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WO2025142589A1 - Composé ou sel ou solvate de celui-ci, son utilisation et son procédé de production - Google Patents

Composé ou sel ou solvate de celui-ci, son utilisation et son procédé de production Download PDF

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WO2025142589A1
WO2025142589A1 PCT/JP2024/044401 JP2024044401W WO2025142589A1 WO 2025142589 A1 WO2025142589 A1 WO 2025142589A1 JP 2024044401 W JP2024044401 W JP 2024044401W WO 2025142589 A1 WO2025142589 A1 WO 2025142589A1
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group
nuclide
deuterium
compound
radioactive halogen
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Japanese (ja)
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正行 破入
謝琳 張
雅之 藤永
明栄 張
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National Institutes For Quantum Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a compound or a salt or solvate thereof, their use, and a method for producing the same.
  • Metabotropic glutamate receptor 1 is a G protein-coupled receptor normally expressed in the central nervous system and contributes to learning or memory formation or neuronal development. Ectopic mGluR1 is carcinogenic, and is presumed to activate the mitogen-activated protein kinase (MAPK) or phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways independent of B-Raf or N-Ras, inducing cancer in melanocytes. It has also been reported that mGluR1 is not expressed in normal skin melanocytes or peripheral organs, but if abnormal expression is induced in melanocytes, melanoma will form with almost 100% probability. It is also known to be frequently expressed in many types of cancer, including human melanoma, breast cancer, pancreatic cancer, and colon cancer, and mGluR1 is expected to be a promising target for the development of cancer diagnosis or treatment.
  • MAPK mitogen-activated protein kina
  • Non-Patent Document 1 The present inventors have developed small molecule PET tracers targeting receptors on various tissues, and have succeeded in developing a small molecule PET tracer ( 18F -FITM) for mGluR1 (Non-Patent Document 1). Using knowledge of the pharmacokinetics of this tracer, we have also succeeded in developing 211At -AITM labeled with 211At , an alpha-emitting nuclide, and have obtained knowledge that can be used as a small molecule radiotherapeutic drug (Non-Patent Documents 2 and 3). However, there have been no reports on the development of a method for modifying the backbone structure that can contribute to further metabolic stability of the compound, particularly a technology that can be applied to radiotherapeutic drugs.
  • Non-Patent Document 4 reports compounds containing deuterium as candidates for radiopharmaceuticals.
  • Non-Patent Document 4 reports findings regarding labeling reactions after deuteration of aliphatic and alicyclic hydrocarbons.
  • the inventors have conducted extensive research to achieve the above object. As a result, they have discovered that by reacting a compound having a deuterated aromatic ring or heteroaromatic ring with a radioactive halogen nuclide under specific conditions, it is possible to obtain a radioactive halogen compound having a radioactive halogen nuclide and deuterium on the aromatic ring or heteroaromatic ring. They have also discovered that the metabolic stability of the obtained compound is improved, which has led to the completion of the present invention.
  • a compound according to one aspect of the present invention is a compound of formula (I), a pharma- ceutically acceptable salt, or a solvate thereof:
  • X1 and X2 are each independently a radioactive halogen nuclide, hydrogen or deuterium; R 1 , R 2 and R 3 are each independently hydrogen or deuterium; At least one of X 1 , X 2 , R 1 , R 2 and R 3 is deuterium; At least one of X1 and X2 is a radioactive halogen nuclide; Y is a methyl group and an isopropyl group.
  • a manufacturing method is a method for manufacturing a radiolabeled deuterated aromatic carbonyl compound, a medicamentarily acceptable salt thereof, or a solvate thereof, comprising a labeling step of labeling the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound with a radioactive halogen nuclide by subjecting the aromatic carbonyl compound, in which at least one hydrogen atom on the aromatic ring or heteroaromatic ring has been substituted with deuterium, to an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at 50°C or higher and 220°C or lower, with a radioactive halogen nuclide.
  • a radioactive halogen compound having a radioactive halogen nuclide and deuterium on an aromatic ring or heteroaromatic ring, which has improved metabolic stability.
  • FIG. 2 shows an HPLC chart of the reaction mixture obtained in the condition study of Example 2.
  • FIG. 2 shows an HPLC chart of 211 At-AITM-D4 obtained in Example 3.
  • FIG. 2 shows the Radio TLC chart of 211 At-AITM-D4 obtained in Example 3.
  • FIG. 1 shows the results of evaluating the stability of 211At -AITM-D4 to serum.
  • FIG. 1 shows the results of measuring the amount of cellular uptake of 211At -AITM-D4.
  • FIG. 1 shows the results of measuring the cellular distribution of 211At -AITM-D4.
  • FIG. 1 shows Radio TLC charts of 123 I-Py[D4] and 123 I-Py after purification.
  • FIG. 1 shows Radio TLC charts of 211 At-Py[D4] and 211 At-Py after purification.
  • FIG. 1 shows the results of a stability test of 123 I-Py[D4] and 211 At-Py[D4].
  • aromatic ring or heteroaromatic ring is deuterated refers to at least one hydrogen atom on the aromatic ring or heteroaromatic ring being replaced with deuterium.
  • heteroaromatic ring refers to an aromatic ring containing at least one heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom.
  • heteroaromatic rings include ⁇ -electron rich and ⁇ -electron deficient aromatic heterocycles, such as a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a triazine ring, a furan ring, a thiophene ring, a thiazole ring, a pyrrole ring, an imidazole ring, and an oxazole ring.
  • a "radioactive halogen nuclide” is a radioactive isotope of a halogen element.
  • halogen elements include fluorine (F), chlorine (Cl), bromine (Br), iodine (I) and astatine (At).
  • pharmaceutically acceptable salts refers to salts that are not harmful to living animals, particularly mammals.
  • Pharmaceutically acceptable salts can be formed using non-toxic acids or bases, including inorganic acids or bases, or organic acids or bases.
  • Pharmaceutically acceptable salts include acid addition salts and base addition salts.
  • acidic salts include salts with alkali metals such as sodium, potassium, and lithium; salts with alkaline earth metals such as calcium and magnesium; metal salts such as aluminum and zinc; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, diethanolamine, ethylenediamine, dicyclohexylamine, procaine, chloroprocaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, meglumine (N-methylglucamine), etc.
  • alkali metals such as sodium, potassium, and lithium
  • salts with alkaline earth metals such as calcium and magnesium
  • metal salts such as aluminum and zinc
  • ammonium salts and salts with nitrogen-containing
  • solvate refers to a solvate formed by the association of one or more solvent molecules with a compound according to one aspect of the present invention.
  • Solvates include, for example, monosolvates, disolvates, trisolvates, and tetrasolvates. Solvates also include hydrates.
  • a and/or B is a concept that includes both A and B and A or B, and can be rephrased as “at least one of A and B.”
  • ⁇ means a range that includes both the numerical values at both ends.
  • One aspect of the present invention is a compound of the following formula (I), or a pharma- ceutical acceptable salt or solvate thereof (hereinafter, these may be collectively referred to as "the compound (I)").
  • Compound (I) has high metabolic stability.
  • the metabolic stability can be measured, for example, by mixing the target compound with a biological sample such as blood (e.g., serum) and allowing to stand for a certain period of time (e.g., 24 hours at 37°C), and then calculating the proportion of the unchanged target compound in the biological sample (amount of the unchanged target compound in the biological sample/total amount of the target compound in the biological sample).
  • a biological sample such as blood (e.g., serum)
  • a certain period of time e.g., 24 hours at 37°C
  • radioactive halogen nuclide of the compound (I) examples include 18 F, 34m Cl, 36 Cl, 75 Br, 76 Br, 77 Br, 80 Br, 82 Br, 123 I, 124 I, 125 I, 131 I, 211 At, etc.
  • the radioactive halogen nuclide is preferably 123 I, 18 F, 76 Br, 124 I.
  • the radioactive halogen nuclide is preferably 211 At, 77 Br, 131 I.
  • the two hydrogen atoms adjacent to the radioactive halogen nuclide on the aromatic ring are replaced with deuterium.
  • X1 is a radioactive halogen nuclide
  • X2 and R3 are each deuterium
  • X1 and R1 are each deuterium.
  • one of X1 and X2 is 211At and the other is deuterium, and R1 , R2 and R3 are each deuterium.
  • a more preferable example of the present compound (I) is a compound of the following formula (IA). In formula (IA), D is deuterium.
  • Compound (I) can be produced by the method for producing a radiolabeled deuterated aromatic carbonyl compound, a medicamentously acceptable salt thereof, or a solvate thereof, which will be described later.
  • Radioactive therapeutic or diagnostic agent A radiotherapeutic agent or radiodiagnostic agent containing the present compound (I) as an active ingredient is also included in one aspect of the present invention.
  • the radiotherapeutic or diagnostic agent may be contained in a medicament acceptable carrier.
  • the medicament acceptable carrier is not particularly limited, but may be, for example, sterile water, saline, normal saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer's injection.
  • radioactive therapeutic agents or radioactive diagnostic agents can be preferably used for the treatment or diagnosis of diseases involving cells expressing metabotropic glutamate receptor 1 (mGluR1) (particularly cells expressing it at a high level). They can also be preferably used for the treatment or diagnosis of cancer (tumor), and in particular, for the treatment or diagnosis of cancer (tumor) expressing mGluR1.
  • mGluR1 metabotropic glutamate receptor 1
  • Examples of diseases involving cells expressing mGluR1 include cancer (tumors) and fatty liver.
  • cancers (tumors) that express mGluR1 highly include melanoma, breast cancer, pancreatic cancer, colon cancer, glioma, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, gastric cancer, thyroid cancer, thymic cancer, renal cell carcinoma, chromophobe renal cell carcinoma, testicular germ cell cancer, endometrial cancer, sarcoma, and uterine sarcoma.
  • the radioactive therapeutic drug or radioactive diagnostic drug is not particularly limited, but can be administered, for example, parenterally, intravenously, or intraperitoneally.
  • the compound (I) may be a single substance, or may be supported by a DDS (drug delivery system).
  • the radioactive therapeutic drug or radioactive diagnostic drug may consist of only the compound (I).
  • the dosage of the compound (I) may be appropriately determined depending on the type of substance used, the age, weight, health condition, sex, and diet of the subject to be administered, the number of administrations, and the route of administration, etc.
  • An aspect of the present invention also includes a method for diagnosing or treating a disease involving cells expressing mGluR1 using the above radioactive therapeutic agent or radioactive diagnostic agent.
  • An aspect of the present invention also includes a method for diagnosing or treating cancer using the above radioactive therapeutic agent or radioactive diagnostic agent.
  • the diagnostic or therapeutic method includes a step of administering the above radioactive therapeutic agent or radioactive diagnostic agent to a subject.
  • the administration route is not particularly limited and may be selected from common drug administration routes such as parenteral administration, intravenous administration, or intraperitoneal administration.
  • the method for diagnosing cancer using the radioactive diagnostic agent further includes detecting a compound that has accumulated in the cancer.
  • a radiation detector that detects radiation emitted from the radioactive halogen nuclide in the compound (I).
  • PET positron emission tomography
  • Compounds that have accumulated in tumors can also be detected by nuclear magnetic resonance imaging (MRI) or hyperpolarized nuclear magnetic resonance.
  • the labeled precursor has at least one hydrogen atom on the aromatic ring or heteroaromatic ring substituted with deuterium.
  • the aromatic ring or heteroaromatic ring of the labeled precursor is labeled with a radioactive halogen nuclide by an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at 50°C or higher and 220°C or lower with the radioactive halogen nuclide.
  • a radioactive halogen compound having a radioactive halogen nuclide and deuterium on the aromatic ring or heteroaromatic ring can be produced.
  • Example 2 Study of reaction temperature for preparation of 211 At-AITM-D4
  • the conditions for preparing a compound ( 211 At-AITM-D4) in which 211 At was introduced into compound 5 were studied.
  • 211 At in a glass vial was extracted with 460 ⁇ L of 2 mg/mL N-chlorosuccinimide/methanol solution.
  • Two reaction solutions were prepared by adding 200 ⁇ L of 211 At solution to 100 ⁇ L of 3% acetic acid/methanol solution containing compound 5 at a concentration of 1 mg/mL. After leaving the solution at room temperature (1°C to 30°C) and 70°C for 20 minutes, the reaction was terminated by adding 50 ⁇ L of 2 mg/mL sodium sulfite aqueous solution.
  • the labeling efficiency was measured by RadioHPLC.
  • Example 3 Labeling synthesis of 211At -AITM-D4 200 ⁇ L of 2 mg/mL N-chlorosuccinimide/methanol solution and 100 ⁇ L of 3% acetic acid/methanol solution with a concentration of 1 mg/mL of compound 5 were added to 211 At in a glass vial. After the reaction solution was left at 70°C for 20 minutes, 50 ⁇ L of 2 mg/mL sodium sulfite aqueous solution was added to terminate the reaction, and then 1 mL of distilled water was added. Purification was performed by RadioHPLC and the retention time was about 16 minutes was separated.
  • Example 5 Cellular uptake and distribution of 211At -AITM-D4 Transplantable B16Fl0 melanoma cells in C57BL/6J mice were obtained from the American Type Culture Collection. B16Fl0 cells were maintained and passaged in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, penicillin (100 U/mL), and streptomycin (0.1 mg/mL). B16F10 melanoma cells (5 ⁇ 104 cells) were seeded in a 24-well plate and cultured for 24 hours as adherent cells.
  • Radioactivity was measured using a ⁇ -counter (PerkinElmer), and the protein content of the cell lysate was quantified using a protein assay kit (Bio-RAD).
  • the amount of uptake into the cells was calculated as the amount of radioactivity used per protein weight (mg) (%ICD/mg protein).
  • the measurement results of the amount of uptake into the cells are shown in Figure 5.
  • the amount of cellular uptake after 1 hour for 211At -AITM was 20.64 ⁇ 2.97 (%ICD/mg protein), whereas for 211At -AITM-D4 it was 57.61 ⁇ 8.38 (%ICD/mg protein), a 2.5-fold increase in cellular uptake.
  • the results of cellular distribution are shown in Figure 6. It was also confirmed that the internalization rate of 211At -AITM-D4 was higher than that of 211At-AITM-D4.
  • the reaction solution was added to 10 mL of water and collected in a Sep-PAK C18 light column, and the column was washed with 10 mL of water, and the target product was recovered with 300 ⁇ L of ethanol. After drying the EtOH, the target product ( 123 I-Py[D4]) was obtained by redissolving in physiological saline.
  • 123I -Py[D4] is a compound in which four hydrogen atoms on the pyridine ring of pyridine are replaced with deuterium and further labeled with 123I .
  • the radiochemical yield was 96.3% and the radiochemical purity was 97.8%.
  • the RadioTLC chart after purification is shown on the left in Figure 7.
  • Example 7 Preparation of 123 I-Py 123 I-Py was synthesized in the same manner as in Example 6, with a radiochemical yield of 96.2% and a radiochemical purity of 96.2%. The RadioTLC chart after purification is shown on the right side of Figure 7. 123 I-Py is pyridine labeled with 123 I.
  • Example 8 Preparation of 211 At-Py[D4] 50 ⁇ L of 0.1 mol/L Na 2 CO 3 was added to 211 At in a glass vial, and after standing for 1 minute, 300 ⁇ L of methanol was added. 40 ⁇ L of acetonitrile, 15 ⁇ L of a methanol solution containing 1mg of Cu(OTf) 2 (Py) 4 and 355 ⁇ g of 3,4,7,8-tetramethyl-1,10-phenanthroline, and 150 ⁇ L of the 211 At solution prepared above were added to 1mg of 3 -pyridine-d 4 -boronic acid, and the mixture was left to stand at 70°C for 20 minutes.
  • the reaction solution was added to 10mL of water and collected in a Sep-PAK C18 light column, and the column was washed with 10mL of water, and the target product ( 211 At-Py[D4]) was collected with 300 ⁇ L of ethanol.
  • 211 At-Py[D4] is a compound in which the four hydrogen atoms on the pyridine ring of pyridine are replaced with deuterium and further labeled with 211 At. After drying the EtOH, the product was redissolved in saline to obtain the target compound.
  • the radiochemical yield was 19.5%, and the radiochemical purity was 98.0%.
  • the RadioTLC chart after purification is shown on the left in Figure 8.
  • Example 9 Preparation of 211 At-Py 211 At-Py was synthesized in the same manner as in Example 8, with a radiochemical yield of 20.3% and a radiochemical purity of 95.6%. The RadioTLC chart after purification is shown on the right side of Figure 8. 211 At-Py is pyridine labeled with 211 At.
  • Example 10 Stability test of 123I -Py[D4] and 211At -Py[D4]
  • the stability in serum was measured using deuterated pyridine with radioactive halogen and pyridine with radioactive halogen prepared in Examples 6 to 9. 2 MBq of the radioactive compound was mixed with 10 uL of mouse serum and allowed to stand at 37°C for 24 hours. 1 ⁇ l of the serum mixture was loaded onto a TLC and developed using ethyl acetate as a solvent. After drying, detection was performed using a RadioTLC scanner. The results are shown in Figure 9.

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Abstract

La présente invention concerne des composés de formule (I) et des sels ou solvates pharmaceutiquement acceptables de ceux-ci : dans la formule (I), X1 et X2 sont chacun indépendamment un nucléide d'halogène radioactif, de l'hydrogène ou du deutérium, R1, R2 et R3 sont chacun indépendamment hydrogène ou deutérium, au moins l'un de X1, X2 , R1, R2 et R3 est le deutérium, au moins l'un de X1 et X2 est un nucléide halogéné radioactif et Y est un groupe méthyle et un groupe isopropyle.
PCT/JP2024/044401 2023-12-28 2024-12-16 Composé ou sel ou solvate de celui-ci, son utilisation et son procédé de production Pending WO2025142589A1 (fr)

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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ATTYGALLE ATHULA B., KHARBATIA NAJEH, BIALECKI JASON, RUZICKA JOSEF, SVATOš ALEš, STAUBER EINAR J.: "An unexpected ion‐molecule adduct in negative‐ion collision‐induced decomposition ion‐trap mass spectra of halogenated benzoic acids", RAPID COMMUNICATIONS IN MASS SPECTROMETRY, JOHN WILEY & SONS, GB, vol. 20, no. 15, 15 August 2006 (2006-08-15), GB , pages 2265 - 2270, XP093330918, ISSN: 0951-4198, DOI: 10.1002/rcm.2582 *
KLENNER MITCHELL A.; PASCALI GIANCARLO; FRASER BENJAMIN H.; DARWISH TAMIM A.: "Kinetic isotope effects and synthetic strategies for deuterated carbon-11 and fluorine-18 labelled PET radiopharmaceuticals", NUCLEAR MEDICINE AND BIOLOGY, ELSEVIER, NY., US, vol. 96, 16 April 2021 (2021-04-16), US , pages 112 - 147, XP086578205, ISSN: 0969-8051, DOI: 10.1016/j.nucmedbio.2021.03.011 *
TOMOTERU YAMASAKI; MASAYUKI FUJINAGA; YUICHIRO YOSHIDA; KATSUSHI KUMATA; JOJI YUI; KAZUNORI KAWAMURA; AKIKO HATORI; TOSHIMITSU FUK: "Radiosynthesis and preliminary evaluation of 4-[F]fluoro--[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]--methylbenzamide as a new positron emission tomography ligand for metabotropic glutamate receptor subtype 1", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 21, no. 10, 11 March 2011 (2011-03-11), Amsterdam NL , pages 2998 - 3001, XP028199566, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2011.03.046 *
XIE LIN, HANYU MASAYUKI, FUJINAGA MASAYUKI, ZHANG YIDING, HU KUAN, MINEGISHI KATSUYUKI, JIANG CUIPING, KUROSAWA FUKI, MOROKOSHI YU: "131 I-IITM and 211 At-AITM: Two Novel Small-Molecule Radiopharmaceuticals Targeting Oncoprotein Metabotropic Glutamate Receptor 1", THE JOURNAL OF NUCLEAR MEDICINE, SOCIETY OF NUCLEAR MEDICINE, US, vol. 61, no. 2, 1 February 2020 (2020-02-01), US , pages 242 - 248, XP093330916, ISSN: 0161-5505, DOI: 10.2967/jnumed.119.230946 *
YUAN GENGYANG, SHOUP TIMOTHY M., MOON SUNG-HYUN, BROWNELL ANNA-LIISA: "A concise method for fully automated radiosyntheses of [ 18 F]JNJ-46356479 and [ 18 F]FITM via Cu-mediated 18 F-fluorination of organoboranes", RSC ADVANCES, vol. 10, no. 42, 2 July 2020 (2020-07-02), pages 25223 - 25227, XP055844931, DOI: 10.1039/D0RA04943C *

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