WO2010128595A1 - Procédé de production d'un dérivé d'imidazopyridine marqué à l'iode radioactif - Google Patents

Procédé de production d'un dérivé d'imidazopyridine marqué à l'iode radioactif Download PDF

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Publication number
WO2010128595A1
WO2010128595A1 PCT/JP2010/003112 JP2010003112W WO2010128595A1 WO 2010128595 A1 WO2010128595 A1 WO 2010128595A1 JP 2010003112 W JP2010003112 W JP 2010003112W WO 2010128595 A1 WO2010128595 A1 WO 2010128595A1
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WIPO (PCT)
Prior art keywords
compound
radioactive iodine
reaction
solution
labeled
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PCT/JP2010/003112
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English (en)
Japanese (ja)
Inventor
理 松島
康明 森元
将隆 寺薗
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富士フイルムＲｉファーマ株式会社
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Priority to JP2011512311A priority Critical patent/JPWO2010128595A1/ja
Publication of WO2010128595A1 publication Critical patent/WO2010128595A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a method for producing a radioactive iodine-labeled imidazopyridine derivative useful for diagnosis and treatment of Alzheimer's disease.
  • R 1 represents radioactive iodine
  • Radioiodine-labeled 6-iodo-2- [4- (1H-3-pyrazolyl) phenyl] imidazo [1,2-a] pyridine [Compound (1)] represented by the formula: amyloid aggregates and / or deposits It is useful for imaging diseases caused by them because it specifically binds to substances, and it is useful for the treatment and / or prevention of diseases caused by them because it inhibits aggregation and / or deposition of amyloid. In particular, it is known to be useful for diagnosis and treatment of Alzheimer's disease (Patent Document 1).
  • the compound (1) is obtained by labeling the compound (2) with radioactive iodine to obtain a compound (3), and then performing a deprotection reaction by heating in the presence of hydrochloric acid. It is known that it can be manufactured (Patent Document 1).
  • the present invention has been made in view of the above circumstances.
  • a commercially sufficient amount of the compound (1) is produced, the risk of exposure is suppressed, and a high labeling rate and stability with little variation in production. It is an object of the present invention to provide a novel production method that can ensure a reasonable yield.
  • the present inventor has found that it is common knowledge that the deprotection reaction of the t-butoxycarbonyl group is usually carried out under acidic conditions. Then, after the compound (2) is radioiodinated, a deprotection reaction of the t-butoxycarbonyl group, which is a protecting group for the nitrogen atom of the compound (3), is performed in the presence of a base. The inventors have found that the deprotection reaction proceeds at a very high yield without volatilization, and that the labeling rate of the obtained label is stabilized, thereby completing the present invention.
  • the compound represented by formula (3) is labeled with radioactive iodine.
  • R 1 represents radioactive iodine
  • the present invention provides a method for producing a radioactive iodine-labeled compound represented by:
  • a radioiodine-labeled compound (1) useful for the diagnosis and treatment of Alzheimer's disease can be obtained in a large amount with a high labeling rate and a stable yield with low risk of exposure and with low risk of exposure. be able to. It was completely unexpected that the deprotection reaction of the t-butoxycarbonyl group on the nitrogen atom would proceed in high yield in the presence of a base. In the synthesis of radioactive iodine-labeled compounds, considering the half-life of radioactive iodine, the stability of the labeling rate and yield for each production is extremely important because it cannot be stored after production as in the synthesis of general compounds. .
  • the starting compound (2) of the method of the present invention can be obtained, for example, by the method described in Patent Document 1 (Example 25).
  • the (Bu) 3 Sn (tributylstannyl) group in formula (2) is important in terms of improving the labeling rate in labeling with radioactive iodine, and (Bu) 3 Sn is replaced with a trimethylstannyl group, When the trimethylsilyl group, tetramethyl-dioxaborolanyl group or the like is used, the labeling rate is not sufficient.
  • radioactive iodine examples include 123 I, 124 I, 125 I, and 131 I.
  • the radioactive iodine compound used in the reaction sodium iodide ( 123I ), sodium iodide ( 125I ) or the like is used.
  • a radioactive iodine compound and an oxidizing agent are added to the solution of compound (2) and stirred at 0 to 40 ° C. for 1 to 10 minutes.
  • the amount of radioactive iodine compound added is preferably 0.5 GBq to 10 GBq, particularly 1.0 GBq to 8.0 GBq per 1 mg of compound (2) as the radioactive concentration of radioactive iodine.
  • the reaction temperature is preferably 10 to 30 ° C., and the reaction time is preferably 3 to 6 minutes.
  • a buffer solution is preferable, and examples thereof include a sodium phosphate buffer solution, a potassium phosphate buffer solution, an ammonium phosphate buffer solution, and a sodium acetate buffer solution.
  • a sodium phosphate buffer solution in terms of reaction yield.
  • the oxidizing agent is not particularly limited as long as it can oxidize radioactive iodine in the reaction solution, and preferably chloramine T, N-chlorosuccinimide, hydrogen peroxide, peracetic acid or the like is used. Can do.
  • iodine, sodium iodide, etc. can also be added to a reaction liquid.
  • the solvent for the compound (2) various solvents having no reactivity with the compound (2) and the radioactive iodine compound can be used, and alcohols such as ethanol, methanol, 1-propanol, 2-propanol and the like can be used. And esters such as ethyl acetate. Of these, alcohol, particularly 2-propanol, is preferred from the viewpoint of reaction yield.
  • the reaction for labeling compound (2) with radioactive iodine to obtain compound (3) includes radioactive sodium iodide solution, sodium phosphate buffer, sodium iodide aqueous solution and [compound (2)].
  • a 2-propanol solution is mixed, a chloramine T aqueous solution is added, and it is usually allowed to stand at a temperature of about 10 to 30 ° C. for 5 minutes.
  • the sodium phosphate concentration is, for example, in the range of 0.01 to 0.30 mol / L, preferably 0.02 to 0.20 mol / L.
  • the pH is, for example, in the range of 5.5 to 7.0, preferably 6.0 to 6.5.
  • the concentration of the sodium iodide aqueous solution is, for example, in the range of 7.5 to 375 ⁇ g / mL, preferably 50 to 200 ⁇ g / mL.
  • the concentration of the 2-propanol solution is, for example, in the range of 0.4 to 2.0 mg / mL, preferably 1.0 to 1.5 mg / mL.
  • the concentration of the chloramine T aqueous solution is, for example, in the range of 0.5 to 2.0 mg / mL, preferably 0.6 to 1.2 mg / mL.
  • the base used is not particularly limited as long as the reaction solution can be brought into an alkaline environment.
  • alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc.
  • alkaline earth metal hydroxides examples include alkaline earth metal hydroxides, phosphates such as disodium hydrogen phosphate and trisodium phosphate.
  • alkali metal hydroxides are preferred from the viewpoint of reaction yield and stability.
  • the base concentration is, for example, preferably 1 to 480 mg / mL, particularly 10 to 200 mg / mL.
  • the reaction may be heated to 30 to 90 ° C, particularly preferably 70 to 80 ° C.
  • a reaction time of 10 minutes to 1 hour, particularly 20 to 50 minutes is sufficient.
  • the reaction solution is cooled and purified by adding benzyl alcohol.
  • the amount of benzyl alcohol added is, for example, 10 to 150 ⁇ L, preferably 30 to 100 ⁇ L, with respect to the radioactive iodine compound 10 GBq used in the reaction.
  • the deprotected liquid is passed through a solid phase extraction column to adsorb the compound (1), and ethanol 0.2 to 10 GBq is used for the radioactive iodine compound 10 GBq used in the reaction.
  • Compound (1) is extracted with 1.5 mL, preferably 0.3 to 1.0 mL.
  • the extract is injected into an HPLC equipped with a reverse phase column, and the compound (1) is eluted with an ethanol / water mixed solvent to obtain a preparative solution.
  • benzyl alcohol is added in an amount of 10 to 150 ⁇ L, preferably 30 to 100 ⁇ L, per 10 GBq of the radioactive iodine compound used in the reaction.
  • the fractionated solution is sufficiently diluted with water, passed through a solid phase extraction column to adsorb the compound (1), and 0.5 to 4.5 mL of ethanol with respect to the radioactive iodine compound 10 GBq used in the reaction,
  • the compound (1) is extracted with 1.0 to 2.0 mL.
  • benzyl alcohol is added as a decomposition inhibitor at the time of the subsequent solvent distillation, and 10 to 1000 ⁇ L, preferably 100 to 500 ⁇ L, per 10 GBq of the radioactive iodine compound used in the reaction.
  • Example 3 Purification (purification) of radioiodinated 6-iodo-2- [4- (1H-3-pyrazolyl) phenyl] imidazo [1,2-a] pyridine ( 123 I) [compound (1a)]
  • the deprotection reaction solution obtained in Example 2 was passed through a solid-phase extraction column previously activated with 5 mL of absolute ethanol and 5 mL of water for injection, and the total amount of the solution obtained by washing the reaction glass vial with 5 mL of water for injection was also passed. Further, 5 mL of water for injection was passed through. Next, 1 mL of absolute ethanol was passed through the solid phase extraction column to obtain an extract of compound (1a).
  • the entire amount of the purified solution was passed through a solid phase extraction column previously activated with 5 mL of absolute ethanol and 5 mL of water for injection.
  • 3 mL of absolute ethanol was passed through the solid phase extraction column to obtain an extract of compound (1a).
  • the extract of compound (1a) was recovered in an eggplant type flask to which 450 ⁇ L of benzyl alcohol was added in advance.
  • the labeling rate (%) indicates the radiochemical purity after completion of the labeling reaction
  • the post-deprotection purity (%) indicates the radiochemical purity after the completion of the deprotection reaction.
  • Deprotection rate (%) Represents the value obtained by dividing the purity (%) after deprotection by the labeling rate (%) as a percentage.
  • radioiodinated 6-iodo-2- [4- (1H-3-pyrazolyl) phenyl] imidazo [1,2-a useful for imaging diseases caused by amyloid aggregation and / or deposition Pyridine can be produced in a stable and high yield.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention a pour objet un procédé de production commercialement avantageux de la 6-iodo-2-[4-(1H-3-pyrazolyle) phényle] imidazo [1,2-a] pyridine à l'iode radioactif, qui est utile pour l'imagerie d'une maladie provoquée par une agrégation et/ou un dépôt d'amyloïde. La présente invention a également pour objet un procédé de production d'un composé marqué à l'iode radioactif représenté par la formule (1) [R1 représentant l'iode radioactif], caractérisé en ce qu'il comprend les étapes consistant à : marquer un composé représenté par la formule (2) avec de l'iode radioactif pour donner un composé représenté par la formule (3) [R1 représentant l'iode radioactif] ; et chauffer ensuite ce composé (3) en présence d'une base.
PCT/JP2010/003112 2009-05-07 2010-05-06 Procédé de production d'un dérivé d'imidazopyridine marqué à l'iode radioactif WO2010128595A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2011512311A JPWO2010128595A1 (ja) 2009-05-07 2010-05-06 放射性ヨウ素標識イミダゾピリジン誘導体の製造法

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JP2009-112485 2009-05-07
JP2009112485 2009-05-07

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WO2010128595A1 true WO2010128595A1 (fr) 2010-11-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012161116A1 (fr) 2011-05-20 2012-11-29 日本メジフィジックス株式会社 Nouveau composé ayant une affinité pour la substance amyloïde
WO2012176587A1 (fr) 2011-06-24 2012-12-27 日本メジフィジックス株式会社 Nouveau composé ayant une affinité pour l'amyloïde

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007063946A1 (fr) * 2005-11-30 2007-06-07 Fujifilm Ri Pharma Co., Ltd. Diagnostic et remede pour une maladie provoquee par l’aggregation et/ou le depot d’amyloide
JP2007523142A (ja) * 2004-02-18 2007-08-16 アストラゼネカ アクチボラグ ベンズアミド誘導体、およびグルコキナーゼ活性化物質としてのそれらの使用
JP2009007348A (ja) * 2007-05-30 2009-01-15 Fujifilm Ri Pharma Co Ltd アミロイドの凝集及び／又は沈着に起因する疾患のイメージング薬及び治療薬

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007523142A (ja) * 2004-02-18 2007-08-16 アストラゼネカ アクチボラグ ベンズアミド誘導体、およびグルコキナーゼ活性化物質としてのそれらの使用
WO2007063946A1 (fr) * 2005-11-30 2007-06-07 Fujifilm Ri Pharma Co., Ltd. Diagnostic et remede pour une maladie provoquee par l’aggregation et/ou le depot d’amyloide
JP2009007348A (ja) * 2007-05-30 2009-01-15 Fujifilm Ri Pharma Co Ltd アミロイドの凝集及び／又は沈着に起因する疾患のイメージング薬及び治療薬

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHAKRABARTY, M. ET AL.: "Mild Deprotection of tert-Butyl Carbamates of NH-Heteroarenes under Basic Conditions", SYNTHETIC COMMUNICATIONS, vol. 36, 2006, pages 2069 - 2077 *
KAZZOULI, S.E. ET AL.: "A mild and selective method for the N-Boc deprotection by sodium carbonate", TETRAHEDRON LETTERS, vol. 47, 2006, pages 8575 - 8577 *
LUCKETT, L.W. ET AL.: "Radioiodine volatilization from reformulated sodium iodide 1-131", JOURNAL OF NUCLEAR MEDICINE, vol. 20, no. 5, 1980, pages 477 - 479 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012161116A1 (fr) 2011-05-20 2012-11-29 日本メジフィジックス株式会社 Nouveau composé ayant une affinité pour la substance amyloïde
CN103534253A (zh) * 2011-05-20 2014-01-22 日本医事物理股份有限公司 对淀粉状蛋白具有亲和性的新化合物
EP2716641A1 (fr) * 2011-05-20 2014-04-09 Nihon Medi-Physics Co., Ltd. Nouveau composé ayant une affinité pour la substance amyloïde
US20140228569A1 (en) * 2011-05-20 2014-08-14 Yuki Okumura Novel compound having affinity for amyloid
EP2716641A4 (fr) * 2011-05-20 2014-12-10 Nihon Mediphysics Co Ltd Nouveau composé ayant une affinité pour la substance amyloïde
US9149546B2 (en) 2011-05-20 2015-10-06 Nihon Medi-Physics Co., Ltd. Compound having affinity for amyloid
CN103534253B (zh) * 2011-05-20 2016-02-24 日本医事物理股份有限公司 对淀粉状蛋白具有亲和性的化合物
WO2012176587A1 (fr) 2011-06-24 2012-12-27 日本メジフィジックス株式会社 Nouveau composé ayant une affinité pour l'amyloïde
CN103596950A (zh) * 2011-06-24 2014-02-19 日本医事物理股份有限公司 对淀粉状蛋白具有亲和性的新化合物
US9211350B2 (en) 2011-06-24 2015-12-15 Nihon Medi-Physics Co., Ltd. Compound with amyloid affinity

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