WO2016084193A1 - Procédé de production d'iodo-d-glucose 6-désoxy-6-radioactif et composé polymère utilisé dans ledit procédé - Google Patents

Procédé de production d'iodo-d-glucose 6-désoxy-6-radioactif et composé polymère utilisé dans ledit procédé Download PDF

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Publication number
WO2016084193A1
WO2016084193A1 PCT/JP2014/081394 JP2014081394W WO2016084193A1 WO 2016084193 A1 WO2016084193 A1 WO 2016084193A1 JP 2014081394 W JP2014081394 W JP 2014081394W WO 2016084193 A1 WO2016084193 A1 WO 2016084193A1
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group
carbon atoms
polymer compound
monomer represented
added
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PCT/JP2014/081394
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English (en)
Japanese (ja)
Inventor
高橋　孝志
順 畑澤
浩士 田中
淳 長崎
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国立大学法人東京工業大学
国立大学法人大阪大学
岩城製薬株式会社
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Application filed by 国立大学法人東京工業大学, 国立大学法人大阪大学, 岩城製薬株式会社 filed Critical 国立大学法人東京工業大学
Priority to PCT/JP2014/081394 priority Critical patent/WO2016084193A1/fr
Priority to TW104134700A priority patent/TW201625653A/zh
Publication of WO2016084193A1 publication Critical patent/WO2016084193A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Definitions

  • the present invention relates to a method for producing 6-deoxy-6-radioiodo-D-glucose and a polymer compound used in the method.
  • Labeled compounds for these uses are produced, for example, by the following liquid phase synthesis method or solid phase synthesis method.
  • 6-deoxy-6-iodo [ 123 I] -D-glucose is synthesized for the purpose of providing a radioactive diagnostic agent containing labeled glucose or a galactose derivative.
  • the reaction since the reaction is usually carried out using a very small amount of radioactive iodine, the product contains an excess of unreacted products and requires a great amount of labor for purification.
  • 2-fluoro [ 18 F] -2-deoxy-D-glucose which is a PET tracer, is synthesized by a solid phase synthesis method.
  • the precursor immobilized on the solid phase generally decreases in reactivity.
  • Patent Document 3 a polymer compound containing a residue of a labeled precursor compound and a residue of a phase transfer catalyst is reacted with 18 F ⁇ , and the precursor compound labeled with 18 F is cut out from the polymer compound. , 3-fluoro [ 18 F] -3-deoxy-D-glucose, 2-fluoro [ 18 F] -2-deoxy-D-glucose and the like have been proposed.
  • the method disclosed here there is a possibility that the problem of purification of the compound in the liquid phase synthesis method and the problem of insufficient yield due to the decrease in the reactivity in the solid phase synthesis method may be solved.
  • the compound labeled with 18 F synthesized in Patent Document 3 is useful for PET applications using positron emitting nuclides, but is not suitable for SPECT applications using single photon emitting nuclides. According to the synthesis method disclosed in Examples of Patent Document 3, a polymer compound for the purpose of synthesizing 6-deoxy-6-radioiodo D-glucose could not be synthesized.
  • the present invention has been made in view of the above circumstances, and is expected to lead to the development of a PET / SPECT-use drug that exhibits high accumulation in the brain, tumor, and heart. It is an object of the present invention to provide a method capable of producing -D-glucose easily and efficiently, and a polymer compound used in the method.
  • the present invention includes the following aspects.
  • a polymer compound having a structural unit derived from a monomer represented by the following formula (I) and a structural unit derived from a monomer represented by the following formula (II) A method for producing 6-deoxy-6-radioiodo-D-glucose, characterized by reacting with iodine ions and cutting out a compound labeled with radioactive iodine from a polymer compound.
  • P 1 is a polymerizable group
  • L 1 is a single bond or a linking group
  • R 1 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a haloalkyl group having 1 to 8 carbon atoms.
  • k is an integer of 0 to 4
  • R 2 to R 5 are each independently an alkyl group having 1 to 8 carbon atoms or an unsubstituted or substituted phenyl group.
  • P 2 is a polymerizable group
  • L 2 is a single bond or a linking group
  • Y 2 is a residue of a phase transfer catalyst.
  • P 1 is a polymerizable group
  • L 1 is a single bond or a linking group
  • R 1 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a haloalkyl group having 1 to 8 carbon atoms.
  • k is an integer of 0 to 4
  • R 2 to R 5 are each independently an alkyl group having 1 to 8 carbon atoms or an unsubstituted or substituted phenyl group.
  • P 2 is a polymerizable group
  • L 2 is a single bond or a linking group
  • Y 2 is a residue of a phase transfer catalyst.
  • P 1 is a polymerizable group
  • L 1 is a single bond or a linking group
  • R 1 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a haloalkyl group having 1 to 8 carbon atoms.
  • k is an integer of 0 to 4
  • R 2 to R 5 are each independently an alkyl group having 1 to 8 carbon atoms or an unsubstituted or substituted phenyl group.
  • a structural unit derived from the monomer represented by the specific formula (I) a structural unit derived from the monomer represented by the specific formula (II), 6-deoxy-6-radioiodo-D-glucose can be purified easily and efficiently.
  • the method for producing 6-deoxy-6-radioiodo-D-glucose of the present invention comprises a structural unit derived from a monomer represented by the following formula (I) and a single unit represented by the following formula (II).
  • a polymer compound having a structural unit derived from a monomer is reacted with radioactive iodine ions, and a compound labeled with radioactive iodine is cut out from the polymer compound.
  • P 1 is a polymerizable group
  • L 1 is a single bond or a linking group
  • R 1 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a haloalkyl group having 1 to 8 carbon atoms.
  • k is an integer of 0 to 4
  • R 2 to R 5 are each independently an alkyl group having 1 to 8 carbon atoms or an unsubstituted or substituted phenyl group.
  • P 2 is a polymerizable group
  • L 2 is a single bond or a linking group
  • Y 2 is a residue of a phase transfer catalyst.
  • 6-Deoxy-6-radioiodo-D-glucose is useful as a labeling compound for PET / SPECT applications.
  • these compounds 123 I-, 124 I-, 125 I-, 126 I-, 131 I- and the like can be mentioned.
  • 123 I, 131 I are useful for single photon emission tomography (SPECT) applications, and 124 I is useful for positron tomography (PET) applications.
  • Monomer represented by the formula (II) has a residue of a phase transfer catalyst Y 2.
  • the residue of the phase transfer catalyst of Y 2 may be any residue that can capture the counter cation and activate the radioactive iodine ion of the counter anion.
  • crown ether can be used. Specific examples of the crown ether include cryptfix [2,2,2], 12-crown-4, 15-crown-5, 18-crown-6, benzo-12-crown-4, benzo-15-crown- 5, benzo-18-crown-6, and the like. What is necessary is just to determine the phase transfer catalyst to be used according to the kind of the counter cation of the radioactive iodine ion used for reaction.
  • the counter cation is a potassium ion
  • cryptofix [2,2,2], 18-crown-6, benzo-18-crown-6, etc. are preferably used. It is preferable to use -5, benzo-15-crown-5 or the like.
  • CH 2 CH- group
  • CH 2 CH-O- group
  • CH 2 The ⁇ C ⁇ CH— group is particularly preferred.
  • the linking group of L 1 and L 2 determines the distance between the main chain of the polymer compound and the residue of the phase transfer catalyst of Y 2 and the distance between the main chain of the polymer compound and the ⁇ -D-glucofuranose skeleton.
  • the linker is not particularly limited as long as it can be retained, and is an unsubstituted or substituted alkylene group having 1 to 20 carbon atoms, —SO 2 —, —S—, —S (CS) —, — (CS) S—, —CO —S—, —S—CO—, —O—, —CO—, —CO—O—, —O—CO—, —NR 6 —, —NR 6 —CO—, —CO—NR 6 —, — SO 2 —NR 6 —, —NR 6 —SO 2 —, —NR 6 —CO—O—, —O—CO—NR 6 —, —NR 6 —CO—, —CH
  • R 6 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
  • substitution means that a hydrogen atom is substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms, a cyano group, a halogen atom, or the like, or
  • the —CH 2 — group is —SO 2 —, —S—, —S (CS) —, — (CS) S—, —CO—S—, —S—CO—, —O—, —CO—, —CO—O—, —O—CO—, —NR 6 —, —NR 6 —CO—, —CO—NR 6 —, —SO 2 —NR 6 —, —NR 6 —SO 2 —, —NR 6 —CO—O—, —O—CO—NR 6 —, —NR 6
  • the linking group of L 1 and L 2 is such that the residue of the phase transfer catalyst of Y 2 captures the counter cation, and the activated radioiodine ion easily reacts with the ⁇ -D-glucofuranose skeleton. It preferably has an appropriate length. Specifically, it has 1 to 4 aryl groups (preferably a phenyl group), an alkyl group having 1 to 6 carbon atoms, and a fluoroalkyl having 1 to 6 carbon atoms.
  • the monomer represented by the formula (I) and the monomer represented by the formula (II) are not particularly limited, the monomer represented by the formula (I) is represented by the following formula (I-1):
  • the monomer represented by the formula (II) is preferable, and the monomer represented by the following formula (II-1) is preferable, and the monomer represented by the following formula (I-1) is preferable.
  • a combination of a monomer and a monomer represented by the following formula (II-1) is particularly preferable.
  • the polymer compound is obtained by copolymerizing the monomer represented by the formula (I) containing the residue of the labeling precursor compound and the monomer represented by the formula (II) containing the residue of the phase transfer catalyst. Can be synthesized.
  • a method for producing a polymer compound by copolymerizing the monomer represented by the formula (I-1) or the monomer represented by the formula (II-1) is known in the art (for example, (1) Macromolecules 1994, 27, 4413. (2) Taguchi, M .; Tomita, I .; Endo, T. Angew. Chem. Int. Ed. 2000, 39, 3667.)
  • the target polymer compound can be easily produced from the above literature.
  • Polymer compounds obtained by copolymerizing the monomer represented by the formula (I-1) and the monomer represented by the formula (II-1) are represented by the following formulas (Ia), (Ib) , (IIa), and (IIb).
  • the structural unit for forming a network for example, a structural unit derived from a monomer represented by the following formula (III) can be shown.
  • a functional group may be added to the polymer compound in order to facilitate separation from the solvent.
  • Examples of the functional group to be added include a long chain alkyl group having 4 to 20 carbon atoms.
  • the polymer compound may be supported on a solid phase unnecessary for the solvent. This would facilitate the isolation of the excised 6-deoxy-6-radioiodo-D-glucose.
  • the molecular weight of the polymer compound is not particularly limited, but is preferably 500 to 50,000,000, more preferably 5,000 to 5,000,000, and still more preferably 50,000 to 500,000.
  • the number of structural units derived from the monomer represented by formula (I) contained in the polymer compound is not particularly limited, but is preferably 50 to 50,000, more preferably 50 to 5,000. 50 to 500 is more preferable.
  • the number of structural units derived from the monomer represented by the formula (II) contained in the polymer compound is not particularly limited, but is preferably 50 to 50,000, more preferably 50 to 5,000. 50 to 500 is more preferable.
  • the ratio of the number of structural units derived from the monomer represented by formula (I) and the number of structural units derived from the monomer represented by formula (II) in the polymer compound is not particularly limited.
  • the ratio of the former to the latter is preferably 1000: 1 to 1: 1000, more preferably 100: 1 to 1: 100, and even more preferably 10: 1 to 1:10.
  • the reaction between the polymer compound and the radioactive iodine ion can be carried out by allowing a salt containing the polymer compound and the radioactive iodide ion to coexist in an appropriate solvent.
  • a salt containing radioactive iodide ion include LiI, KI, NaI, CsI and the like.
  • the solvent include acetonitrile, propionitrile, dimethylformamide, dimethyl sulfoxide, ethanol, butanol, dioxane, water, and a mixed solvent thereof.
  • the concentration of the polymer compound in the solvent is not particularly limited, but is preferably 0.1 to 1000 mg / mL, more preferably 1 to 100 mg / mL, and still more preferably 10 to 100 mg / mL. Further, the concentration of the salt containing iodide ions in the solvent is not particularly limited, but is preferably 1 pM to 1 M, more preferably 1 pM to 1 mM, and further preferably 100 pM to 1 ⁇ M.
  • the temperature at the time of the reaction between the polymer compound and the radioactive iodine ion is not particularly limited, but is preferably 0 to 200 ° C, more preferably 50 to 150 ° C, and more preferably 80 to 100 ° C. Further preferred.
  • the reaction time of the polymer compound and radioactive iodine ions is not particularly limited, but is preferably 0.1 to 120 minutes, more preferably 10 to 90 minutes, and further preferably 30 to 60 minutes.
  • Purification of the compound labeled with radioactive iodine from the reaction product can be performed according to a conventional method such as chromatography or filtration.
  • the purified radioiodine-labeled compound can be subjected to deprotection or the like as necessary to obtain the desired 6-deoxy-6-radioiodo-D-glucose.
  • N, N-dimethylformamide 50 mL was added to 1,2-O-isopropylidene-6-O-benzoyl- ⁇ -D-glucofuranose (10.0 g) and stirred, and (+)-10-camphorsulfonic acid ( 2.1 g) and 2,2-dimethoxypropane (16.1 g) were added. After stirring at 50 ° C. for 2 hours, the mixture was cooled to room temperature, tap water was added, and the mixture was extracted with ethyl acetate. After removing the aqueous layer, the organic layer was washed with brine.
  • Tetrahydrofuran (15 mL) was added to 4-fluorosulfonylbenzoic acid (1.00 g) and stirred to give 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride. (1.49 g) was added. After stirring at room temperature for 30 minutes, a solution of tetrahydrofuran (10 mL) in 1-amino-5,6-heptadiene (0.65 g) was slowly added. After stirring at room temperature for 24 hours, the insoluble material was filtered off. The obtained filtrate was concentrated, ethyl acetate was added to the residue and stirred, and then washed with an aqueous sodium hydrogen carbonate solution and then brine.
  • N, N-dimethylformamide (5 mL) was added to sodium hydride (0.10 g), and the mixture was stirred under ice-cooling.
  • a solution of 1,2,3,5-di-O-isopropylidene- ⁇ -D-glucofuranose (1.00 g) in N, N-dimethylformamide (4 mL) was slowly added.
  • N, N-dimethylformamide (4 mL) was added to 4- (hepta-5,6-dien-1-yl-carbamoyl) benzene-1-sulfonyl fluoride (1.14 g). The solution was added slowly. After stirring for 2 hours under ice cooling, tap water was slowly added.
  • Tetrahydrofuran (15 mL) was added to 4-carboxybenzo-15-crown-5 (1.00 g) and stirred to give 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methyl.
  • Morpholinium chloride (0.98 g) was added.
  • a solution of tetrahydrofuran (10 mL) added to 1-amino-5,6-heptadiene (0.53 g) was slowly added.
  • the insoluble material was filtered off. The obtained filtrate was concentrated, chloroform was added to the residue, and the mixture was washed with tap water and then with an aqueous potassium carbonate solution.
  • the copolymer (4 mg) (Example 9) was dissolved in acetonitrile (100 ⁇ l), and the mixture was stirred at 95 ° C. for 1 hour. After cooling, unreacted copolymer was removed from the reaction solution using silica gel column chromatography. The obtained filtrate was concentrated to dryness, 0.5% sulfuric acid (400 ⁇ l) was added, and the mixture was stirred at 90 ° C. for 15 minutes.
  • reaction solution was purified with an anion exchange column (Sep-Pack QMA), neutralized with disodium hydrogenphosphate aqueous solution, and 6-deoxy-6-iodo [ 123 I] with a radiochemical purity of 96.2%. -D-glucose was obtained. It was confirmed by TLC analysis that radioactivity was detected at a site corresponding to the target spot.
  • 6-deoxy-6-radioiodo-D-glucose can be purified easily and efficiently.
  • 6-Deoxy-6-radioiodo-D-glucose can be used as a radioactive probe for PET / SPECT used for diagnosis of various diseases.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract

La présente invention décrit un composé polymère qui a un motif constitutif dérivé d'un monomère représenté par la formule (I) et un motif constitutif dérivé d'un monomère représenté par la formule (II) (P2-L2-Y2). La présente invention concerne un procédé de production d'iodo-D-glucose 6-désoxy-6-radioactif, qui est caractérisé en ce qu'il fait réagir ce composé polymère avec un ion d'iode radioactif, et de découpe d'un composé marqué avec de l'iode radioactif du composé polymère. Dans les formules, chaque P1 et P2 représente un groupe polymérisable ; chaque L1 et L2 représente une simple liaison ou un groupe de liaison ; R1 représente un groupe alkyle ayant de 1 à 8 atomes de carbone, un groupe alcoxy, un groupe halogénoalkyle, un groupe cyano ou un atome d'halogène ; k représente un nombre entier ayant une valeur de 0 à 4 ; chacun de R2-R5 représente un groupe alkyle ayant de 1 à 8 atomes de carbone ou un groupe phényle substitué ou non substitué ; et Y2 représente un résidu d'un catalyseur de transfert de phase.
PCT/JP2014/081394 2014-11-27 2014-11-27 Procédé de production d'iodo-d-glucose 6-désoxy-6-radioactif et composé polymère utilisé dans ledit procédé WO2016084193A1 (fr)

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PCT/JP2014/081394 WO2016084193A1 (fr) 2014-11-27 2014-11-27 Procédé de production d'iodo-d-glucose 6-désoxy-6-radioactif et composé polymère utilisé dans ledit procédé
TW104134700A TW201625653A (zh) 2014-11-27 2015-10-22 ６－去氧－６－放射性碘－ｄ－葡萄糖之製造方法，及使用在該方法之高分子化合物

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007063940A1 (fr) * 2005-12-02 2007-06-07 Nihon Medi-Physics Co., Ltd. Procede de production d’un compose marque avec du fluor radioactif
WO2007066567A1 (fr) * 2005-12-06 2007-06-14 Nihon Medi-Physics Co., Ltd. Procede de production d’un compose marque avec du fluor radioactif
WO2011099480A1 (fr) * 2010-02-12 2011-08-18 国立大学法人東京工業大学 Procédé de production d'un composé marqué au 18f et composé de poids moléculaire élevé à utiliser dans le procédé

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007063940A1 (fr) * 2005-12-02 2007-06-07 Nihon Medi-Physics Co., Ltd. Procede de production d’un compose marque avec du fluor radioactif
WO2007066567A1 (fr) * 2005-12-06 2007-06-14 Nihon Medi-Physics Co., Ltd. Procede de production d’un compose marque avec du fluor radioactif
WO2011099480A1 (fr) * 2010-02-12 2011-08-18 国立大学法人東京工業大学 Procédé de production d'un composé marqué au 18f et composé de poids moléculaire élevé à utiliser dans le procédé

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHIKA NAKAGAWA ET AL.: "Kobunshigata Zenkutai o Mochiiru SPECT-yo Hoshasei Yoso Hyoshikika Kagobutsu no Goseiho no Kaihatsu", SYMPOSIUM ON ORGANIC SYSTHESIS, JAPAN YOSHISHU, 30 May 2014 (2014-05-30), pages 147 - 150 *
CHIKA NAKAGAWA ET AL.: "Zenkutai o Sokusa ni Yusuru Kobunshi o Mochiita Hokokan Yosoka SPECT Probe Gosei", 94TH ANNUAL MEETING OF THE CHEMICAL SOCIETY OF JAPAN IN SPRING 2014 NEN KOEN YOKOSHU, vol. IV, 12 March 2014 (2014-03-12), pages 1443 *
HIROSHI TANAKA ET AL.: "Kobunshi Tanji Shiyaku o Mochiita [18F] PET Probe no Shinki Goseiho no Kaihatsu", 90TH ANNUAL MEETING OF THE CHEMICAL SOCIETY OF JAPAN IN SPRING 2010 NEN KOEN YOKOSHU, vol. IV, 2010, pages 1034 *
RYOTA TAKEUCHI ET AL.: "Fukugo Kinosei Kobunshi o Mochiita [18F] PET Probe no Koritsuteki Goseiho no Kaihatsu", 92ND ANNUAL MEETING OF THE CHEMICAL SOCIETY OF JAPAN IN SPRING 2012 NEN KOEN YOKOSHU, vol. IV, 2012, pages 1240 *

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