EP3986558A1 - Dérivés de 7-(3-(4-(2-([18f]fluor)éthoxy)phényl)propyl)-2-(furane-2-yl)-7h-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine deutérés - Google Patents

Dérivés de 7-(3-(4-(2-([18f]fluor)éthoxy)phényl)propyl)-2-(furane-2-yl)-7h-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine deutérés

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Publication number
EP3986558A1
EP3986558A1 EP20734882.2A EP20734882A EP3986558A1 EP 3986558 A1 EP3986558 A1 EP 3986558A1 EP 20734882 A EP20734882 A EP 20734882A EP 3986558 A1 EP3986558 A1 EP 3986558A1
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EP
European Patent Office
Prior art keywords
compound
radicals
general formula
deuterium
formula
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
EP20734882.2A
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German (de)
English (en)
Inventor
Thu Hang Lai
Rodrigo Teodoro
Magali Toussaint
Daniel Gündel
Winnie DEUTHER-CONRAD
Sladjana Dukic-Stefanovic
Susann Schröder
Rares-Petru Moldovan
Peter Brust
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ROTOP PHARMAKA GmbH
Helmholtz Zentrum Dresden Rossendorf eV
Original Assignee
ROTOP PHARMAKA GmbH
Helmholtz Zentrum Dresden Rossendorf eV
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Application filed by ROTOP PHARMAKA GmbH, Helmholtz Zentrum Dresden Rossendorf eV filed Critical ROTOP PHARMAKA GmbH
Publication of EP3986558A1 publication Critical patent/EP3986558A1/fr
Pending legal-status Critical Current

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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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 invention relates to deuterated 7- (3- (4- (2 - ([ 18 F] fluoro) ethoxy) phenyl) propyl) -2- (furan-2-yl) -7i7-pyrazolo [4, 3-e] [l, 2,4] triazolo [l, 5-c] pyrimidin-5-amine derivatives and their use as medicaments. It relates in particular to the use of these derivatives as radiopharmaceuticals for nuclear medicine imaging of adenosine A2 A receptors by means of positron emission tomography (PET).
  • PET positron emission tomography
  • the derivatives are described as ligands for adenosine A2 A receptors. They should therefore be suitable as therapeutic agents for the treatment of diseases which are related to adenosine A 2 A receptors.
  • Adenosine A2 A receptors belong to the group of G-protein-coupled receptors (GPCRs), which mediate the effects of adenosine on different organ systems.
  • GPCRs G-protein-coupled receptors
  • Adenosine A2 A receptors couple in particular to stimulatory G s proteins.
  • the coupled G s proteins in turn activate adenylyl cyclases and thus stimulate the production of cAMP.
  • a pharmacological blockade or stimulation of the adenosine A2 A receptors can therefore have an impact on various diseases in humans.
  • the object of the invention is to eliminate the disadvantages of the prior art.
  • 7- (3- (4- (2 - ([ 18 F] fluoro) ethoxy) phenyl) propyl) - 2- (furan-2-yl) -7iT-pyrazolo [4,3-e] [l , 2,4] triazolo [l, 5-c] pyrimidin-5-amine derivatives are indicated which - compared to compound D - have a higher molar activity and a higher metabolic stability.
  • radicals X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each independently hydrogen or deuterium, with the proviso that at least one of the radicals X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , X 5a and X 5b is deuterium.
  • X denotes any radical of the radicals X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , X 5a and X 5b .
  • radicals X la , X lb , X 2a and X 2b are each independently hydrogen or deuterium and that the radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen, at least one of the radicals X la , X lb , X 2a and X 2b being deuterium.
  • radicals X la and X lb are each deuterium
  • radicals X 2a and X 2b are each independently hydrogen or deuterium
  • radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen.
  • radicals X la , X lb , X 2a and X 2b are each deuterium and the radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each because they are hydrogen.
  • This compound is also referred to below as [ 18 F] FLUDA and is shown below:
  • the compounds according to the invention of the general formula I represent ligands for adenosine A 2 A receptors. They can therefore be used for the diagnosis of neurodegenerative diseases and / or oncological diseases.
  • the oncological diseases can be neuro-oncological diseases.
  • the compounds of general formula I according to the invention can therefore be used for the diagnosis of cancer diseases and other hyper- and / or dysproliferative diseases.
  • Cancer diseases include in particular benign and malignant tumor diseases (neoplasms), in particular tumor diseases of the lungs, the brain, the spinal cord, the prostate, the urinary bladder, the kidneys, the esophagus, the stomach, the pancreas, the ovary, the skeletal system.
  • An example of a tumor disease of the lung is the non-small-cell lung carcinoma.
  • the compounds of general formula I according to the invention can thus be used as a medicament, in particular as a medicament for neurodegenerative diseases and / or oncological diseases.
  • a pharmaceutically acceptable salt of a compound of general formula I can also be used as a medicament, in particular as a medicament for neurodegenerative diseases and / or oncological diseases.
  • the compounds of the general formula I according to the invention can be used as medicaments for the diagnosis of a non-small cell lung carcinoma.
  • a pharmaceutically acceptable salt of a compound of the general formula I can be used as a medicament, in particular as a medicament for the diagnosis of a non-small cell lung carcinoma.
  • the compounds according to the invention can be used for the diagnosis of cardiovascular diseases.
  • the compounds of the general formula I according to the invention can thus be used as medicaments for cardiovascular diseases.
  • a pharmaceutically acceptable salt of a compound of the general formula I can also be used as a medicament for cardiovascular diseases.
  • the use of a compound of general formula I is provided as a medicament. Furthermore, the use of a compound of general formula I as a medicament for diagnosing illnesses in which an adenosine A2 A receptor is involved is provided.
  • the drug is a radiopharmaceutical.
  • the medicament is preferably a radiopharmaceutical for nuclear medicine imaging of adenosine A2 A receptors by means of positron emission tomography (PET).
  • PET positron emission tomography
  • a pharmaceutically acceptable salt of this compound can be used.
  • radicals X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each independently hydrogen or deuterium, with one [ 18 F] fluoride containing solution a first precursor of the general formula II
  • radicals X la , X lb , X 2a and X 2b have the meaning given in connection with formula IA and the radicals Y 1 and Y 2, independently of one another, are each tosyl or mesyl, and a second precursor of the formula III
  • radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b have the meaning given in connection with formula IA, are reacted to obtain the compound of the general formula IA.
  • the term “Y” denotes any radical of the radicals Y 1 and Y 2 .
  • the compound of the general formula I corresponds to the compound of the general formula IA, except that the compound of the general formula IA necessarily has a radical X which is deuterium.
  • all radicals X in the compound of the general formula IA can be hydrogen.
  • the compound of the general formula IA is the compound D, in which is known from the prior art which is Z 18 F.
  • the process according to the invention is suitable for the preparation of both the compound D and the deuterated derivatives of the compound D in a one-pot process.
  • the compounds of general formula I are deuterated derivatives of the compound D.
  • the first process according to the invention is preferably a process for the preparation of a compound of the general formula I. More preferably, the first process for the preparation of a compound of the general formula IA is used in which at least one of the radicals X la , X lb , X 2a and X 2b is deuterium and the radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen. To produce such a compound, compound 1 is preferably used as the second precursor:
  • Compound 1 is a compound of the general formula III in which X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen.
  • Compound 1 can be combined with a compound of the general formula II to form a compound of the general formula IB
  • Formula IB corresponds to formula IA, except that in formula IB the radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen.
  • the first process according to the invention is particularly preferably a process for the preparation of [ 18 F] FLUDA.
  • the radicals Y 1 and Y 2 are each, independently of one another, tosyl or mesyl.
  • the radicals Y 1 and Y 2 are particularly preferably both tosyl.
  • the first process according to the invention can comprise a first reaction step in which the first precursor is added to the [ 18 F] fluoride-containing solution and is converted there to a compound of the general formula IV, as described below Scheme 1 is shown.
  • radicals X la , X lb , X 2a and X 2b have the meanings given in connection with For mel IA and the radicals Y 1 and Y 2 have the meanings given above.
  • radicals X la , X lb , X 2a , X 2b and Y 1 have the meanings given in connection with formula II.
  • a compound of the formula IV differs from a compound of the formula II only in the nucleophilic substitution of the radical OY 2 by [ 18 F] fluoride.
  • the compound of general formula IV is reacted with the second precursor to form the compound of general formula IA, as shown in Scheme 2.
  • Scheme 2A illustrates the reaction of a compound of general formula IV with compound 1 to give a compound of general formula IB.
  • Formula IB corresponds to formula IA, except that in formula IB the radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen.
  • [ 18 F] FLUDA is an example of a compound of general formula IB.
  • the [ 18 F] fluoride anion can be prepared by known methods.
  • the [ 18 F] fluoride anion is produced in the cyclotron by irradiating at least 97% enriched Fb 18 0 with protons with an energy of 9.6 MeV.
  • the aqueous [ 18 F] fluoride solution obtained in this way can be fixed on an anion exchange cartridge (QMA) and eluted with the aid of an aqueous solution of a base such as potassium carbonate, cesium carbonate, sodium hydride or tetralkylammonium hydrogen carbonate.
  • An aqueous solution of potassium carbonate is preferably used as the base.
  • the basic [ 18 F] fluoride solution is eluted in a reaction vessel which contains a phase transfer catalyst (PTC) such as crown ethers, quaternary ammonium salts or alkali or alkaline earth salts.
  • PTC phase transfer catalyst
  • a [2,2,2] cryptand (Kryptofix® or K222), tetra - // - butyl ammonium phosphate, hydroxide, oxalate, toluene sulfonate, or optionally other crown ethers such as 18 -Crown-6 used.
  • the [ 18 F] fluoride complex obtained in this way can be subjected to azeotropic drying under vacuum.
  • the organic solvent can be a non-protic, polar solvent such as acetonitrile (MeCN), dimethylformamide (DMF), A f , A f -dimethylacetamide (DMAA), A f -methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or mixtures thereof.
  • Acetonitrile is preferably used as the solvent.
  • the azeotropic drying is preferably carried out with thermal reaction conditions in a closed reaction vessel at an elevated temperature. The temperature is preferably between 50 and 60 ° C. Azeotropic drying can also be carried out with the help of microwaves. To this end, microwaves with a power of 50 to 150 W, preferably 65 to 85 W and particularly preferably 75 W can be used.
  • the azeotropically dried [ 18 F] fluoride complex is preferably dissolved in an organic solvent.
  • the organic solvent can be a non-protic, polar solvent such as acetonitrile (MeCN), dimethylformamide (DMF), A (A-dimethylacetamide (DMAA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide ( DMSO) or mixtures thereof.
  • Acetonitrile is preferably used as the solvent.
  • the first precursor is then added to this solution.
  • the first precursor is preferably previously dissolved in an organic solvent.
  • This solvent is preferably the same solvent as is contained as a solvent in the [ 18 F] fluoride-containing solution, i.e. acetonitrile.
  • the first precursor dissolved in the solvent is then added to the [ 18 F] fluoride-containing solution.
  • the first reaction step of the first process according to the invention is preferably carried out at an elevated temperature.
  • the temperature is preferably between 80 and 110 ° C, particularly preferably 90 ° C.
  • the first reaction step is preferably carried out for a period of 5 to 15 minutes and particularly preferably 10 minutes.
  • the first reaction step of the process according to the invention is preferably carried out at ambient pressure.
  • the first reaction step is preferably carried out with movement of the reaction mixture, for example with stirring.
  • a compound of the general formula IV is obtained in a reaction mixture.
  • the compound of the general formula III which is the second precursor, is added to this reaction mixture.
  • the second reaction step of the first process according to the invention is preferably carried out at an elevated temperature.
  • the temperature is preferably between 100 and 140 ° C, particularly preferably 120 ° C.
  • the second reaction step is preferably carried out for a period of 5 to 15 minutes and particularly preferably 10 minutes.
  • the second reaction step of the process according to the invention is preferably carried out at ambient pressure.
  • the second reaction step is preferably carried out with movement of the reaction mixture, for example with stirring.
  • the second precursor is subjected to a pretreatment before it is added to the reaction mixture which contains the compound of the general formula IV.
  • the pretreated second precursor is added to this reaction mixture.
  • the pretreatment can comprise treating the second precursor with a base which serves to deprotonate the phenol group of the second precursor. This base is also referred to below as the activation base.
  • the second precursor is brought into contact with the activation base in an organic solvent.
  • This solvent is preferably the same solvent that is contained as the solvent in the [ 18 F] fluoride-containing solution, that is to say acetonitrile.
  • the second precursor dissolved in the solvent is then added to the reaction mixture.
  • the pretreatment of the second precursor is preferably carried out at an elevated temperature.
  • the temperature is preferably between 80 and 110 ° C, particularly preferably 90 ° C.
  • the pretreatment is preferably carried out for a period of 5 to 15 minutes and particularly preferably 10 minutes.
  • the pretreatment is preferably carried out at ambient pressure.
  • the pretreatment is preferably carried out with movement of the reaction mixture, for example with stirring.
  • the concentration of the activation base is preferred wise between 35 and 45 wt .-%, based on the solution containing the second precur sor and the phase transfer catalyst, particularly preferably 40 wt .-%.
  • the concentration of the activation base, based on the solution containing the second precursor and the phase transfer catalyst can be between 1 and 10% by weight, preferably 2 and 8% by weight and particularly preferably 5% by weight. -% lie.
  • the activation base can have a cation with the general formula N ⁇ R ⁇ lGR ⁇ R 4 ), where R 1 , R 2 , R 3 and R 4 are the same or different from one another and are each unsubstituted or substituted Ci-Cö- Are alkyl.
  • R 1 , R 2 , R 3 and R 4 are each unsubstituted Ci-C6-alkyl, more preferably propyl, butyl or pentyl, particularly preferably each // - butyl.
  • the activation base has an anion which is selected from the group comprising hydroxy, hydrogen carbonate, hydrogen sulfate, oxalate, phosphate and toluene sulfonate.
  • An activation base which has the cation tetra - «- butyl ammonium is also referred to below as TBA.
  • a particularly preferred activation base is tetra - «- butyl ammonium hydroxide (TBAOH).
  • TBAOH tetra - «- butyl ammonium hydroxide
  • the cation with the general formula N + (R 3 R 2 R 3 R 4 ) and the anion can be present in a stoichiometric ratio.
  • the first process according to the invention is a two-stage one-pot process.
  • a one-pot process is understood to mean a process in which the first reaction step and the second reaction step are carried out in one and the same reaction vessel. It is therefore advisable to use the same solvent both for the first reaction step and for the second reaction step.
  • the first inventive method enables the preparation of 7- (3- (4- (2- [ 18 F] fluoroethoxy) phenyl) propyl) -2- (furan-2-yl) -7H-pyrazolo- [4, 3-e] [l, 2,4] -triazolo [l, 5-c] pyrimidin-5-amine, which is not deuterated, by means of suitable precursors.
  • the 18 F-labeled radiotracers of the general formula I accessible by means of the invention can be used for in vitro and / «- v / vo studies of the expression of adenosine A2 A receptors in organisms by positron emission tomography (PET)
  • PET positron emission tomography
  • radicals X la , X lb , X 2a and X 2b are each independently hydrogen or deuterium and the radicals Y 1 and Y 2 are each independently tosyl or mesyl, see provided for the preparation of a compound of the general formula IA, in which the radicals X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , X 5a and X 5b have the meanings given in connection with formula I.
  • the compound of the general formula II is reacted as the first precursor with a compound of the general formula III as the second precursor. Details on this have been explained above in connection with the method according to the invention. Reference is made to these explanations.
  • the use according to the invention can in particular provide the use of a compound of the general formula II for the preparation of a compound of the general formula IB.
  • the compound of the general formula II is reacted as the first precursor with compound 1 as the second precursor.
  • a preferred compound of the general formula II is compound 2 shown below (ethane 1,2-diyl-1/ 4 -bis (4-methylbenzenesulfonate)).
  • Compound 2 can be used to prepare [ 18 F] FLUDA.
  • Compound 2 is preferably reacted with compound 1 to produce [ 18 F] FLUDA.
  • the invention enables both higher radiochemical yields and molar activities of compounds of the general formula IA, including the compound [ 18 F] D and deuterated 7- (3- (4- (2- [ lx F] fluoroethoxy) phenyl) propyl) -2- (furan-2-yl) -7 // - pyrazolo [4,3-e] [l, 2,4] triazolo [l, 5- c] pyrimidin-5-amine derivatives of the general formula F
  • the compounds of the general formula I show a significantly higher metabolic stability compared to the known 18 F -labeled compound D. This applies in particular to [ 18 F] FLUDA.
  • the invention thus differs from the prior art in particular through the two-step one-pot radiosynthesis of deuterated 7- (3- (4- (2- [ 18 F] fluoroethoxy) phenyl) propyl) -2- (furan 2-yl) -Z7 / -pyrazolo [4,3-e] [l, 2,4] -triazolo [l, 5-c] pyrimidine-5-amine derivatives of the general formula I and the subsequent use as a radiotracer for nuclear medicine imaging of adenosine A2 A receptors using positron emission tomography (PET).
  • PET positron emission tomography
  • the compounds of general formula I have a high affinity and selectivity for adenosine A2 A receptors. They are therefore particularly suitable as radiopharmaceuticals for nuclear medical imaging of adenosine A2 A receptors by means of PET.
  • radicals X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen or deuterium, a precursor of the general formula V
  • the second process according to the invention is preferably a process for preparing a compound of the general formula I. More preferably, the second process is used for preparing a compound of the general formula IA in which at least one of the radicals X la , X lb , X 2a and X 2b is deuterium and the radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen.
  • a compound of the general formula VA is used to produce such a compound:
  • Compound VA is a compound of the general formula V in which X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen.
  • Compound VA can lead to a compound of the general formula IB
  • the second process according to the invention is particularly preferably a process for the preparation of [ 18 F] FLUDA.
  • sulfonate is understood to mean an R s -S0 2 -0 group.
  • R s can be, for example, a branched or unbranched substituted or unsubstituted Ci-C6-alkyl group, an aryl group or an alkylaryl group.
  • R s is preferably CH3-, CF3-, CH3-C6H4- or NO2-C6H4-.
  • the sulfonate can, for example, be selected from the group consisting of a toluene sulfonic acid ester group, a methyl sulfonic acid ester group, a trifluoromethyl sulfonic acid ester group and a /.- nitrobenzene sulfonic acid ester group.
  • a toluenesulfonic acid ester group is understood to mean an -OTs group, where Ts is tosyl.
  • a methyl sulfonic acid ester group is understood to mean an -OMs group, where Ms is mesyl.
  • a trifluoromethylsulfonic acid ester group is understood to mean CF3-SO2-O-.
  • a /.Nitrobenzene sulfonic acid ester group is understood to mean an NCk-C ö H t -SCk-O group.
  • AG is -OMs or -OTs.
  • AG -OTs is particularly preferred. It can be provided that the sulfonate does not Dibromobenzenesulfonic acid ester group ((Br) 2 -CöH 4 -S0 2 -0-group), in particular no 3,4-dibromobenzenesulfonic acid ester group.
  • Scheme 6 illustrates the preparation of a compound of the general formula IA by means of the second process according to the invention.
  • Scheme 6A illustrates the preparation of a compound of the general formula IB by means of the second process according to the invention, starting from compound VA.
  • the compound of the formula IB differs from a compound of the formula VA only in the nucleophilic aliphatic substitution of the group AG by [ 18 F] fluoride.
  • the [ 18 F] fluoride anion can be produced in the same way that has been described in connection with the first process according to the invention.
  • the azeotropically dried [ 18 F] fluoride complex is preferably dissolved in an organic solvent.
  • the organic solvent can be a non-protic, polar solvent such as acetonitrile (MeCN), dimethylformamide (DMF), A'V-dimethylacetamide (DMAA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or mixtures thereof.
  • Acetonitrile is preferably used as the solvent.
  • the compound of the general formula V is then added to this solution.
  • the compound of the general formula V is preferably dissolved beforehand in an organic solvent.
  • This solvent is preferably the same solvent that is used as the solvent in the [ 18 F] fluoride-containing solution solution is contained, i.e. acetonitrile.
  • the compound of the general formula V dissolved in the solvent is then added to the [ 18 F] fluoride-containing solution.
  • the second method according to the invention is preferably carried out at an elevated temperature.
  • the temperature is preferably between 80 and 110 ° C, particularly preferably 90 ° C.
  • the first reaction step is preferably carried out for a period of 5 to 15 minutes and particularly preferably 10 minutes.
  • the first reaction step of the process according to the invention is preferably carried out at ambient pressure.
  • the first reaction step is preferably carried out with movement of the reaction mixture, for example with stirring.
  • the compound of the general formula V can be prepared by reacting a compound of the general formula III with a compound of the general formula VII, as shown in Scheme 7.
  • the groups AG independently of one another, each have those in connection with the compound of the general Formula V meanings given, where both groups AG can be the same or different. Both groups are preferably each a sulfonate, preferably each -OTs.
  • Scheme 7A illustrates the preparation of a compound of the general formula VA using compound 1.
  • the compound V is preferably prepared using an organic solvent.
  • the organic solvent can be a non-protic, polar solvent such as acetonitrile (MeCN), dimethyl formamide (DMF), A (A-dimethylacetamide (DMAA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO ) or mixtures thereof.
  • the preferred solvent used is acetonitrile.
  • the reaction is preferably carried out at an elevated temperature. The temperature is preferably between 100 and 140 ° C., particularly preferably 120 ° C.
  • the reaction is preferably carried out for one Period of time from 5 to 15 min and particularly preferably 10 min.
  • the reaction is preferably carried out at ambient pressure. preferably carried out with agitation of the reaction mixture, for example with stirring.
  • the compound of the general formula III is subjected to a pretreatment, as is described in connection with the pretreatment of the second precursor in the first process according to the invention.
  • An activation base described there can be used for this purpose.
  • the second process according to the invention is a one-step process for preparing a compound of the general formula IA.
  • the second inventive method enables the preparation of 7- (3- (4- (2- [ 18 F] fluoroethoxy) phenyl) propyl) -2- (furan-2-yl) -7H-pyrazolo- [4, 3-e] [l, 2,4] -triazolo [l, 5-c] pyrimidin-5-amine, which is not deuterated. It also enables the preparation of the deuterated 7- (3- (4- (2- [ 18 F] fluoroethoxy) phenyl) propyl) -2- (furan-2-yl) -7H-pyrazolo- [4, 3-e] [l, 2,4] -triazolo [l, 5-c] pyrimidine-5-amine derivatives of the general formula I.
  • radicals X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each independently hydrogen or deuterium, with the proviso that at least one of the radicals X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , X 5a and X 5b is deuterium, a compound of the general formula VII in a [ 18 F] fluoride-containing solution
  • radicals X la , X lb , X 2a and X 2b have the meaning given in connection with formula I and the two radicals AG are each independently a leaving group selected from the group consisting of one Sulfonate, chlorine, bromine and iodine, and a precursor of formula III
  • the third method according to the invention corresponds to the first method according to the invention, except that the compound of the general formula VII is used instead of the first precursor of the general formula II.
  • the compound of the general formula VII can be converted into the [ 18 F] fluoride-containing Given solution and converted there to a compound of the general formula VIII, as shown in scheme 9 below.
  • the radicals X la , X lb , X 2a and X 2b have the meanings given in connection with For mel IA and the two groups AG have the meanings given above.
  • the radicals X la , X lb , X 2a , X 2b and Y 1 have the meanings given in connection with formula VII.
  • a compound of the formula VIII differs from a compound of the formula VII only in the nucleophilic aliphatic substitution of one of the two groups AG by [ 18 F] fluoride.
  • the compound of the general formula VIII is reacted with the precursor of the general formula III to give the compound of the general formula IA, as shown in Scheme 10.
  • Scheme 10A illustrates the reaction of a compound of the general formula VIII with compound 1 to give a compound of the general formula IB.
  • the first precursor of the general formula II used in the first process is a preferred compound of the general formula VII, in which the two groups AG are each -OTs or -OMs.
  • the first method according to the invention can thus be viewed as a preferred embodiment of the third method according to the invention. Details of the first method according to the invention can therefore be found in the description of the first method according to the invention.
  • the compound of the general formula VII takes the place of the first precursor.
  • the compound of the general formula III used in the third process according to the invention is referred to as the second precursor in connection with the first process according to the invention.
  • the two groups AG are preferably a sulfonate, as has been described in connection with the second process according to the invention.
  • AG is -OMs or -OTs.
  • AG -OTs is particularly preferred.
  • the third process is preferably used to prepare a compound of general formula I in which at least one of the radicals X la , X lb , X 2a and X 2b is deuterium and the radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen.
  • the third process according to the invention can be carried out as a two-stage one-pot process.
  • the first reaction step and the second reaction step are carried out in one and the same reaction vessel. It is therefore advisable to use the same solvent for both the first reaction step and the second reaction step.
  • the third method according to the invention enables the preparation of 7- (3- (4- (2- [ 18 F] fluoroethoxy) phenyl) propyl) -2- (furan-2-yl) -7H-pyrazolo- [4, 3-e] [l, 2,4] -triazolo [l, 5-c] pyrimidin-5-amine, which is not deuterated.
  • any atom that is not specifically named as a specific isotope is a stable isotope.
  • a radical that is designated as hydrogen or H is understood to mean a radical which has hydrogen in its natural isotope ratio.
  • a radical which is designated as deuterium or D is understood to mean a radical which has deuterium in a frequency which is at least 3000 times greater than the natural frequency of deuterium.
  • isotopologues describes molecules that only differ in their isotopic composition. They have the same chemical formula and the same bonding ratios between the atoms, but they differ by at least one atom that has a different number of neutrons.
  • the relationship between the abundance of an isotope in a compound and the natural abundance of the isotope is referred to as the "isotope enrichment factor".
  • the isotope enrichment factor should be at least 3000 for each atom designated as deuterium (45% incorporation of deuterium with a remainder designated as deuterium).
  • the isotope enrichment factor can be at least 3500 (52.5% incorporation of deuterium), at least 4000 (60% incorporation of deuterium), at least 4500 (67.5% incorporation of deuterium), at least 5000 (75% incorporation of deuterium), at least 5500 (82.5% incorporation of deuterium), at least 6000 (90% incorporation of deuterium), at least 6333.3 (95% incorporation of deuterium), at least 6466.7 (97% incorporation of deuterium), at least 6600 (99 % Incorporation of deuterium), or at least 6633.3 (99.5% incorporation of deuterium).
  • a compound which, according to the invention, should have at least one deuterium atom can be viewed as a group of isotopologues.
  • the proportion of isotopologues that make up a compound can vary.
  • a compound which, according to the invention, is to have at least one deuterium atom contains smaller amounts of isotopologues which have hydrogen atoms instead of one or more of the specified deuterium atoms.
  • the relative amount of these Isotopo loge should, based on the compound, be less than 55% of the compound.
  • the relative amount of these isotopologues is less than 50%, less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less is than 1% or less than 0.5%.
  • Ethane 1,2-diyl-i / 4 -bis (4-methylbenzenesulfonate) (4.520 mg; 1.39 mmol) was dissolved in acetonitrile (10 ml) and treated with tetrabutylammonium fluoride (TBAF, under an argon atmosphere) 1 M in tetrahydrofuran (THF); 2.22 ml; 2.22 mmol) were added.
  • THF tetrabutylammonium fluoride
  • THF tetrahydrofuran
  • EtOAc ethyl acetate
  • FLUDA The synthesis of FLUDA was carried out in a microwave-assisted reaction of 4- (3- (5-amino-2- (furan-2-yl) -7H-pyrazolo [4,3-e] [1,2,4 ] triazolo [l, 5-c] pyrimidine-7-yl) propyl) phenol (1,50.7 mg; 0.135 mmol) and 2 -fluoroethyl 1,1,2,2-7 4 -4-methylbenzenesulfonate (5; 90 mg; 0.405 mmol) with cesium carbonate (132 mg, 0.405 mmol) in methanol (MeOH; 2.5 ml) at 1 h / 100 ° C / 100 W.
  • Fig. 1 shows the UV and radio-HPLC chromatograms of the formulated radiotracer [ 18 F] FLUDA with co-injection of the reference compound of 7- (3- (4- (2- (fluoro) ethoxy-1, 1,2,2-6?
  • Example 4 was repeated several times. A molar activity of 72-180 GBq / pmol (EOS) was obtained for [ 18 F] FLUDA.
  • EOS 72-180 GBq / pmol
  • Scheme 8 shows the synthesis of [ 18 F] FLUDA according to the second process according to the invention.
  • the compound of the general formula VB is a compound of the general formula V in which the radicals X la , X lb , X 2a and X 2b are each deuterium, and the radicals X 3a , X 3b , X 4a , X 4b , X 5a and X 5b are each hydrogen and AG has the meaning given in connection with the general formula V.
  • Scheme 11 shows the synthesis of [ 18 F] FLUDA according to the third process according to the invention.

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Abstract

L'invention concerne un composé représenté par la formule générale (I) dans laquelle les radicaux X1a, X1b, X2a, X2b, X3a, X3b, X4a, X4b, X5a et X5b sont indépendamment les uns des autres hydrogène ou deutérium, à la condition qu'au moins un des radicaux X1a, X1b, X2a, X2b, X3a, X3b, X4a, X4b, X5a et X5b est deutérium.
EP20734882.2A 2019-06-24 2020-06-22 Dérivés de 7-(3-(4-(2-([18f]fluor)éthoxy)phényl)propyl)-2-(furane-2-yl)-7h-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine deutérés Pending EP3986558A1 (fr)

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DE102019116986.0A DE102019116986A1 (de) 2019-06-24 2019-06-24 Deuterierte 7-(3-(4-(2-([18F]Fluor)ethoxy)phenyl)propyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amin-Derivate
PCT/EP2020/067343 WO2020260196A1 (fr) 2019-06-24 2020-06-22 Dérivés de 7-(3-(4-(2-([18f]fluor)éthoxy)phényl)propyl)-2-(furane-2-yl)-7h-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine deutérés

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WO2025137640A1 (fr) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Inhibiteurs azaspiro de wrn
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IT1264901B1 (it) 1993-06-29 1996-10-17 Schering Plough S P A Analoghi eterociclici di 1,2,4-triazolo(15-c)pirimidine ad attivita' antagonista per il recettore a2 dell'adenosina
IT1277392B1 (it) 1995-07-28 1997-11-10 Schering Plough S P A Analoghi eterociclici di 1,2,4-triazolo(1,5-c]pirimidine ad attivita' antagonista per il recettore a2a dell'adenosina
SI1283839T1 (fr) 2000-05-26 2005-08-31 Schering Corp
US6916811B2 (en) 2001-11-30 2005-07-12 Schering Corporation Adenosine A2a receptor antagonists
AU2003304527B2 (en) 2002-12-19 2010-09-09 Merck Sharp & Dohme Corp. Uses of adenosine A2a receptor antagonists
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