WO2020085238A1 - Sel d'un composé précurseur marqué au fluor radioactif - Google Patents

Sel d'un composé précurseur marqué au fluor radioactif Download PDF

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WO2020085238A1
WO2020085238A1 PCT/JP2019/041118 JP2019041118W WO2020085238A1 WO 2020085238 A1 WO2020085238 A1 WO 2020085238A1 JP 2019041118 W JP2019041118 W JP 2019041118W WO 2020085238 A1 WO2020085238 A1 WO 2020085238A1
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compound
salt
labeled
formula
substituted
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PCT/JP2019/041118
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English (en)
Japanese (ja)
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浩章 市川
壮一 中村
侑紀 奥村
彰宏 井澤
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日本メジフィジックス株式会社
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a salt of a labeled precursor compound of 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole derivative compound, which is a compound having CYP11B2 selective binding property.
  • the 2- (3-pyridinyl) -1H-benzimidazole derivative compound is known to have high selectivity for CYP11B2 (Patent Document 1).
  • Non-patent Document 1 reports that 18 F-CDP2230, which is a 2- (3-pyridinyl) -1H-benzimidazole derivative compound, visualized a primary aldosterone-producing tumor with PET (Patent Document 1).
  • a 2- (3-pyridinyl) -1H-benzimidazole derivative compound is also expected as a non-invasive diagnostic imaging agent for heart disease (Patent Document 2).
  • Patent Documents 3 and 4 Furthermore, the applicant has the ability to selectively inhibit CYP11B2 even with respect to 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole derivative compounds, which are not disclosed in Patent Documents 1 and 2. Has been applied for a patent (Patent Documents 3 and 4).
  • the present invention has been made in view of the above circumstances, and improves the stability of a radioactive fluorine-labeled precursor compound of a 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole derivative compound.
  • the purpose is to
  • the present inventors have conducted extensive studies in order to achieve the above object, and as a result, found that the compound represented by the following formula (2) can be stably stored by inducing it into a salt, and completed the present invention. Came to do.
  • one aspect of the present invention is a stabilized composition of a labeling precursor compound of a radioactive fluorine-labeled compound, wherein the radioactive fluorine-labeled compound is a compound represented by the following formula (1) or a salt thereof,
  • the present invention provides a stabilized composition of a labeled precursor compound, wherein the precursor compound contains a salt of the compound represented by the following formula (2) as a main component.
  • X 1 represents a hydrogen atom or a halogen atom
  • X 2 represents a fluorine atom or a nitrile group
  • X 3 represents a radioactive fluorine atom
  • X 1 represents a hydrogen atom or a halogen atom
  • X 2 represents a fluorine atom or a nitrile group
  • R 1 represents a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group.
  • a method for preserving a labeled precursor compound for a radiofluorine-labeled compound wherein the radiofluorine-labeled compound is a compound represented by the above formula (1) or a salt thereof
  • a method for storing a labeled precursor compound of a radioactive fluorine-labeled compound which comprises storing the labeled precursor compound as a salt, wherein the labeled precursor compound is a compound represented by the above formula (2).
  • a method for producing a labeling precursor compound for a radiofluorine-labeled compound wherein the radiofluorine-labeled compound is a compound represented by the above formula (1) or a salt thereof.
  • a method for producing a labeled precursor compound for a radioactive fluorine compound which comprises preparing the labeled precursor compound as a salt, wherein the precursor compound is a compound represented by the above formula (2).
  • the compound represented by the formula (2) or a salt thereof derived from the stabilized composition of the present invention is subjected to radiofluorination reaction as a labeled precursor compound.
  • a method for producing a radioactive fluorine-labeled compound or a salt thereof which comprises a step of obtaining a radioactive fluorine-labeled compound represented by the above formula (1) or a salt thereof.
  • a compound represented by the above formula (2) which is a radioactive fluorine-labeled precursor compound of a 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl] benzimidazole derivative compound, is converted into a salt. Since it is stored in the form, the stability can be improved.
  • Example 5 is a graph showing the results (30 ° C., with argon sealed) obtained in Reference Example 1, Example 1 and Example 2 for comparison.
  • 3 is a graph showing the results ( ⁇ 25 ° C., with argon sealed) obtained in Reference Example 1, Example 1 and Example 2 for comparison.
  • the “halogen atom” is at least one selected from a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the “salt” may be any one that is pharmaceutically acceptable, and examples thereof include inorganic acid salts and organic acid salts.
  • examples thereof include inorganic acid salts and organic acid salts.
  • a sulfate is preferable as the inorganic acid salt
  • a sulfonate is preferable as the organic acid salt
  • a substituted or unsubstituted alkyl sulfonate and a substituted or unsubstituted aryl sulfonate are more preferable. preferable.
  • methane sulfonic acid (mesyl acid) salt methane sulfonic acid (mesyl acid) salt
  • ethane sulfonate propane sulfonate, butane sulfonate, trifluoromethane sulfonate, pentafluoroethane sulfonate, heptafluoro
  • propane sulfonate and nonafluorobutane sulfonate include propane sulfonate and nonafluorobutane sulfonate.
  • substituted or unsubstituted aryl sulfonate examples include benzene sulfonic acid (besyl acid) salt, p-toluene sulfonic acid (tosylic acid) salt, p-nitrobenzene sulfonate, and trinitrobenzene sulfonate.
  • a salt in which the same ion as the sulfonate ion generated when the substituent R 1 of the formula (2) is eliminated by radiofluorination is used as a counter ion is more preferable.
  • the “radioactive fluorine atom” is a radioactive isotope of fluorine, and preferably 18 F can be used.
  • X 1 is a hydrogen atom
  • X 2 is preferably a fluorine atom.
  • X 1 is a halogen atom
  • X 2 is preferably a fluorine atom or a nitrile group.
  • X 1 is a fluorine atom
  • X 2 is preferably a fluorine atom or a nitrile group.
  • Preferred examples of the compound represented by the above formula (1) include three compounds represented by the following chemical formulas.
  • preferable compounds include the following compounds 201, 202 and 203.
  • the substituted or unsubstituted alkylsulfonyloxy group represented by R 1 is preferably a substituted or unsubstituted alkylsulfonyloxy group having 1 to 12 carbon atoms.
  • the hydrogen atom of the alkyl chain may be replaced with a halogen atom, preferably the fluorine atom.
  • the substituted or unsubstituted arylsulfonyloxy group represented by R 1 is preferably a substituted or unsubstituted benzenesulfonyloxy group, more preferably a substituted benzenesulfonyloxy group. is there.
  • the substituted arylsulfonyloxy group preferably has a hydrogen atom on the aryl ring substituted with an alkyl group having 1 to 12 carbon atoms or a nitro group.
  • R 1 is preferably a substituted or unsubstituted arylsulfonyloxy group, and particularly preferably a p-toluenesulfonyloxy group.
  • R 1 is p- toluenesulfonyloxy group
  • said R 1 is p- toluenesulfonyloxy group
  • Compound 201 is particularly preferred.
  • X 1 represents a hydrogen atom or a halogen atom
  • X 2 represents a fluorine atom or a nitrile group.
  • the compound (free form) represented by the above formula (2) By mixing the compound (free form) represented by the above formula (2) with an inorganic acid or an organic acid, the basic group and the inorganic acid or organic acid in the compound represented by the above formula (2) are mixed. An acid-base reaction with an acidic group can occur to form a salt.
  • an acid corresponding to the above-mentioned salt can be used.
  • sulfuric acid is used when forming a sulfate
  • sulfonic acid is used when forming a sulfonate.
  • the inorganic acid or the organic acid can be used in a neat state, in a state of being dissolved in a solvent, or in a state of forming a salt.
  • an inorganic acid or an organic acid is added.
  • the reaction may be carried out, and it is preferable to react the compound (free form) represented by the above formula (2) with an inorganic acid or an organic acid in a solvent, more preferably with stirring.
  • Any solvent may be used as long as it can dissolve the free form of the compound represented by the above formula (2) and the inorganic acid or organic acid, and examples thereof include alcohols having 1 to 4 carbon atoms (eg, methanol, ethanol, n- Propanol, isopropanol, n-butanol, t-butanol, etc.), acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethyl acetate, acetone are used.
  • the salt-forming reaction may be carried out by adding the inorganic acid or the organic acid to the free form fraction purified by the chromatography method as it is or after appropriately concentrating it. By doing so, the decomposition of the free form can be reduced and the salt can be obtained in good yield.
  • the stirring time may be sufficient for the mixture to become a uniform solution or suspension.
  • the above reaction may be carried out at room temperature or while heating. When heating, it is preferable to use a block heater, a water bath, an oil bath or the like to heat to 30 to 40 ° C.
  • the salt of the compound represented by the above formula (2) can be obtained by evaporating the solvent.
  • the solvent may be filtered before being evaporated to remove insoluble impurities. The filtration may be carried out in an air atmosphere or an atmosphere of an inert gas such as nitrogen gas or argon gas.
  • a solvent may be added to the filter to dissolve the residue and evaporate the solvent.
  • the residue thus obtained constitutes the stabilized composition of the present invention and contains the salt of the compound represented by the above formula (2) as a main component.
  • the stabilized composition of the present invention may be solid or amorphous. Specific examples of the solid include powders, granules, emulsions, pastes and the like, but the solid is not limited thereto as long as the decomposition of the salt of the compound represented by the formula (2) is suppressed.
  • the salt of the compound represented by the above formula (2) and the stabilized composition of the present invention containing the salt as a main component can be stored in a container, preferably sealed.
  • the container for housing the composition may be made of glass or plastic. Further, the container may be filled with an inert gas (nitrogen, argon, etc.) as appropriate.
  • the storage temperature of the salt of the compound represented by the above formula (2) and the stabilizing composition of the present invention is not particularly limited, but the upper limit is 50 ° C. or lower, preferably 40 ° C. or lower, More preferably, it is 30 ° C. or lower.
  • the lower limit is not particularly limited, but may be ⁇ 200 ° C. or higher, preferably ⁇ 100 ° C. or higher, more preferably 0 ° C. or higher.
  • it can be stably stored even at a refrigeration temperature or higher (10 ° C. or higher).
  • the lower limit of the storage period of the salt of the compound represented by the above formula (2) and the stabilized composition of the present invention is 1 week or longer, preferably 2 weeks or longer, and more preferably 1 month or longer.
  • the upper limit is preferably 5 years or less, more preferably 3 years or less, and even more preferably 2 years or less.
  • the stabilized composition of the present invention contains the labeled precursor compound of the radioactive fluorine-labeled compound represented by the above formula (2) in the form of a salt, its decomposition is suppressed.
  • an OH compound in which R 1 of the compound represented by the above formula (2) is substituted with a hydroxy group and a compound in which R 1 of the compound represented by the above formula (2) is substituted with a chloro group Generation of a certain Cl body and a dimer of the compound represented by the following formula (3) is reduced.
  • the stabilized composition of the present invention may contain a salt of the compound represented by the above formula (2) as its main component and one or more other components as secondary components.
  • the main subcomponent include the OH form, the Cl form, and the dimer.
  • the stabilizing composition of the present invention may contain at least one of these subcomponents, but preferably contains substantially no subcomponents other than these subcomponents.
  • substantially free means that the target component is undetected in the method for quantifying the content of each component, or the content is below the detection limit. .
  • composition of the present invention is appropriately contained in the above container and stored at the above storage temperature for the above storage period to contain the salt of the compound represented by the formula (2) as the main component.
  • the amount can be maintained at 90% or more, preferably 95% or more, more preferably 98% or more in the peak area ratio on the chromatogram by the high performance liquid chromatography method.
  • the content of the OH form is preferably 10% or less, more preferably 5% or less, still more preferably 1% or less, still more preferably 0.1% in the peak area ratio on the chromatogram by the high performance liquid chromatography method.
  • the content of Cl is preferably 10% or less, more preferably 5% or less, still more preferably 1% or less, still more preferably 0.1% in terms of the peak area ratio on the chromatogram by the high performance liquid chromatography method.
  • the content of the dimer of the compound represented by the formula (3) in the peak area ratio on the chromatogram by the high performance liquid chromatography method is preferably 30% or less, more preferably 10% or less, and further preferably It becomes possible to maintain it at 5% or less, and even more preferably at 1% or less.
  • the conditions of this high performance liquid chromatography method are shown below.
  • Sample dissolution solvent Methanol Sample concentration: 0.2 mg / mL Injection volume: 10 ⁇ L Detector: UV-visible absorptiometer (measurement wavelength: 293 nm) Column: (filler) phenylhexyl group-modified silica gel, (size) 4.6 x 150 mm Column temperature: 40 ° C Mobile phase: A mixed solvent of 60 vol% of mobile phase A (10 mmol / L ammonium hydrogen carbonate aqueous solution) and 40 vol% of mobile phase B (methanol) was added over 55 minutes to 40 vol% of mobile phase A and 60 vol% of mobile phase B Use as a mixed solvent. Retention time of OH body: about 7 minutes Retention time of Cl body: about 14 minutes Retention time of main component: about 24 minutes Retention time of dimer: about 41 minutes
  • the stabilized composition of the present invention may be subjected to a radiofluorination reaction as it is, or may be subjected to a radiofluorination reaction after being dissolved in a solvent.
  • the preferred radiofluorination reaction includes a nucleophilic substitution reaction of the compound represented by the above formula (2) to the group represented by R 1 using a radiofluoride ion, and the radiofluoride ion is used.
  • the nucleophilic substitution reaction is preferably carried out in the presence of a base such as an alkali metal carbonate (for example, sodium carbonate or potassium carbonate) or tetraalkylammonium.
  • the radiofluorination reaction is preferably carried out in the presence of a phase transfer catalyst
  • the phase transfer catalyst include 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8. 8] -hexacosane (trade name: Cryptofix 222) or the like can be used.
  • the radioactive fluorination reaction is preferably carried out by heating, more preferably at the boiling point of the organic solvent or higher, and for example, the lower limit is preferably 50 ° C. or higher, 70 ° C. or higher, 90 ° C. or higher, and the upper limit is 200 ° C. Hereinafter, it is preferable to carry out at 180 ° C. or lower and 150 ° C. or lower.
  • radioactive fluorine-labeled compound represented by the above formula (1) or a salt thereof is used as a drug
  • unreacted radioactive fluorine and insoluble impurities are filled with a membrane filter or various fillers. It is desirable to purify by a column, HPLC or the like.
  • the molecular structure of each compound was identified by 1 H-NMR spectrum.
  • NMR apparatus As the NMR apparatus, AVANCEIII (manufactured by Bruker) having a resonance frequency of 500 MHz) was used, tetramethylsilane (TMS) was used as an internal standard, and the TMS resonance was set to 0.00 ppm. All chemical shifts are in ppm on the delta scale ( ⁇ ), and for fine splitting of the signal, abbreviations (s: singlet, d: doublet, t: triplet, dd: double doublet, dt: double triplet, m: Multiplet, bs: broad singlet, q: quintet).
  • room temperature in the examples is 25 ° C.
  • each step in the compound synthesis was repeated as necessary to secure a necessary amount when used as an intermediate or the like in another synthesis.
  • Sample dissolution solvent methanol
  • Sample concentration powder sample; 1.0 mg / mL, solution sample; 0.2 mg / mL
  • Injection volume 10 ⁇ L
  • Detector UV-visible absorptiometer (measurement wavelength: 293 nm)
  • Column XBridge Phenyl 3.5 ⁇ m, 4.6 ⁇ 150 mm, manufactured by Nippon Waters Co., Ltd.
  • Column temperature Constant temperature around 40 ° C.
  • Mobile phase A 10 mmol / L ammonium hydrogen carbonate solution
  • mobile phase B Transfer of methanol mobile phase for liquid chromatography : Flow rate controlled by concentration gradient by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1: 1.0 mL / min Area measurement range: 45 minutes Re-equilibration time: 10 minutes Retention time of compound 201: Approximately 24 minutes
  • Example 1 In the synthesis of the compound 201 of Production Example 1, the same procedure as in Production Example 1 was performed up to the step of obtaining a main fraction containing Compound 201 (free form) by amino silica gel chromatography. The obtained main distillate fraction was concentrated under reduced pressure at 30 ° C. or lower to about 20 mL. A sulfuric acid salt of compound 201 was obtained by adding a solution of sulfuric acid (0.44 g, 1.5 equivalents) in ethyl acetate to the concentrated solution, stirring the mixture for 1 hour, and then filtering. The sulfate salt of compound 201 (5 mg) was stored under the same conditions as in Reference Example 1.
  • Example 2 In the synthesis of the compound 201 of Production Example 1, the same procedure as in Production Example 1 was performed up to the step of obtaining a main fraction containing Compound 201 (free form) by amino silica gel chromatography. The obtained main distillate fraction was concentrated under reduced pressure at 30 ° C. or lower to about 20 mL. The concentrate was added to a solution of p-toluenesulfonic acid monohydrate (2.26 g, 4 equivalents) in ethyl acetate, stirred for 1 hour, and then filtered to obtain a tosylate salt of Compound 201. The tosylate salt of compound 201 (5 mg) was stored under the same conditions as in Reference Example 1.
  • the tosylate salt may be a tritosylate salt. It turned out that it is highly effective. By storing in the form of salts such as sulfates and tosylate salts, reduction in purity can be reduced even from room temperature conditions of 30 ° C. to freezing conditions of ⁇ 25 ° C. Among them, storage in the form of tosylate salts is possible. It turned out to be particularly effective.

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Abstract

Afin d'améliorer la stabilité d'un composé précurseur d'un composé marqué au fluor radioactif, la présente invention offre une composition stabilisée qui contient, en tant que constituant principal, un sel d'un composé représenté par la formule (2). [Dans la formule, X1 représente un atome d'hydrogène ou un atome d'un halogène, X2 représente un atome de fluor ou un groupe nitrile, et R1 représente un groupe alkylsulfonyloxy substitué ou non substitué ou un groupe arylsulfonyloxy substitué ou non substitué.] La conversion d'un composé représenté par la formule (2) en un sel permet de stabiliser le composé représenté par la formule (2) et de le stocker pendant une longue période de temps.
PCT/JP2019/041118 2018-10-24 2019-10-18 Sel d'un composé précurseur marqué au fluor radioactif WO2020085238A1 (fr)

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JP2018-200389 2018-10-24
JP2018200389 2018-10-24

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013528161A (ja) * 2010-05-11 2013-07-08 ランセウス メディカル イメージング， インコーポレイテッド 造影剤の合成および使用のための組成物、方法およびシステム
WO2015199205A1 (fr) * 2014-06-26 2015-12-30 日本メジフィジックス株式会社 Composé dérivé de 2-(3-pyridinyl)-1h-benzimidazole et médicament le contenant
WO2019131458A1 (fr) * 2017-12-28 2019-07-04 日本メジフィジックス株式会社 Composé de dérivé 2 － [5 －imidazole －１－ylméthyle）pyridine－３－yl］benzimidazole, et médicament contenant celui-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013528161A (ja) * 2010-05-11 2013-07-08 ランセウス メディカル イメージング， インコーポレイテッド 造影剤の合成および使用のための組成物、方法およびシステム
WO2015199205A1 (fr) * 2014-06-26 2015-12-30 日本メジフィジックス株式会社 Composé dérivé de 2-(3-pyridinyl)-1h-benzimidazole et médicament le contenant
WO2019131458A1 (fr) * 2017-12-28 2019-07-04 日本メジフィジックス株式会社 Composé de dérivé 2 － [5 －imidazole －１－ylméthyle）pyridine－３－yl］benzimidazole, et médicament contenant celui-ci

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