WO2022186273A1 - Composé radioactif - Google Patents

Composé radioactif Download PDF

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WO2022186273A1
WO2022186273A1 PCT/JP2022/008860 JP2022008860W WO2022186273A1 WO 2022186273 A1 WO2022186273 A1 WO 2022186273A1 JP 2022008860 W JP2022008860 W JP 2022008860W WO 2022186273 A1 WO2022186273 A1 WO 2022186273A1
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compound
formula
group
phase
hydrogen atom
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PCT/JP2022/008860
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Japanese (ja)
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知也 上原
博元 鈴木
祐太 貝塚
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国立大学法人千葉大学
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • 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
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a radioactive compound, a method for producing the same, and a radiopharmaceutical composition.
  • Non-Patent Document 1 amino acid derivatives labeled with astatine-211 ( 211 At), which is an ⁇ -emitting nuclide, are expected to enable nuclear medicine treatment using ⁇ -rays, enabling integrated diagnosis and treatment.
  • 211 At-labeled tyrosine derivatives and 211 At-labeled phenylalanine derivatives have been developed as 211 At-labeled drugs (eg, Non-Patent Document 2).
  • Amino acid derivatives labeled with radioactive fluorine or radioactive iodine that have been developed so far have high in vivo stability and high uptake into tumors, and their usefulness has been recognized.
  • 211 At-labeled amino acid derivatives exhibit high uptake into tumors
  • 211 At is observed to be lost in vivo, and non-specific accumulation in the stomach and thyroid is a problem. This not only leads to increased side effects due to radiation exposure, but also leads to decreased radioactivity in tumor tissue, resulting in insufficient therapeutic effects. Therefore, development of 211 At-labeled amino acid derivatives with high in vivo stability is desired.
  • TECHNICAL FIELD The present invention relates to novel radioactive compounds, particularly to radioactive compounds or pharmaceutically acceptable salts thereof having high biostability.
  • the present invention includes the following aspects. ⁇ 1> A radioactive compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • R a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R b each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • X represents a group represented by the following formula (x1), formula (x2) or formula (x3)
  • R a represents a hydrogen atom or a methyl group
  • ⁇ 4> A method for producing the radioactive compound or a pharmaceutically acceptable salt thereof according to any one of ⁇ 1> to ⁇ 3> above, comprising the following steps [1] to [4]. [1] providing a compound (i) represented by the following formula (y1), formula (y2) or formula (y3);
  • Z 1 each independently represents a hydrogen atom, an amino group-protecting group or R b
  • Z 2 represents a hydrogen atom or a carboxy-protecting group.
  • R a , R b , ⁇ are the same as above.
  • each L 1 independently represents a leaving group.
  • [3] (a) Substitution of the hydrogen atom of the side chain amino group or hydroxy group in the compound (i) with a group excluding one L 1 in the compound (ii), and (b) the compound Y of the other L 1 in (ii) [wherein Y is the same as above. ] to obtain a compound (iii) represented by the following formula (III);
  • Step ⁇ 5> Deprotecting the protecting group of compound (iii) above ⁇ 5> A radioactive compound comprising the radioactive compound or a pharmaceutically acceptable salt thereof according to any one of ⁇ 1> to ⁇ 3> above pharmaceutical composition.
  • ⁇ 6> The radiopharmaceutical composition according to ⁇ 5> above, which is for diagnostic imaging.
  • ⁇ 7> The radiopharmaceutical composition according to ⁇ 5> above, which is for therapeutic use.
  • a novel radioactive compound or a pharmaceutically acceptable salt thereof is provided by the present invention.
  • the radioactive compounds of the present invention have high biostability.
  • FIG. 1 shows the results of HPLC analysis of compound (8) and compound (14) of Synthesis Example 1.
  • FIG. 2 shows the results of HPLC analysis of compound (12) and compound (16) of Synthesis Example 1.
  • FIG. 3 shows the results of Evaluation Example 2.
  • FIG. 4 shows the results of Evaluation Example 3.
  • the radioactive compound of the present invention (hereinafter also referred to as the compound of the present invention) is a radioactive compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • R a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • R b each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • X represents a group represented by the following formula (x1), formula (x2) or formula (x3)
  • Y represents 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 132 I, or 211 At; ⁇ indicates an asymmetric carbon.
  • alkyl group having 1 to 6 carbon atoms for R a and R b includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, specifically methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and the like.
  • R a represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, more preferably a hydrogen atom or a methyl group, still more preferably a hydrogen atom is.
  • Each R b independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, preferably represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, more preferably represents a hydrogen atom or a methyl group, further preferably is a hydrogen atom.
  • Two of R b are preferably both hydrogen atoms, or one is a hydrogen atom and the other is the above alkyl group, more preferably both are hydrogen atoms.
  • Y is a radioactive halogen atom and represents 18 F, 76 Br, 77 Br, 123 I, 124 I, 125 I, 132 I or 211 At, preferably 18 F, 125 I or 211 At, more preferably Indicates 125 I or 211 At.
  • the compound of the present invention has an asymmetric carbon.
  • the configuration of ⁇ C carbon, which is an asymmetric carbon, is the following L configuration
  • R a , R b and X are the same as above.
  • R a , R b and X are the same as above.
  • R a preferably represents a hydrogen atom or a methyl group
  • R b each independently represents a hydrogen atom or a methyl group.
  • Preferred embodiments of the compounds of the present invention include radioactive compounds represented by the following formulas (Ia-1), (Ia-2) or (Ia-3), or pharmaceutically acceptable salts thereof.
  • a more preferred embodiment of the compound of the present invention includes a radioactive compound represented by the following formula (Ib-1), (Ib-2) or (Ib-3) or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention may be a pharmaceutically acceptable salt of the radioactive compound represented by formula (I) above.
  • Salts include acid addition salts and base addition salts.
  • the acid addition salt may be either an inorganic acid salt or an organic acid salt.
  • inorganic acid salts include hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate.
  • organic acid salts include citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, and benzenesulfonic acid. salts, p-toluenesulfonate.
  • the base addition salt may be either an inorganic base salt or an organic base salt.
  • Inorganic base salts include, for example, sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts.
  • Organic base salts include, for example, triethylammonium salts, triethanolammonium salts, pyridinium salts, and diisopropylammonium salts.
  • the compounds of the present invention may be solvates such as hydrates.
  • the solvent is not particularly limited as long as it is a pharmaceutically acceptable solvent.
  • the compound of the present invention can be suitably used as an active ingredient of a radiopharmaceutical composition for diagnostic imaging, treatment, etc., which will be described later.
  • a radioactive compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be produced, for example, by a method including the following steps [1] to [4]. [1] providing a compound (i) represented by the following formula (y1), formula (y2) or formula (y3);
  • Z 1 each independently represents a hydrogen atom, an amino group-protecting group or R b
  • Z 2 represents a hydrogen atom or a carboxy-protecting group
  • R a , R b , ⁇ are the same as above.
  • each L 1 independently represents a leaving group.
  • [3] (a) Substitution of the hydrogen atom of the side chain amino group or hydroxy group in the compound (i) with a group excluding one L 1 in the compound (ii), and (b) the compound Y of the other L 1 in (ii) [wherein Y is the same as above. ] to obtain a compound (iii) represented by the following formula (III);
  • step [1] compound (i) represented by formula (y1), formula (y2) or formula (y3) is provided.
  • the compound represented by formula (y1) is histidine or its ⁇ -alkyl type and/or N-alkyl type derivative whose amino group and carboxy group bonded to ⁇ carbon may be protected.
  • the compound represented by formula (y2) is tyrosine or its ⁇ -alkyl type and/or N-alkyl type derivative whose amino group and carboxy group bonded to ⁇ carbon may be protected.
  • the compound represented by formula (y3) is ⁇ -alkyl and/or N-alkyl tryptophan or a derivative thereof in which the amino group and carboxy group bonded to the ⁇ carbon may be protected.
  • Examples of protective groups for amino groups include tert-butoxycarbonyl group (Boc group), benzyloxycarbonyl group (Cbz group), 9-fluorenylmethyloxycarbonyl group (Fmoc group) and the like.
  • Examples of the carboxy-protecting group include methyl group, ethyl group, benzyl group, tert-butyl group and the like.
  • Z 1 is an amino group-protecting group and Z 2 is a carboxy group-protecting group
  • Z 1 and Z 2 are a combination of an amino group-protecting group and a carboxy group-protecting group that can be deprotected under the same conditions, more preferably an amino group-protecting group and a carboxyl group that can be deprotected with an acid catalyst such as trifluoroacetic acid.
  • an acid catalyst such as trifluoroacetic acid.
  • Such combinations include, for example, Z 1 is a Boc group and Z 2 is a tert-butyl group.
  • Introduction of an amino-protecting group and a carboxy-protecting group can be carried out by a conventional method.
  • step [2] compound (ii) represented by formula (II) is provided.
  • Compound (ii) is obtained by reacting two adjacent hydroxy groups of pentaerythritol with 2,2-dimethoxypropane to protect the can be obtained by reacting the other two hydroxy groups with an activating agent as leaving groups.
  • Leaving groups represented by L 1 include trifluoromethanesulfonate (triflate, —OTf) group, nonafluorobutanesulfonate (nonaflate) group, p-toluenesulfonate (tosylate) group, methanesulfonate (mesylate) group, and p-nitrosulfonyloxy (nosylate) group.
  • trifluoromethanesulfonate group and nonafluorobutanesulfonate group are preferable from the viewpoint of reactivity.
  • step [3] (a) substitution of the hydrogen atom of the side chain amino group or hydroxy group in the compound (i) with a group excluding one L 1 in the compound (ii), and (b ) Y of the other L 1 in the above compound (ii) [wherein Y is the same as above. ] to obtain the compound (iii) represented by the formula (III).
  • Step (a) In the step (a), the hydrogen atom of the side chain amino group or hydroxy group in the compound (i) is substituted with the group excluding one L 1 in the compound (ii).
  • 0.1 to 10 mol preferably 0.5 to 2 mol of compound (ii) can be reacted with 1 mol of compound (i).
  • the reaction can be carried out in the presence of, for example, 0.1 to excess mol, preferably 0.5 to 10 mol of base per 1 mol of compound (i), if necessary.
  • the base examples include organic bases such as pyridine, triethylamine, diisopropylethylamine (DIPEA), and 2,6-lutidine; alkali metal carbonates such as sodium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; Inorganic bases such as alkali metal hydrides are included.
  • the reaction is preferably carried out in a solvent.
  • solvents include organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane, but are limited to these. not to be
  • the solvent may be either a single solvent or a mixture of two or more solvents.
  • step (b) the radioactive atom Y[Y of the other L1 in compound (ii) is the same as above. ].
  • 0.1 to 10 mol, preferably 0.5 to 5 mol of a halogenating agent can be reacted with 1 mol of compound (ii) or the compound obtained in step (a).
  • the halogenating agent include radioactive halogen molecules corresponding to Y, alkali metal salts of Y such as sodium, oxides of Y, and N-halogen succinimide.
  • the reaction is carried out in the presence of, for example, 0.1 to excess mol, preferably 0.5 to 10 mol of a base, relative to 1 mol of compound (ii) or the compound obtained in step (a), if necessary.
  • a base include organic bases such as pyridine, triethylamine, diisopropylethylamine (DIPEA), and 2,6-lutidine; alkali metal carbonates such as sodium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; Inorganic bases such as alkali metal hydrides are included. Among them, organic bases are preferable from the viewpoint of reactivity.
  • an organic base that is liquid at room temperature is more preferable.
  • the reaction temperature can be, for example, 0-40°C.
  • the reaction time can be, for example, 30 minutes to 10 days.
  • the reaction is preferably carried out in a solvent.
  • solvents include organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane, but are limited to these. not to be
  • the solvent may be either a single solvent or a mixture of two or more solvents.
  • step (a) and step (b) are not limited, and step (b) may be performed after step (a), or step (a) may be performed after step (b). , from the viewpoint of reducing the number of steps for handling radioactive isotopes, step (b) is preferably carried out after step (a).
  • the compound (iii) represented by the formula (III) obtained in this way is subjected to isolation steps such as filtration, concentration, and extraction, and/or purification steps such as column chromatography and recrystallization, if necessary. After that, it can be subjected to the next step [4].
  • isolation steps such as filtration, concentration, and extraction, and/or purification steps such as column chromatography and recrystallization are performed to obtain the target compound. can be done.
  • step [4] the protecting group of compound (iii) is deprotected.
  • the protecting group of the compound (iii) means that Z 1 derived from the compound (i) is an amino-protecting group and Z 2 is a carboxy-protecting group, and that the compound (ii) is derived from It is an acetal protecting group with a neopentyl structure.
  • Deprotection of a protecting group can be performed by a conventional method.
  • the acetal protecting group with a neopentyl structure can be deprotected using an acid catalyst in an amount of, for example, 0.1 mol to excess, preferably about 0.5 mol to 10 mol, per 1 mol of compound (iii).
  • acid catalysts include organic acids such as trifluoroacetic acid and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. Among them, trifluoroacetic acid is preferred.
  • a person skilled in the art can appropriately set the reaction temperature and the reaction time.
  • the reaction temperature can be, for example, about 10 to 40°C.
  • the reaction time can be, for example, about 30 minutes to 24 hours. From the viewpoint of reaction progress, the reaction is preferably carried out in a solvent.
  • solvents include aqueous solvents such as water.
  • step [4] the target radioactive compound represented by the formula (I) or its pharmacological properties is obtained through isolation steps such as filtration, concentration, and extraction, and/or purification steps such as column chromatography and recrystallization, as necessary.
  • isolation steps such as filtration, concentration, and extraction, and/or purification steps such as column chromatography and recrystallization, as necessary.
  • purification steps such as column chromatography and recrystallization, as necessary.
  • commercially acceptable salts can be obtained.
  • the radioactive compound of the invention is produced. Synthesis of the radioactive compound of the present invention can be confirmed by known means such as 1 H-NMR measurement, 13 C-NMR measurement and mass spectrometry.
  • an ⁇ -amino acid in which the amino group and carboxy group bonded to the ⁇ carbon may be protected, other than the compound (i) represented by formula (y1), formula (y2) or formula (y3).
  • a radioactive compound derived from the amino acid or a pharmaceutically acceptable salt thereof can be obtained.
  • ⁇ -amino acids include lysine, arginine, asparagine, and glutamine having an amino group in the side chain; serine, threonine, etc. having a hydroxy group in the side chain.
  • ⁇ -amino acids also include glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, cysteine, methionine, etc., which do not have amino groups or hydroxyl groups in their side chains.
  • the hydrogen atom of the amino group bonded to the ⁇ carbon is substituted with the group excluding one L 1 in the compound (ii).
  • An example of the radioactive compound thus obtained is shown below.
  • Radiopharmaceutical composition The present invention provides a radiopharmaceutical composition containing the above radioactive compound or a salt thereof as an active ingredient.
  • a radiopharmaceutical can be prepared as a pharmaceutical composition containing the above-mentioned radioactive compound or a salt thereof as an active ingredient and, if necessary, one or more pharmaceutically acceptable carriers.
  • Carriers include aqueous buffers, pH adjusters such as acids and bases, stabilizers such as ascorbic acid and p-aminobenzoic acid, excipients such as D-mannitol, tonicity agents, and preservatives. I can give an example.
  • Compounds such as citric acid, tartaric acid, malonic acid, sodium gluconate, sodium glucoheptonate, etc. may also be added to help improve radiochemical purity.
  • Radiopharmaceutical compositions can be provided in the form of aqueous solutions, frozen solutions, and lyophilizates.
  • the radiopharmaceutical composition of the present invention can be used, for example, for diagnostic imaging.
  • Diagnostic imaging includes, for example, Single Photon Emission Computed Tomography (also simply referred to as "SPECT"), Positron Emission Tomography (also simply referred to as “PET”), and the like.
  • SPECT Single Photon Emission Computed Tomography
  • PET Positron Emission Tomography
  • Diagnosis is not particularly limited, and it is used for various diseases such as tumors, inflammation, infectious diseases, cardiovascular diseases, brain and central system diseases, and radiological image diagnosis of organs or tissues.
  • Types of cancer include solid cancers in the stomach, large intestine, lung, liver, prostate, pancreas, esophagus, bladder, gallbladder/bile duct, breast, uterus, thyroid gland, ovary, and the like.
  • the radiopharmaceutical composition of the invention can be used, for example, for therapy. Preferably, it can be used for radiotherapy to suppress cancer.
  • it When used as an anticancer agent, for example, it has a preventive action to prevent the occurrence of cancer, metastasis/implantation, and recurrence, as well as suppressing the growth of cancer cells and shrinking cancer. It has the broadest meaning including both therapeutic actions such as prevention of progression of cancer and amelioration of symptoms, and should not be construed as limited in any case.
  • Y in formula (I) above is preferably 211 At, an ⁇ -emitting nuclide.
  • the administration target of the radiopharmaceutical composition of the present invention is not particularly limited.
  • mammals, including humans are suitable administration subjects.
  • Humans are not particularly limited in terms of race, sex, and age.
  • Mammals other than humans include pet animals such as dogs and cats.
  • the route of administration of the radiopharmaceutical composition of the present invention includes, for example, parenteral administration such as intravenous administration or intraarterial administration, and oral administration, with intravenous administration being preferred.
  • the administration route is not limited to these routes, and any route can be used as long as the radiopharmaceutical composition can effectively express its action after administration.
  • the radioactivity intensity of the radiopharmaceutical composition is arbitrary as long as it is an intensity that can achieve the purpose by administering the radiopharmaceutical composition and the radiation exposure of the subject is the lowest possible clinical dose. .
  • the radioactivity intensity can be determined with reference to the radioactivity intensity used in general diagnostic methods and therapeutic methods using radiopharmaceutical compositions.
  • the dose is determined in consideration of various conditions such as the patient's age, body weight, radiographic imaging device to be used, and the state of the target disease. For humans, the amount of radioactivity in the radiopharmaceutical composition is as follows.
  • the dosage of the diagnostic agent is not particularly limited, but for example, 1.0 MBq / kg to 3.0 MBq / kg as the radioactivity of a radioactive element (eg 211 At) is.
  • the reagents and solvents used in each step are as follows.
  • (a) (i) DIC, tBuOH, CuCl(I);
  • ( ii ) CH2Cl2 (b) 2,2-Dimethoxypropane, (+)-10-Camphorsulfonic acid, DMF
  • (c) Tf 2 O, 2,6-Lutidine, CH 2 Cl 2 ( d) 2,6 - Lutidine, CH2Cl2 (e) NaI, MeCN (f) TFA, H2O
  • the reagents and solvents used in each step are as follows. (g) NaH, THF (h) NaI, MeCN (i) TFA, H2O
  • HPLC high performance liquid chromatography
  • ODS column Unison US-C18, manufactured by Intact Co., Ltd., 150 x 20 mm
  • MilliQ water as the mobile phase for phase A and MeCN for phase B
  • the flow rate was At 1 mL/min, 40% A phase, 60% B phase, 30% A phase, 70% B phase for 0-20 minutes after initiation, and 30% A phase 20-30 minutes after initiation
  • the product was purified by a linear gradient method varying from 70% B phase to 0% A phase to 100% B phase.
  • Compound (13) was obtained with a radiochemical yield of 84.6%.
  • the separated solution was concentrated to 50 ⁇ L with a rotary evaporator, TFA (450 ⁇ L) was added to the concentrated solution, and reacted at 37° C. for 1 hour. After the reaction, the TFA in the solution was removed under a stream of nitrogen, and saturated NaHCO3 aqueous solution was added to neutralize the remaining TFA.
  • HPLC high performance liquid chromatography
  • ODS column Unison US-C18, manufactured by Intact Co., Ltd., 150 x 20 mm
  • the mobile phase was MilliQ water for phase A and MeCN for phase B, and the flow rate was 1 mL/min.
  • HPLC high performance liquid chromatography
  • ODS column Unison US-C18, manufactured by Intact Co., Ltd., 150 x 20 mm
  • MilliQ water as the mobile phase for phase A and MeCN for phase B
  • the flow rate was As 1 mL / min, from 0 to 20 minutes after the start, change from 30% A phase, 70% B phase to 20% A phase, 80% B phase, and 20 to 30 minutes after the start 20% A phase , B phase 80% to A phase 0%, B phase 100%.
  • Compound (15) was obtained with a radiochemical yield of 89.6%.
  • the separated solution was concentrated to 50 ⁇ L with a rotary evaporator, TFA (450 ⁇ L) was added to the concentrated solution, and reacted at 37° C. for 1 hour. After the reaction, the TFA in the solution was removed under a stream of nitrogen, and saturated NaHCO3 aqueous solution was added to neutralize the remaining TFA.
  • HPLC high performance liquid chromatography
  • ODS column Unison US-C18, manufactured by Intact Co., Ltd., 150 x 20 mm
  • the mobile phase was MilliQ water for phase A and MeCN for phase B, and the flow rate was 1 mL/min.
  • FIG. 1 shows the results of HPLC analysis of compound (8) and compound (14).
  • FIG. 2 shows the results of HPLC analysis of compound (12) and compound (16). The absorbance of compound (8) was measured and analyzed at 220 nm, and the absorbance of compound (12) was measured and analyzed at 254 nm. Compounds (14) and (16) were analyzed by connecting a gamma ray detector (Gabistar, manufactured by Raytest) online.
  • a gamma ray detector Gibstar, manufactured by Raytest
  • Tumor-bearing mice were prepared by transplanting C6 cells (5 ⁇ 10 6 cells/mouse) into the left leg of 4-week-old BALB/c Slc-nu/nu strain male mice. It should be noted that experiments using mice in the present specification were performed with approval from the Animal Ethics Committee of Chiba University.
  • mice were sacrificed 1 hour and 2 hours after administration, and organs of interest and tumors were harvested. After measuring the mass, the radioactivity was measured with an Autowell gamma system (WIZARD3, manufactured by PerkinElmer). As a control compound, the following compounds were used
  • the results are shown in Table 1.
  • the unit in the table is the radioactivity accumulation rate (%) [% ID/g] with respect to 100% of the radioactivity injected dose per 1 g of organ or tissue, except for the stomach, intestine and neck.
  • the radioactivity accumulation rate (%) [% ID] is the radioactivity accumulation rate (%) [% ID] with respect to 100% of the injected dose per organ or tissue.
  • phase A contained 0.1% TFA/MilliQ water and phase B contained 0.1% TFA/MilliQ water.
  • the flow rate is 1 mL / min, and from 0 to 20 minutes after the start, the phase A is changed from 90%, the B phase 10% to the A phase 50%, the B phase 50%.
  • the product was purified by a linear gradient method varying from 50% phase A, 50% phase B to 0% phase A, 100% phase B during 20-30 minutes.
  • Compound (17) was obtained with a radiochemical yield of 48.3% and a radiochemical purity of >98%.
  • the reagents and solvents used in each step are as follows. (n) [ 211 At]/MeCN, DIPEA, MeCN (o) TFA, H2O
  • WIZARD3 Autowell gamma system
  • the results and the corresponding results for compound (16) obtained in Evaluation Example 1 are shown in FIG.
  • the unit in the figure is the radioactivity accumulation rate (%) [% ID/g] with respect to 100% of the radioactivity dose (injected dose) per 1 g of tissue for blood and tumor.
  • the radioactivity accumulation rate (%) [% ID] with respect to 100% of the radioactivity dose (injected dose) per organ.
  • FIG. 4 in tumor-bearing mice to which compound (17) was administered, high accumulation of radioactivity was observed in tumors. Therefore, compound (17) was found to be efficiently taken up by tumors.
  • compound (17) showed less accumulation of radioactivity in the stomach of tumor-bearing mice and was highly stable in vivo. found to have sex.
  • the radioactive compound of the present invention or a pharmaceutically acceptable salt thereof is efficiently taken up by tumors and the like, and has high stability in vivo.
  • a radiopharmaceutical composition is provided.

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Abstract

Un but de la présente invention est de fournir un nouveau composé radioactif, en particulier un composé radioactif ayant une biostabilité élevée.　La présente invention concerne un composé radioactif représenté par la formule (I) ou un sel pharmacologiquement acceptable de celui-ci. [Dans la formule, Ra, Rb, X, Y, et † sont tels que définis dans la description.]
PCT/JP2022/008860 2021-03-03 2022-03-02 Composé radioactif WO2022186273A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101333138A (zh) * 2008-07-23 2008-12-31 北京师范大学 一种能同时制备三种不同18f放射性药物的装置与工艺
WO2013042668A1 (fr) * 2011-09-22 2013-03-28 日本メジフィジックス株式会社 Composé marqué par du fluor radioactif
JP2016166151A (ja) * 2015-03-10 2016-09-15 国立大学法人群馬大学 ペプチド化合物及びペプチド化合物の製造方法
JP2017052713A (ja) * 2015-09-08 2017-03-16 日本メジフィジックス株式会社 放射性フッ素標識前駆体化合物及びそれを用いた放射性フッ素標識化合物の製造方法
CN107088228A (zh) * 2017-03-10 2017-08-25 南京大学 基于色氨酸及其衍生物的新型影像诊疗试剂的开发与应用
WO2019089603A1 (fr) * 2017-10-31 2019-05-09 Dana-Farber Cancer Institute, Inc. Procédés de détermination et de traitement de la résistance cellulaire à la toxine adp-ribosylante
WO2019151384A1 (fr) * 2018-01-31 2019-08-08 国立大学法人千葉大学 Produit pharmaceutique radioactif

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101333138A (zh) * 2008-07-23 2008-12-31 北京师范大学 一种能同时制备三种不同18f放射性药物的装置与工艺
WO2013042668A1 (fr) * 2011-09-22 2013-03-28 日本メジフィジックス株式会社 Composé marqué par du fluor radioactif
JP2016166151A (ja) * 2015-03-10 2016-09-15 国立大学法人群馬大学 ペプチド化合物及びペプチド化合物の製造方法
JP2017052713A (ja) * 2015-09-08 2017-03-16 日本メジフィジックス株式会社 放射性フッ素標識前駆体化合物及びそれを用いた放射性フッ素標識化合物の製造方法
CN107088228A (zh) * 2017-03-10 2017-08-25 南京大学 基于色氨酸及其衍生物的新型影像诊疗试剂的开发与应用
WO2019089603A1 (fr) * 2017-10-31 2019-05-09 Dana-Farber Cancer Institute, Inc. Procédés de détermination et de traitement de la résistance cellulaire à la toxine adp-ribosylante
WO2019151384A1 (fr) * 2018-01-31 2019-08-08 国立大学法人千葉大学 Produit pharmaceutique radioactif

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TATSUTA, MAHO; WASHIYA, NANA; SATO, YUI; SUZUKI, HIROYUKI; UEHARA, TOMOYA; ARANO, YASUSHI; TANAKA, HIROSHI: "2D3-49 Synthesis of radioactive neopentyl iodides as dual-responsive molecular probe for theranostics", PROCEEDINGS OF THE 98TH CSJ ANNUAL MEETING; MARCH 20 TO 23, 2018, CHEMICAL SOCIETY OF JAPAN, JP, vol. 98, 6 March 2018 (2018-03-06) - 23 March 2018 (2018-03-23), JP, pages 2D3 - 49, XP009539437 *

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