel cognitive function enhancer or antidepressant (see Neuropharmacol., 46 (7), 907-917
  • PET Positron emission tomography
  • PET tracers which are radioactive molecules that target one or more receptors of interest.
  • PET allows measuring the presence of the radioactive tracers at a receptor of interest, then monitors the replacement of the tracers at the receptors of interest following administration of a therapeutic intended to exert their biological function on the same receptors.
  • PET may be used as an evaluator of pharmacodynamic response to a therapeutic.
  • Embodiments provide radiolabeled compounds.
  • the radiolabeled compounds are tetrahydroimidazo[ l ,5-d] [l ,4]oxazepine derivatives.
  • the compounds may be in the form of a free base or a pharmaceutically acceptable acid-addition salt.
  • Embodiments may have high specificity for group II metabotropic glutamate receptors.
  • Embodiments may be useful as radiolabeled tracers for PET applications. Particular embodiments may be useful as radiolabeled tracers for PET applications directed to the mGlu receptors mGluR2 and/or mGluR3.
  • a compound is represented by the following formula (XXIX), which is also referred to as "Compound (XXIX)", or a pharmaceuticall acceptable acid addition salt thereof:
  • At least one fluorine is fluorine- 18 ( F)
  • at least one carbon is carbon- 1 1 ( 1 1 C)
  • at least one nitrogen is nitrogen- 13 ( 13 N)
  • at least one oxygen is oxygen- 15 ( 15 0).
  • a further embodiment may provide a radioimaging composition
  • a radioimaging composition comprising Compound (XXIX) wherein at least one fluorine is fluorine- 18, at least one carbon is carbon- 1 1 , at least one nitrogen is nitrogen- 13, or at least one oxygen is oxygen- 15, or a pharmaceutically acceptable acid addition salt thereof, as well as one or more pharmaceutically acceptable excipients.
  • a further embodiment may provide a method for radioimaging comprising administering as a PET tracer a radioimaging composition comprising Compound (XXIX), wherein at least one fluorine is fluorine- 18, at least one carbon is carbon- 1 1 , at least one nitrogen is nitrogen- 13, or at least one oxygen is oxygen- 15.
  • a further embodiment provides a compound represented by the following Formula (XXX):
  • a further embodiment may provide a radioimaging composition comprising the compound of Formula (XXX), which is also referred to as "Compound (XXX)."
  • a further embodiment may provide a method for radioimaging comprising administering as a PET tracer a radioimaging composition comprising Compound (XXX).
  • the radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivatives or pharmaceutically acceptable acid addition salts thereof have a potential use as a tracer for use with PET imaging when developing therapies for diseases or symptoms for which the antagonistic action against group II metabotropic glutamate receptors effectively works.
  • a disease is Alzheimer's disease.
  • Particular embodiments may have a potential use as a tracer for the mGluR2 and mGluR3 receptors.
  • FIG. 1A and FIG. IB show, respectively, top and side views of summed images from 5-90 minutes of acquisition of PET data from a single Sprague Dawley rat brain as reported in Example 1 , below. These images show a baseline following injection of Compound (XXX).
  • FIG. 2A and FIG. 2B show, respectively, top and side views of summed images from 5-90 minutes of acquisition of PET data from a single Sprague Dawley rat brain as reported in Example 1 , below. These images show the effect of blocking of Compound (XXX) by injection of the compound of Formula (XXXI), which is also referred to as "Compound (XXXI)."
  • FIG. 3A and FIG. 3B show, respectively, top and side views of summed images from 5-90 minutes of acquisition of PET data from a single common marmoset brain as reported in Example 1 , below. These images show a baseline following injection of Compound (XXX).
  • FIG. 4A and FIG. 4B show, respectively, top and side views of summed images from 5-90 minutes of acquisition of PET data from a single common marmoset brain as reported in Example 1 , below. These images show the effect of blocking of Compound (XXX) by injection of Compound (XXXI).
  • FIG. 5A and FIG. 5B show, respectively, time activity curves for Compound (XXX) for a single Sprague Dawley rat in the absence and presence of a high blocking dose of Compound (XXXI).
  • FIG. 6A and FIG. 6B show, respectively, time activity curves for Compound (XXX) for a single common marmoset in the absence and presence of a high blocking dose of Compound (XXXI).
  • FIG. 7 shows a compound of formula (XXIX).
  • a compound of the present invention may have an asymmetric carbon atom in a molecule thereof and exist as an optically active substance or in a racemic mixture. Stereoisomers of compounds of the present invention may differ in their activities, such as for example, binding affinities.
  • Compounds of the present invention may exist as crystal polymorphs, which includes single crystals or mixtures thereof, hydrates, solvate as well as anhydrate forms.
  • Compounds of the present invention may exist as salts. These salts may exist as single crystals or mixtures thereof, and the salts may have various crystal polymorphisms.
  • An isotopically-labeled compound of the present invention may be prepared, for example, by using a readily available isotopically-labeled reagent instead of a nonisotopically-labeled reagent and by performing procedures disclosed in schemes and/or examples described below.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and is preferably a fluorine atom or a chlorine atom.
  • radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivative of embodiments presented herein may exist in the form of a salt.
  • salt forms are pharmaceutically acceptable acid-addition salts.
  • a pharmaceutically acceptable acid addition salts may include inorganic acid salts (such as a sulfate, a nitrate, a perchlorate, a phosphate, a carbonate, a bicarbonate, a hydrofluoride, a hydrochloride, a hydrobromide and a hydroiodide), organic carboxylates (such as an acetate, an oxalate, a maleate, a tartrate, a fumarate and a citrate), organic sulfonates (such as a methanesulfonate, a trifluoromethanesulfonate, an ethanesulfonate, a benzene sulfonate, a toluene sulfonate and a camphorsulfonate), and amino acid salts (such as an aspartate and a glutamate).
  • inorganic acid salts such as a sulfate, a nit
  • a compound is represented by the following Formula XXIX) or a pharmaceutically acceptable acid addition salt thereof:
  • At least one fluorine is fluorine- 18, at least one carbon is carbon- 1 1 , at least one nitrogen is nitrogen- 13, or at least one oxygen is oxygen- 15.
  • a further embodiment provides a compound represented by the following Formula (XXX):
  • Table 1 provides further examples of compounds that may be
  • the compounds of Table 1 are generally believed to be potent negative allosteric modulators of mGluR2 and/or mGluR3 receptors .
  • Table 2 shows a number of reactions that may be suitable for radiolabeling intermediates to provide radiolabeled compounds as reported herein.
  • Derivatives of 3-phenyl- l-(pyridin-4-yl)-5,6,8,9- tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine may be labeled with 1 1 C and 18 F by one or more of these radiolabeling methods.
  • Scheme A as reported in Liu, Y., et al., Optimization of automated radiosynthesis of [ 1 1 8 0 F]AV-45: a new PET imaging agent for Alzheimer's disease. Nucl Med Biol, 2010.
  • n C may be introduced to phenyl (Scheme B) (as reported in Andersen, V.L., et al., Palladium-mediated conversion of para-aminoarylboronic esters into para-aminoaryl- n C-methanes. Tetrahedron Letters, 2013. 54: p. 213- 16; and in Forngren, T., L. Samuelsson, and B.
  • a further embodiment may provide a radioimaging composition comprising at least one radiolabeled compound of Formula (XXIX), the compound of Formula (XXX), and/or at least one radiolabeled compound presented in Table 1.
  • a further embodiment may provide a method for radioimaging using a radiolabeled compound or combination of radiolabeled compounds reported herein.
  • the compound (I) (wherein R, R 1 ; R 2 , R 3 and R 4 represent substituents as shown in Table 1) can be prepared in accordance with Scheme 1 by, for example, the Suzuki-Miyaura reaction of a compound (II) with a compound (III).
  • the Suzuki-Miyaura reaction can be performed by heating the compound (II) and the compound (III) in a solvent in the presence of, for example, a palladium catalyst and a base, with a phosphorus ligand added if necessary.
  • the palladium catalyst for example, tetrakis(triphenylphosphine)palladium (0), palladium (II) acetate, Pd 2 DBA 3 or (A-taPhos) 2 PdCl 2 can be used.
  • the base for example, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate or cesium carbonate can be used.
  • the phosphorus ligand for example, triphenylphosphine, butyl di( l- adamantyl)phosphine or 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl can be used.
  • the solvent used in the reaction is not especially limited as long as it is an inert solvent, and for example, THF, DME, DMF, 1 ,4-dioxane, water or a mixed solvent of these can be used.
  • the reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating by microwaves can be employed as occasion demands.
  • R 4 is, for example, a hydroxymethyl group
  • the compound can be also produced from a compound in which R 4 is methyl by oxidation with mCPBA or the like, rearrangement reaction with acetic anhydride or the like, and alkaline hydrolysis .
  • R 2 is, for example, a hydroxymethyl group
  • the compound can be also produced by deprotecting a corresponding compound in which a hydroxymethyl group is protected by MOM or the like.
  • the compound can be also produced by alkylating a compound, which is obtained by deprotecting a corresponding alcohol compound protected by MOM, benzyl, methyl or the like, with alkyl bromide, alkyl iodide, alkyl triflate or the like, in a solvent such as DMF or THF in the presence of a base such as potassium carbonate or cesium carbonate.
  • This reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • R 4 or R 2 is, for example, a fluoromethyl group
  • the compound can be produced by fluorination of a hydroxymethyl group with DAST, BAST or the like.
  • the compound (II) (wherein R, Ri and R 2 represent the same as defined above) can be prepared in accordance with Scheme 2 by, for example, ester hydrolysis of a compound (IV) and decarboxylative bromination of a resulting compound (V).
  • a solvent used in the ester hydrolysis of the compound (IV) is not especially limited as long as it is an inert solvent, and for example, methanol, ethanol, THF or a hydrous solvent thereof can be used.
  • a base for example, sodium hydroxide or potassium hydroxide can be used. This reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • a solvent used in the decarboxylative bromination of the compound (V) is not especially limited, and for example, DMF, ethanol or a mixed solvent of DMF and ethanol can be used.
  • a bromine source can be, for example, NBS . If potassium carbonate or the like is used as the base, the reaction is accelerated, and the reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • the compound can be also produced by alkylating a compound, which is obtained by deprotecting a corresponding alcohol compound protected by MOM, benzyl, methyl or the like, with alkyl bromide, alkyl iodide, alkyl triflate or the like in a solvent such as DMF or THF in the presence of a base such as potassium carbonate or cesium carbonate.
  • This reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • the compound (IV) (wherein R, Ri and R 2 represent the same as defined above) can be prepared in accordance with Scheme 3 by, for example, condensing a compound (VI) with a compound (VII) and treating a resulting compound (VIII) with a base.
  • a solvent used in the condensation of the compounds (VI) and (VII) is not especially limited as long as it is an inert solvent, and for example, toluene, THF, DME or a mixed solvent of these can be used.
  • the reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating with microwaves can be employed as occasion demands.
  • a solvent used in the treatment of the compound (VIII) with a base is not especially limited as long as it is an inert solvent, and for example, methanol can be used.
  • the base can be, for example, sodium methoxide.
  • the reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating with microwaves can be employed as occasion demands.
  • the compound can be also produced by alkylating a compound, which is obtained by deprotecting a corresponding alcohol compound protected by MOM, benzyl, methyl or the like, with alkyl bromide, alkyl iodide, alkyl triflate or the like in a solvent such as DMF or THF in the presence of a base such as potassium carbonate or cesium carbonate.
  • This reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • the compound (VI) (wherein Ri and R 2 represent the same as defined above) can be prepared in accordance with Scheme 4 by, for example, acid chloridization of a compound (IX), amidation of a resulting compound (X) and a compound (XI) under basic conditions, and cyclization of a resulting compound (XII).
  • a solvent used in the acid chloridization of the compound (IX) is not especially limited as long as it is an inert solvent, and for example, toluene or DCM can be used.
  • oxalyl chloride or thionyl chloride can be used for the reaction, and the reaction is accelerated by addition of DMF.
  • the reaction is accelerated by heating, but is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution.
  • a solvent used in the amidation of the compounds (X) and (XI) is not especially limited as long as it is an inert solvent, and for example, toluene, THF, DCM, water or a mixed solvent of these can be used.
  • a base for example, sodium hydroxide or potassium hydroxide can be used.
  • This reaction is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution.
  • a solvent used in the cyclization of the compound (XII) is not especially limited as long as it is an inert solvent, and for example, toluene or THF can be used.
  • methyl chloroformate, isopropyl chloroformate, DCC or the like can be used for the cyclization. This reaction is generally performed at a temperature ranging from -78°C to the reflux temperature of the solution.
  • the compound (IV) (wherein R, R and R 2 represent the same as defined above) can be prepared also in accordance with Scheme 5 by, for example, the Suzuki-Miyaura reaction of a compound (XIII) (wherein X is halogen) and a compound (XIV).
  • the Suzuki-Miyaura reaction can be performed by heating the compound (XIII) and the compound (XIV) in a solvent in the presence of, for example, a palladium catalyst and a base, with a phosphorus ligand added if necessary.
  • the palladium catalyst for example, tetrakis(triphenylphosphine)palladium (0), palladium (II) acetate, Pd 2 DBA 3 or (A-taPhos) 2 PdCl 2 can be used.
  • the base for example, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate or cesium carbonate can be used.
  • the phosphorus ligand for example, triphenylphosphine, butyl di( l- adamantyl)phosphine or 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl can be used.
  • the solvent used in the reaction is not especially limited as long as it is an inert solvent, and for example, THF, DME, DMF, 1 ,4-dioxane or benzene can be used.
  • the reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating by microwaves can be employed as occasion demands.
  • the compound (XIII) (wherein R is the same as defined above and X is halogen) can be prepared in accordance with Scheme 6 by, for example, condensation of the compound (VII) with a compound (XV), a Hofmann rearrangement reaction of a resulting compound (XVI), and halogenation of a resulting compound (XVII).
  • a solvent used in the condensation of the compounds (VII) and (XV) is not especially limited as long as it is an inert solvent, and for example, toluene, THF, DMF, DME or a mixed solvent of these can be used.
  • the reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating with microwaves can be employed as occasion demands.
  • a solvent used in the rearrangement reaction of the compound (XVI) is not especially limited as long as it is an inert solvent, and for example, toluene, THF, DME or a mixed solvent of these can be used. Furthermore, iodobenzene diacetate or the like can be used in the reaction.
  • the reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • a solvent used in the halogenation of the compound (XVII) is not especially limited as long as it is an inert solvent, and for example, toluene can be used.
  • phosphorus oxychloride or phosphorus oxybromide can be used in the reaction.
  • the reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • the compound (VII) (wherein R is the same as defined above) can be prepared in accordance with Scheme 7 by, for example, four steps of a 1 ,4- addition reaction of a compound (XVIII) and a compound (XIX), alcoholysis of a resulting compound (XX) under acidic conditions, cyclization of a resulting compound (XXI) under basic conditions, and O-alkylation of a resulting compound (XXII).
  • the compound(XIX) can be used as a solvent.
  • a base DBU, TEA, DIPEA or the like can be used.
  • This reaction is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution.
  • a solvent used in the alcoholysis of the compound (XX) is not especially limited as long as it is an inert solvent, and for example, 1 ,4-dioxane can be used.
  • As an acid hydrogen chloride or the like can be used.
  • This reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • a solvent used in the cyclization of the compound (XXI) is not especially limited as long as it is an inert solvent, and for example, methanol or the like can be used.
  • As a base DBU, TEA, potassium carbonate or cesium carbonate can be used.
  • This reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • a solvent used in the O-alkylation of the compound (XXII) is not especially limited as long as it is an inert solvent, and for example, DCM or toluene can be used.
  • an alkylating agent trimethyloxonium tetrafluoroborate, dimethyl sulfate or the like can be used.
  • This reaction is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution.
  • the compound (XXII) (wherein R is the same as defined above) can also be prepared in accordance with Scheme 8 by, for example, four steps of dehydrative condensation of a compound (XXIII) with a compound (XXIV), cyclization of a resulting compound (XXV) performed under acidic conditions, hydrogenation of a resulting compound (XXVI), and deprotection of a resulting compound (XXVII).
  • a solvent used in the dehydrative condensation of the compound (XXIII) with the compound (XXIV) is not especially limited as long as it is an inert solvent, and for example, THF, DMF or DCM can be used.
  • a condensation agent can be DCC, EDC, HOBt, HATU, HBTU or a combination of any of these.
  • DIPEA, TEA or the like can be used as an additive in the reaction. This reaction is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution.
  • a solvent used in the cyclization of the compound (XXV) is not especially limited as long as it is an inert solvent, and for example, THF, acetonitrile, toluene or xylene can be used.
  • an acid can be, for example, PTS or PPTS . The reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • a solvent used in the hydrogenation of the compound (XXVI) is not especially limited as long as it is an inert solvent, and for example, methanol, ethanol or THF can be used.
  • a catalyst palladium/carbon, palladium hydroxide/carbon, platinum oxide or the like can be used. This reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • the deprotection of the compound (XXVII) can be performed, for example, in a solvent such as TFA.
  • a scavenger such as a triethyl silane can be used. This reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.
  • the compound (I) thus obtained can be prepared into a pharmaceutically acceptable salt by a conventional method as occasion demands.
  • the preparation method can be an appropriate combination of, for example, methods conventionally employed in the field of synthetic organic chemistry.
  • a specific example of the method includes neutralization titration of a solution of the free form of the present compound with an acid solution.
  • the compound (I) of the present invention can be changed into a solvate by a known solvate forming reaction as occasion demands.
  • the compound (I) can also be provided with a radiolabel by reaction as shown in Table 2.
  • the compound (I) when the compound (I) is obtained in the form of a salt of the compound (I), it can be changed, by a conventional method, into a free form of the compound (I). Furthermore, various isomers (such as a geometric isomer, an optical isomer based on asymmetric carbon, or stereoisomers) obtained as the compound (I) can be purified and isolated by general separation means such as recrystallization, a diastereomeric salt formation method, enzymatic resolution, and various types of chromatography (including thin layer chromatography, column chromatography and gas chromatography).
  • general separation means such as recrystallization, a diastereomeric salt formation method, enzymatic resolution, and various types of chromatography (including thin layer chromatography, column chromatography and gas chromatography).
  • the radiolabeled tetrahydroimidazo[ l ,5-d] [l ,4]oxazepine derivatives of the present invention or a pharmaceutically acceptable acid addition salt thereof may be useful as tracers for PET. Accordingly, they may be useful in studies directed to therapeutic agents for diseases in which the antagonistic action against the group II metabotropic glutamate receptors effectively works. Examples of a disease in which the antagonistic action against the group II metabotropic glutamate receptors effectively works includes Alzheimer's disease.
  • an embodiment as reported herein may be administered orally, intravenously, or by any other method deemed suitable to the skilled technician.
  • an excipient, a binder, a disintegrator, a lubricant, a colorant and the like can be added, if necessary, to the radiolabeled tetrahydroimidazo[ l ,5- d] [ l ,4]oxazepine derivative of the present invention or a pharmaceutically acceptable acid addition salt thereof, and the resulting mixture can be prepared by a conventional method into tablets, granules, powders or capsules. Furthermore, the tablets, granules, powders or capsules can be coated with a film if necessary.
  • Non-limiting examples of the excipient include lactose, corn starch and crystalline cellulose
  • non-limiting examples of the binder include hydroxypropyl cellulose and hydroxypropylmethyl cellulose
  • non-limiting examples of the disintegrator include carboxymethylcellulose calcium and croscarmellose sodium
  • non-limiting examples of the lubricant include magnesium stearate and calcium stearate
  • a non-limiting example of the colorant includes titanium oxide
  • non-limiting examples of a film-coating agent include hydroxypropyl cellulose, hydroxypropylmethyl cellulose and methyl cellulose.
  • a solid formulation such as a tablet, a capsule, a granule or a powder may contain a radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivative reported herein, a pharmaceutically acceptable salt thereof, or a solvate thereof in a content of generally 0.001 to 99.5% by weight, preferably 0.001 to 90% by weight, and the like.
  • a pH adjuster for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration or the like
  • a buffer for producing an injection formulation (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration or the like), a pH adjuster, a buffer, a suspending agent, a solubilizing agent, an antioxidant, a preservative (an antiseptic agent), a tonicity adjusting agent and the like may be added, if necessary, to a radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivative or a pharmaceutically acceptable acid addition salt thereof, and the resulting mixture can be prepared into an injection formulation by a conventional method.
  • Non-limiting examples of the pH adjuster and the buffer include organic acids, inorganic acids and/or salts thereof, non-limiting examples of the suspending agent include methyl cellulose, Polysorbate 80 and carboxymethyl cellulose sodium, non-limiting examples of the solubilizing agent include Polysorbate 80 and polyoxyethylene sorbitan monolaurate, a non-limiting example of the antioxidant includes alpha-tocopherol, non- limiting examples of the preservative include methyl paraoxybenzoate and ethyl paraoxybenzoate, and non-limiting examples of the tonicity adjusting agent include glucose, sodium chloride and mannitol.
  • Such an injection formulation may contain a tetrahydroimidazo[ l ,5- d] [ l ,4]oxazepine derivative of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof in a content of generally 0.000001 to 99.5% by weight, preferably 0.000001 to 90% by weight, and the like.
  • DIPEA diisopropylethylamine
  • NBS N-bromosuccinimide
  • THF tetrahydrofuran
  • Ts paratoluenesulfonyl
  • a boron trifluoride-ethyl ether complex (0.694 mL, 5.48 mmol) was added to a mixture of (2R)-(-)-glycidyl tosylate (25.0 g, 109 mmol), benzyl alcohol (22.7 mL, 219 mmol), and toluene (200 mL) under ice-cooling.
  • the reaction mixture was stirred at room temperature overnight.
  • the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution (50.0 mL) twice and further with water (50.0 mL) twice. Ethanol was added to the organic layer until the suspension became clear.
  • the solvent was evaporated under vacuum and the residue was purified with silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (28.0 g, 83.0 mmol).
  • Trimethyloxonium tetrafluoroborate (3.31 g, 22.3 mmol) was added to a solution of the compound obtained in Production Example l -(4) (4.78 g, 20.3 mmol) in DCM (60.0 mL) at room temperature, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under vacuum to obtain a title compound (5.05 g, 20.3 mmol).
  • Example 2 Alternative Method for Synthesis of (S -(l-(2,6- dimethylp yridin-4-yl)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-5, 6,8,9- tetrahydroimidazor 1 ,5-dl ⁇ 1 ,41 oxazepin-6-yl)methanol
  • the flow rate was set to 20 ⁇ /min and reactor temperature at 160 °C; the collected reaction mixture was purified on HPLC system with a reverse phase semipreparative column.
  • the product was eluted with a mixture of water (0.1 % Triethylamine) and acetonitrile (50:50, v/v) at a flow rate of 5 ml/min.
  • the product peak was collected from 18 to 20 min.
  • the HPLC solvent was the evaporated under reduced pressure; the product was re-dissolved in a mixture saline and ethanol (3 ml 90: 10 v/v).
  • the solution was sterile filtered through 0.22 um membrane filter.
  • the product 1 to 2 mCi) was delivered immediately after formulation for animal PET imaging experiments.
  • Quality control was performed on an analytical HPLC system with a reverse phase analytical column eluted with a mixture of acetonitrile and water (40 mM NH 4 OAc) (gradient from 30/70 to 100/0 in 12 min, 100/0 for 5 min).
  • the product co-eluted at 10 min with the compound prepared according to Example 4.
  • UV detection was performed at 254 nm.
  • the radiochemical yield is in the range 20 to 35% (decay non-corrected); the specific activity is in the range of 0.5 to 1.0 Ci/ ⁇ .
  • Lithium bis(trifluoromethanesulfonyl)imide (87 g, 304.5 mmol) was added to a solution of 2,4-dimethoxybenzylamine (CAS No. 20781 -20-8; 46.7 mL, 310.6 mmol) and (S)-(+)-benzyl glycidyl ether (CAS No. 16495- 13-9;
  • a mixed solvent of toluene/ethyl acetate (5/1 ) and a saturated aqueous sodium chloride solution were added to the resultant residue to separate the organic layer.
  • the organic layer was further washed with a saturated aqueous sodium chloride solution twice.
  • the organic layer was concentrated under reduced pressure and the resultant residue was purified serially by silica gel column chromatography (n-heptane/ethyl acetate) and NH silica gel column chromatography (n-heptane/ethyl acetate) to obtain a crude title compound (41 g).
  • Triethylsilane (27.4 mL, 171.7 mmol) was added to a solution of the compound obtained in Production Example 2-(5) (41 g) in TFA (300 mL) at room temperature. The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n- heptane/ethyl acetate — > ethyl acetate/methanol) to obtain a title compound (15 g, 101.94 mmol).
  • Trimethyloxonium tetrafhioroborate 17.34 g, 1 17.2 mmol was added to a solution of the compound obtained in Production Example l -(6) ( 15 g, 101.94 mmol) in DCM (400 mL) at room temperature. The reaction solution was stirred at room temperature for 14 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Chloroform was added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain a title compound ( 14.9 g, 93 mmol).
  • Pd(dppf)C12-CH2C12 171 mg, 209 ⁇ was added to a solution of 4- bromo-2-methoxy- l-(trifluoromethoxy)benzene (CAS No. 672948-65- 1 ; 5.23 g, 19.7 mmol), potassium acetate (616 mg, 6.28 mmol), and bis(pinacolate)diboron ( 1.06 g, 4.19 mmol) in DMF ( 10 mL) at room temperature. The reaction mixture was stirred at 1 10°C for 2 hours and then cooled to room temperature.
  • 4- bromo-2-methoxy- l-(trifluoromethoxy)benzene CAS No. 672948-65- 1 ; 5.23 g, 19.7 mmol
  • potassium acetate 616 mg, 6.28 mmol
  • bis(pinacolate)diboron 1.06 g, 4.19 mmol
  • reaction solution was diluted with ethyl acetate, then the resultant was washed with water five times and then with a saturated aqueous sodium chloride solution.
  • organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure.
  • the resultant residue was purified by silica gel column chromatography (n-heptane/ethyl acetate) to obtain a crude title compound (4.58 g, 14.4 mmol).
  • Oxalyl chloride (9.59 mL, 1 12 mmol) was added dropwise into a suspension of 3-methoxy-4-(trifluoromethyl)benzoic acid (CAS No. 276861- 63-3; 20.5 g, 93.1 mmol) and DMF (0.205 mL, 2.65 mmol) in THF (41 mL)/DCM ( 164 mL) under ice-cooling. The reaction mixture was warmed to room temperature and further stirred for 2 hours. The solvent was evaporated under reduced pressure to obtain corresponding crude acid chloride.
  • a 2 N aqueous sodium hydroxide solution (3.31 mL) was added to a solution of the compound obtained in Example 5-(3) (3.18 g, 8.23 mmol) in ethanol (40 mL).
  • the reaction mixture was heated under reflux for 2 hours.
  • the reaction mixture was cooled to room temperature and acidified with a 5 N hydrochloric acid.
  • the mixture was concentrated under reduced pressure.
  • Ethanol (50 mL) was added to the resultant residue and the insolubles were separated through filtration.
  • the resultant filtrate was concentrated under reduced pressure and dissolved in ethanol (5 mL) and DMF (50 mL).
  • 2,4-Dimethoxybenzaldehyde (CAS No. 613-45-65; 55.8 g, 336 mmol) was added to a solution of (R)-(-)-l-amino-2-propanol (CAS No.2799-16-8; 24.0 g, 320 mmol) and acetic acid (40.2 mL, 703 mmol) in THF (440 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour.
  • Sodium triacetoxyborohydride ( 102 g, 479 mmol) was added to the reaction liquid at room temperature, and the mixture was stirred for 18 hours. The solvent was concentrated under reduced pressure after the reaction.
  • a 5 N aqueous sodium hydroxide solution ( 100 mL) and ethyl acetate (500 mL) were added to the resultant residue to separate the organic layer.
  • Chloroform (300 mL) was added to the resultant water layer to separate the organic layer.
  • the resultant organic layers were combined, and the resultant was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was evaporated under reduced pressure.
  • the resultant residue was filtered through NH silica gel (ethyl acetate) for purification to obtain a crude title compound (72 g).
  • DIPEA 173 mL, 995 mmol
  • a solution of the compound obtained in Example 6-(l) 74.7 g, 332 mmol
  • 3,3- dimethoxypropionic acid CAS No. 6191-98-6; 38.5 g, 287 mmol
  • EDC 95 g, 497 mmol
  • HOBT HOBT
  • Water (1 L) and ethyl acetate (1 L) were added to the reaction mixture to separate the organic layer.
  • the resultant organic layer was washed with water ( 1 L) and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the solvent was evaporated under reduced pressure.
  • the resultant residue was purified by NH-silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (61 g, 179 mmol).
  • Triethylsilane (26.2 mL, 164 mmol) was added to a solution of the compound obtained in Example 6-(4) (30.5 g, 1 10 mmol) in TFA (150 mL) at room temperature, and the mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain a title compound ( 12.3 g, 95 mmol).
  • Trimethyloxonium tetrafluoroborate ( 16.8 g, 1 14 mmol) was added to a solution of the compound obtained in Example 6-(5) (13.4 g, 103 mmol) in DCM (500 mL) at room temperature, and the mixture was stirred for 18 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer was separated. DCM was added to the resultant water layer, and the organic layer was separated.
  • Test Example 1
  • Embodiments as reported above were characterized for specificity of binding in the brain and brain penetration using positron emission tomography (PET) in vivo in Sprague Dawley rats and common marmosets.
  • PET positron emission tomography
  • the injected dose was 21.5 +2.9 MBq (mean + SD) for the Sprague Dawley rats and 20.2 + 3.2 MBq (mean + SD) for common marmosets.
  • Sprague Dawley rats were dosed with a bolus of 3.1 mg/kg + 1.8 mg/kg/hr; and common marmosets were dosed at 1.5 mg/kg bolus + 0.42 mg/kg/hr. The doses were based on the pharmacokinetics in each species. Plasma concentration of Compound (XXXI) was measured immediately prior to tracer injection. The scan was initiated at the time of tracer injection and continued for 120 minutes in each Sprague Dawley rat and 90 minutes in each common marmoset.
  • FIG. 1A, FIG. I B , FIG. 2A, and FIG. 2B Summed images from 5-90 minutes of acquisition are shown for a single Sprague Dawley rat brain (in FIG. 1A, FIG. I B , FIG. 2A, and FIG. 2B), and a single common marmoset brain (in FIG. 3A, FIG. 3B, FIG. 4A, and FIG. 4B).
  • FIG. 3A, FIG. 3B, FIG. 4A, and FIG. 4B For each species there is a transverse and sagittal image for the baseline of Compound (XXX) alone and blocked with Compound (XXXI).
  • FIG. 1A through FIG. 4B were obtained at the level of the striatum.
  • the images show uptake that is greater in the striatum and cortical regions that is reduced after the treatment with the blocking Compound (XXXI).
  • the data were reconstructed using the software on the NanoPET camera using OSEM algorithms.
  • the data was binned into 23 frames with the following time points; 4 x 15 sec, 4 x 60 sec, 5 x 180 sec, 4 x 300 sec, 4 x 600 sec and 2 x 1200 sec for Sprague Dawley rats and 22 frames with the following time points 4 x 15 sec, 4 x 60 sec, 5 x 180 sec, 4 x 300 sec, and 5 x 600 sec in common marmoset.
  • MRI generated regions of interest in the brain were placed on the CT aligned, PET reconstructed data to calculate the counts in each brain region for each frame using the VivoQuantTM program (InVicro, Boston, MA., Ver 1.2).
  • the count rates in MBq/mm 3 were standardized to the animal weight and injected dose and reported as the standard uptake value (SUV) for each time frame.
  • TAC time activity curve
  • FIG. 5A for a single Sprague Dawley rat.
  • XXXI Compound
  • FIG. 6A and FIG. 6B For a single common marmoset, the time activity curves under baseline conditions and in the presence of a plasma concentration of 2452 ng/ml Compound (XXXI) are shown in FIG. 6A and FIG. 6B, respectively.
  • the tracer Compound (XXX) in the baseline scans demonstrated the rapid uptake in all brain regions of the compounds, followed by washout in the regions which have a low receptor density (medulla, midbrain).
  • the compounds were retained in regions of the brain that have been reported to have a high density of mGluR2 and/or mGluR3 receptors including cortex, striatum, hippocampus and cerebellum (Richards, et al., J. Comp. Neurol 487: 15, 2005).
  • Specificity of the binding was demonstrated by blocking the binding of the PET ligands in regions of the brain displaying specific uptake with a competing non-radiolabeled compound of different structure (Compound (XXXI)).

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Abstract

Un composé représenté par la formule (XXIX) ou un sel de celui-ci, tel que montré dans la figure 7, dans lequel au moins un fluor est du fluor-18, au moins un carbone est du carbone-11, au moins un atome d'azote est de l'azote 13, ou au moins un atome d'oxygène est de l'oxygène-15, fonctionne comme un traceur destiné à être utilisé dans la tomographie par émission de positrons.
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