Compound or salt or solvate thereof, use thereof, and method for producing same

Abstract

The present disclosure relates to compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof: in formula (I), X1 and X2 each independently are a radioactive halogen nuclide, hydrogen, or deuterium, R1, R2, and R3 each independently are hydrogen or deuterium, at least one of X1, X2 , R1, R2, and R3 is deuterium, at least one of X1 and X2 is a radioactive halogen nuclide, and Y is a methyl group and an isopropyl group.

Description

Compounds or salts or solvates thereof, their uses and methods for producing them

[0001] The present invention relates to a compound or a salt or solvate thereof, their use, and a method for preparing them.

[0002] Metabotropic glutamate receptor 1 (mGluR1) is a G protein-coupled receptor normally expressed in the central nervous system and contributes to learning, memory formation, and neuronal development. Ectopic mGluR1 expression is carcinogenic, activating the mitogen-activated protein kinase (MAPK) or phosphatidylinositol-3-kinase (PI3K) / protein kinase B (AKT) pathways independently of B-Raf or N-Ras, leading to melanocyte carcinogenesis. Furthermore, mGluR1 is not expressed in normal skin melanocytes or peripheral organs, but its aberrant expression in melanocytes has been reported to result in melanoma formation with a nearly 100% success rate. Furthermore, mGluR1 is frequently expressed in many types of human cancer, including melanoma, breast cancer, pancreatic cancer, and colorectal cancer. Therefore, mGluR1 is considered a promising target for the development of cancer diagnostics and therapeutics.

[0003] The present inventors have previously developed small molecule PET tracers that target receptors in various tissues, and have developed a small molecule PET tracer for mGluR1 ( 18 They have succeeded in developing a new tracer called F-FITM (Non-Patent Document 1). Utilizing the knowledge of the pharmacokinetics of this tracer, they have succeeded in developing a new tracer called 2F-FITM (Non-Patent Document 1). １１ Labeled with At 211 The development of At-AITM has also been successful, providing insights into its potential use as a small molecule radiotherapeutic drug (Non-Patent Documents 2 and 3). However, no methods have been reported for modifying the backbone structure of compounds to further enhance their metabolic stability, particularly techniques applicable to radiotherapeutic drugs.

[0004] One method for improving the metabolic stability of compounds is the use of stable isotopes. Deuterium is the most commonly used isotope. Compounds containing deuterium have been actively studied in recent years, and many reports have been published on their ability to improve the metabolic stability of drugs. For example, Non-Patent Document 4 reports compounds containing deuterium as candidates for radiopharmaceuticals.

[0005] Xie L., Fujinaga M., Zhang MR., et al., Int J Cancer. 2014; 135:1582-1859Xie L., Hanyu, M., Fujinaga M., Zhang MR., et al., J. Nucl. Med. 2019;61:242-248Xie L., Hanyu, M., Fujinaga M., Zhang MR., et al. al., Cell Reports Medicine, 2023;4: 100960Klenner, MA, Pascali G., Fraser BH, Darwish TA., Nucl. Bio. Med., 2021: 96-97; 112-147

[0006] Non-Patent Document 4 reports findings regarding labeling reactions after deuteration of aliphatic and alicyclic hydrocarbons. However, it has been found that the introduction reaction of radioactive halogen nuclides into aliphatic and alicyclic hydrocarbons, especially when At is used, hardly progresses at all. This is because the nucleophilicity of At is much weaker than that of other radioactive halogen nuclides. Furthermore, the carbon-At bond energy in hydrocarbons is much smaller than that of carbon-radioactive halogen nuclides in other hydrocarbons, resulting in a decrease in the stability of the compound.

[0007] Furthermore, while the introduction of radioactive halogen nuclides into aromatic or heteroaromatic rings has been widely studied, there has been no research into improving the metabolic stability of the compound skeleton due to the difficulty of developing small molecule radiopharmaceuticals containing radioactive halogen nuclides.

[0008] To date, no radiohalogen compounds have been reported that contain deuterium on the aromatic or heteroaromatic ring.

[0009] One aspect of the present invention is to provide a radiohalogen compound or the like having a radiohalogen nuclide and deuterium on an aromatic ring or heteroaromatic ring, which has improved metabolic stability.

[0010] The present inventors have conducted extensive research to achieve the above object. As a result, they have found that a radioactive halogen compound having a radioactive halogen nuclide and deuterium on the aromatic or heteroaromatic ring can be obtained by reacting a compound having a deuterated aromatic or heteroaromatic ring with a radioactive halogen nuclide under specific conditions. Furthermore, they have found that the metabolic stability of the obtained compound is improved, which has led to the completion of the present invention.

[0011] A compound according to one aspect of the present invention is a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof: In formula (I), X １ and X ２ are each independently a radioactive halogen nuclide, hydrogen or deuterium, R １ , R ２ and R ３ are each independently hydrogen or deuterium, １ , X ２ 、 R １ , R ２ and R ３ At least one of X is deuterium; １ and X ２ At least one of the groups is a radioactive halogen nuclide, and Y is a methyl group and an isopropyl group.

[0012] Furthermore, a production method according to one aspect of the present invention is a method for producing a radiolabeled deuterated aromatic carbonyl compound, a pharmaceutically 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 an 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 a temperature of 50°C or higher and 220°C or lower.

[0013] According to one aspect of the present invention, it is possible to provide a radiohalogen compound having a radiohalogen nuclide and deuterium on an aromatic ring or heteroaromatic ring, which has improved metabolic stability.

[0014] 1 shows an HPLC chart of the reaction mixture obtained in the condition study of Example 2. 211 FIG. 1 shows an HPLC chart of At-AITM-D4 obtained in Example 3. 211 FIG. 1 shows a Radio TLC chart of At-AITM-D4. 211 FIG. 1 shows the results of evaluating the stability of At-AITM-D4 in serum. 211 FIG. 1 shows the results of measuring the amount of cellular uptake of At-AITM-D4. 211 FIG. 1 shows the results of measuring the cellular distribution of At-AITM-D4. 123 I-Py[D4] and 123 FIG. 1 shows a Radio TLC chart of purified I-Py. 211 At-Py[D4] and 211 FIG. 1 shows a Radio TLC chart of purified At-Py. 123 I-Py[D4] and 211 FIG. 1 shows the results of a stability test of At-Py[D4].

[0015] [Definition of Terms, etc.] In this specification, the phrase "an aromatic ring or heteroaromatic ring is deuterated" means that at least one hydrogen atom on the aromatic ring or heteroaromatic ring has been substituted with deuterium.

[0016] As used herein, the term "heteroaromatic ring" refers to an aromatic ring containing at least one heteroatom such as a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of heteroaromatic rings include π-electron rich and π-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.

[0017] As used herein, a "radioactive halogen nuclide" refers to a radioactive isotope of a halogen element, such as fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or astatine (At).

[0018] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is not harmful to living animals, particularly mammals. Pharmaceutically acceptable salts can be formed using non-toxic acids or bases, including inorganic acids or inorganic bases, or organic acids or organic bases. Pharmaceutically acceptable salts include acid addition salts and base addition salts.

[0019] Examples of 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-β-phenethylamine, 1-ephenamine, and N,N′-dibenzylethylenediamine, meglumine (N-methylglucamine), and the like.

[0020] Examples of basic salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

[0021] As used herein, the term "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.

[0022] In the present specification, when isomers exist, the term "compound or a pharmaceutically acceptable salt thereof" encompasses all of the isomers, and also encompasses hydrates, solvates, and all crystalline forms. Examples of isomers include optical isomers, geometric isomers, and tautomers.

[0023] In this specification, "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." Furthermore, in this specification, the symbol "to" means a range that includes both the numerical values ​​at both ends.

[0024] [Compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof] One aspect of the present invention is a compound of the following formula (I) or a pharmaceutically acceptable salt or solvate thereof (hereinafter, these may be collectively referred to as "the present compound (I)"). In formula (I), X １ and X ２ are each independently a radioactive halogen nuclide, hydrogen or deuterium, R １ , R ２ and R ３ are each independently hydrogen or deuterium, １ , X ２ 、 R １ , R ２ and R ３ At least one of X is deuterium; １ and X ２ At least one of the groups is a radioactive halogen nuclide, and Y is a methyl group and an isopropyl group.

[0025] The present 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 it to stand for a certain period of time (e.g., 24 hours at 37°C), and then calculating the proportion of the unchanged form of the target compound in the biological sample (the amount of the unchanged form of the target compound in the biological sample / the total amount of the target compound in the biological sample). When the proportion of the unchanged form of the target compound is 80% or more, the metabolic stability of the target compound is high, and the proportion is preferably 90% or more.

[0026] Examples of the radioactive halogen nuclide of the present compound (I) 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 When the compound (I) is used as a radioactive diagnostic agent, the radioactive halogen nuclide is １２３ I, １８ F. ７６ Br, １２４ When the compound (I) is used as a radiotherapeutic agent, the radioactive halogen nuclide is preferably I. ２１１ At, ７７ Br, １３１ I is preferred.

[0027] In order to further improve the structural stability and metabolic stability of the present compound (I), it is preferable that two hydrogen atoms adjacent to the radioactive halogen nuclide on the aromatic ring are substituted with deuterium atoms. １ When is a radioactive halogen nuclide, X ２ and R ３ are preferably deuterium. ２ When is a radioactive halogen nuclide, X １ and R １ Preferably, each of is deuterium.

[0028] The present compound (I) has improved structural stability and metabolic stability, and therefore, the present compound (I) is preferably X １ and X ２ One of the ２１１ At, the other is deuterium, and R １ , R ２ and R ３ More preferably, each of the is a deuterium atom. A more preferred example of the present compound (I) is a compound of the following formula (IA). In formula (IA), D is deuterium.

[0029] The present compound (I) can be produced by the below-mentioned method for producing a radiolabeled deuterated aromatic carbonyl compound, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0030] [Radiotherapeutic or radiodiagnostic agent] A radiotherapeutic or radiodiagnostic agent containing the present compound (I) as an active ingredient is also included in one aspect of the present invention.

[0031] The radiotherapeutic or radiodiagnostic agent may be contained in a pharmaceutically acceptable carrier, such as, but not limited to, 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.

[0032] The radiotherapeutic or radiodiagnostic agent can be preferably used for the treatment or diagnosis of diseases involving cells expressing metabotropic glutamate receptor 1 (mGluR1), particularly cells expressing mGluR1 at high levels, and can also be preferably used for the treatment or diagnosis of cancer (tumor), particularly cancer (tumor) expressing mGluR1.

[0033] Examples of diseases involving cells expressing mGluR1 (particularly cells with high expression) include cancer (tumors), fatty liver, etc. Examples of cancers (tumors) with high expression of mGluR1 include melanoma, breast cancer, pancreatic cancer, colorectal 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.

[0034] The radiotherapeutic or radiodiagnostic agent may be administered, for example, parenterally, intravenously, or intraperitoneally, without particular limitation. Compound (I) may be a single substance or may be carried in a DDS (drug delivery system). The radiotherapeutic or radiodiagnostic agent may consist solely of Compound (I).

[0035] The dosage of the present 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, the route of administration, etc.

[0036] Another aspect of the present invention is a method for diagnosing or treating a disease involving cells expressing mGluR1 using the above radiotherapeutic or radiodiagnostic agent. Another aspect of the present invention is a method for diagnosing or treating cancer using the above radiotherapeutic or radiodiagnostic agent. The diagnostic or therapeutic method comprises administering the above radiotherapeutic or radiodiagnostic agent to a subject.

[0037] The route of administration is not particularly limited, and may be selected from common drug administration routes such as parenteral administration, intravenous administration, or intraperitoneal administration.

[0038] A method for diagnosing cancer will be described. The method for diagnosing cancer using the radioactive diagnostic agent further includes detecting a compound accumulated in cancer. The method for detecting the compound is not particularly limited, but it is preferable to detect it using a radiation detector that detects radiation emitted from the radioactive halogen nuclide in the present compound (I). For example, positron emission tomography (PET) is an example of such a radiation detector. Furthermore, nuclear magnetic resonance imaging (MRI) or hyperpolarized nuclear magnetic resonance spectroscopy can also detect a compound accumulated in a tumor.

[0039] When the radioactive diagnostic agent is used in a method for diagnosing cancer, the dose to be administered to a subject may be appropriately determined depending on the detection method for detecting compounds accumulated in cancer, etc.

[0040] The results of detecting compounds accumulated in cancer are preferably output as an image. In other words, one aspect of the present invention includes a cancer imaging method (imaging method) using the above radioactive diagnostic agent. Another aspect of the present invention includes a cancer imaging agent (imaging agent) using the above radioactive diagnostic agent.

[0041] A method for treating cancer using the radioactive therapeutic agent will now be described. The radioactive therapeutic agent is administered to a subject in an amount that provides a radioactive concentration sufficient to achieve a therapeutic effect on cancer. In general, to achieve a sufficient therapeutic effect on cancer, it is preferable to set the dose of the radioactive therapeutic agent so that the radioactive concentration is higher than that of the radioactive diagnostic agent.

[0042] [Method for Producing a Radiolabeled Deuterated Aromatic Carbonyl Compound, a Pharmaceutically Acceptable Salt Thereof, or a Solvate Thereof] A method for producing a radiolabeled deuterated aromatic carbonyl compound, a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter, these may be collectively referred to as "methods for producing a radiolabeled deuterated aromatic carbonyl compound") is also included in one aspect of the present invention.

[0043] The method for producing a radiolabeled deuterated aromatic carbonyl compound includes a labeling step of labeling the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound with a radioactive halogen nuclide by subjecting an aromatic carbonyl compound in which at least one hydrogen atom on an aromatic ring or heteroaromatic ring has been substituted with deuterium to an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at a temperature of 50° C. to 220° C. Hereinafter, the "aromatic carbonyl compound in which at least one hydrogen atom on an aromatic ring or heteroaromatic ring has been substituted with deuterium" may be referred to as a "labeled precursor."

[0044] In the labeled precursor, at least one hydrogen atom on the aromatic ring or heteroaromatic ring is substituted with deuterium. The aromatic ring or heteroaromatic ring of the labeled precursor is labeled with the radioactive halogen nuclide by an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at a temperature of 50° C. to 220° C. This labeling allows the production of a radioactive halogen compound having the radioactive halogen nuclide and deuterium on the aromatic ring or heteroaromatic ring.

[0045] Deuteration of the aromatic ring or heteroaromatic ring in the label precursor can be carried out by methods well known to those skilled in the art.

[0046] In order to facilitate the introduction of a radioactive halogen nuclide onto the aromatic ring or heteroaromatic ring of the label precursor, the aromatic ring or heteroaromatic ring of the label precursor preferably has a radioactive halogen nuclide-introducing group.

[0047] Examples of radioactive halogen nuclide-introducing groups include boronic acid, boronic acid ester, trialkylstannyl group, trialkylsilyl group, trialkylgermyl group, chloro, bromo, iodo, nitro group, trimethylammonium trifluoromethanesulfonate, sulfonic acid group, iodonium salt, and iodonium ylide group. In terms of the relative ease with which radioactive halogen can be introduced, trialkylstannyl groups and boronic acid esters are preferred. Furthermore, in terms of their high reactivity with electrophiles and the ability to undergo Sn-halogen substitution reactions at low reaction temperatures, trialkylstannyl groups are more preferred. Examples of trialkylstannyl groups include tri(C1-C4 alkyl)stannyl groups, with tributylstannyl groups being more preferred. Examples of trialkylsilyl groups include tri(C1-C4 alkyl)silyl groups, with trimethylsilyl groups being more preferred. Examples of C1-C4 alkyl groups include methyl, ethyl, propyl, and butyl groups.

[0048] For example, an aromatic carbonyl compound having a radioactive halogen nuclide-introducing group on the aromatic ring or heteroaromatic ring can be obtained by a substitution reaction between an aromatic carbonyl compound in which hydrogen on the aromatic ring or heteroaromatic ring has been substituted with a halogen element and a radioactive halogen nuclide-introducing group.

[0049] In order to further improve the structural stability of a radioactive halogen compound having a radioactive halogen nuclide and deuterium on an aromatic ring or heteroaromatic ring, when the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound has a radioactive halogen nuclide-introducing group, it is preferable that two hydrogen atoms adjacent to the radioactive halogen nuclide-introducing group on the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound are substituted with deuterium, and it is more preferable that each of the hydrogen atoms on the aromatic ring or heteroaromatic ring is substituted with deuterium.

[0050] An example of the label precursor is a compound of the following formula (II): In formula (II), X １１ and X １２ are each independently a radioactive halogen nuclide introducing group, hydrogen or deuterium, R１１ , R １２ , and R １３ are each independently hydrogen or deuterium, １１ , X １２ 、 R １１ , R １２ and R １３ At least one of X is deuterium; １１ and X １２ at least one of the above is a radioactive halogen nuclide introducing group, Y is a methyl group or an isopropyl group, and the radioactive halogen nuclide introducing group is a boronic acid, a boronic acid ester, a trialkylstannyl group, a trialkylsilyl group, a trialkylgermyl group, a chloro, a bromo, an iodo, a nitro group, a trimethylammonium trifluoromethanesulfonate, a sulfonic acid group, an iodonium salt, or an iodonium ylide group.

[0051] In terms of the structural stability of the aromatic ring labeled with a radioactive halogen nuclide, X １１ and X １２ one of which is the radioactive halogen nuclide introducing group and the other is deuterium, and R １１ , R １２ and R １３ Preferably, each of is deuterium.

[0052] The present compound (I) can be produced by labeling the aromatic ring on the compound of formula (II) above with a radioactive halogen nuclide.

[0053] Examples of solvents used in the labeling step include methanol (MeOH), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), etc. The solvents may be used alone or in combination of two or more.

[0054] The labeling step utilizes an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction, and the aromatic electrophilic substitution reaction is preferably carried out in the presence of an acid and an oxidizing agent.

[0055] Examples of the acid include carboxylic acids and sulfonic acids. Examples of carboxylic acids include formic acid, acetic acid, trifluoroacetic acid, citric acid, gluconic acid, lactic acid, oxalic acid, and tartaric acid. Examples of sulfonic acids include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. From the viewpoints of activating the oxidizing agent and improving the solubility of the substrate, acetic acid, formic acid, and the like are preferred. One acid may be used alone, or two or more acids may be used in combination. An acid may be added to the solvent in an amount of 0.01% to 10% of the reaction solvent, preferably 0.1% to 7.0%, and more preferably 0.5% to 2.0%. Note that % is by mass.

[0056] Examples of the oxidizing agent include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, OXONE (registered trademark), chloramine-T, metachloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, di-tert-butyl hydroperoxide, bis(trimethylsilyl)peroxide, N-chlorosaccharin, N-bromosaccharin, and N-iodosaccharin. In terms of high activity achieved by the formation of halogen cation species through oxidation of halide ions and solubility in solvents, the oxidizing agent is preferably an N-halogen succinimide, and more preferably N-chlorosuccinimide. One type of oxidizing agent may be used alone, or two or more types may be used in combination. ２１１ The labeling step may be carried out by adding an oxidizing agent to the solvent at a concentration of 0.05 mg / mL to 10 mg / mL relative to the radioactivity of At, preferably the oxidizing agent concentration is 0.5 mg / mL to 7.5 mg / mL, more preferably the oxidizing agent concentration is 1.0 mg / mL to 2.0 mg / mL.

[0057] The reaction temperature in the labeling step is 50°C or higher and 220°C or lower. The reaction temperature may be selected depending on the type of solvent used in the labeling step. In terms of improving the reaction efficiency of the aromatic electrophilic substitution reaction or aromatic nucleophilic substitution reaction, the reaction temperature is preferably 60°C or higher, more preferably 70°C or higher. The reaction temperature is also preferably 200°C or lower, more preferably 150°C or lower, and even more preferably 80°C or lower.

[0058] The reaction time in the labeling step can be appropriately selected depending on the type or amount of the aromatic carbonyl compound, the radioactive halogen nuclide, the solvent or reagent used in the labeling step, etc. For example, the reaction time may be 5 minutes or more and 120 minutes or less, preferably 10 minutes or more and 60 minutes or less, and more preferably 15 minutes or more and 20 minutes or less.

[0059] Methods for determining the radiochemical purity of a radiolabeled deuterated aromatic carbonyl compound include analysis by HPLC or Radio-TLC.

[0060] [Method for Producing a Radioactive Therapeutic or Radioactive Diagnostic Agent] One aspect of the present invention also includes a method for producing a radioactive therapeutic or radioactive diagnostic agent, the method comprising the step of producing a radioactively labeled deuterated aromatic carbonyl compound, a pharmaceutically acceptable salt thereof, or a solvate thereof by the above-described method for producing a radioactively labeled deuterated aromatic carbonyl compound.

[0061] [Summary] The compound according to aspect 1 of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof: In formula (I), X １ and X ２ are each independently a radioactive halogen nuclide, hydrogen or deuterium, R １ , R ２ and R ３ are each independently hydrogen or deuterium, １ , X ２ 、 R １ , R ２ and R ３At least one of X is deuterium; １ and X ２ At least one of the groups is a radioactive halogen nuclide, and Y is a methyl group and an isopropyl group.

[0062] The compound according to aspect 2 of the present invention is the compound according to aspect 1 of the present invention, wherein the radioactive halogen nuclide is ２１１ It may also be At.

[0063] The compound according to aspect 3 of the present invention is the compound according to aspect 1 or 2 of the present invention, wherein X １ and X ２ One of the ２１１ At and the other is deuterium, and R １ , R ２ and R ３ may each be deuterium.

[0064] A radiotherapeutic or radiodiagnostic agent according to Aspect 4 of the present invention comprises, as an active ingredient, a compound according to any one of Aspects 1 to 3 of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0065] A method for producing a radiolabeled deuterated aromatic carbonyl compound, a pharmaceutically acceptable salt thereof, or a solvate thereof according to Aspect 5 of the present invention comprises a labeling step of labeling the aromatic ring or heteroaromatic ring of the aromatic carbonyl compound with a radioactive halogen nuclide by subjecting an 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 a temperature of 50°C or higher and 220°C or lower.

[0066] A sixth aspect of the present invention relates to a production method according to the fifth aspect of the present invention, wherein the labeling step may be carried out in the presence of an acid and an oxidizing agent.

[0067] A production method according to Aspect 7 of the present invention is the production method according to Aspect 5 or 6 of the present invention, wherein the aromatic carbonyl compound has a radioactive halogen nuclide-introducing group on the aromatic ring or heteroaromatic ring, and the radioactive halogen nuclide-introducing group may be selected from boronic acid, boronic acid ester, trialkylstannyl group, trialkylsilyl group, trialkylgermyl group, chloro, bromo, iodo, nitro group, trimethylammonium trifluoromethanesulfonate, sulfonic acid group, iodonium salt, or iodonium ylide group.

[0068] In the production method according to Aspect 8 of the present invention, in any one of Aspects 5 to 7 of the present invention, the aromatic carbonyl compound may be a compound of the following formula (II): In formula (II), X １１ and X １２ are each independently a radioactive halogen nuclide introducing group, hydrogen or deuterium, R １１ , R １２ , and R １３ are each independently hydrogen or deuterium, １１ , X １２ 、 R １１ , R １２ and R １３ At least one of X is deuterium; １１ and X １２ at least one of the above is a radioactive halogen nuclide introducing group, Y is a methyl group or an isopropyl group, and the radioactive halogen nuclide introducing group is a boronic acid, a boronic acid ester, a trialkylstannyl group, a trialkylsilyl group, a trialkylgermyl group, a chloro, a bromo, an iodo, a nitro group, a trimethylammonium trifluoromethanesulfonate, a sulfonic acid group, an iodonium salt, or an iodonium ylide group.

[0069] The manufacturing method according to aspect 9 of the present invention is the same as that according to aspect 8 of the present invention, except that X １１ and X １２ one of which is the radioactive halogen nuclide introducing group and the other is deuterium, and R １１ , R １２ and R １３ may each be deuterium.

[0070] A method for producing a radiotherapeutic or radiodiagnostic agent according to Aspect 10 of the present invention comprises the step of producing a radiolabeled deuterated aromatic carbonyl compound, a pharmaceutically acceptable salt thereof, or a solvate thereof by the production method of any of Aspects 5 to 9 of the present invention.

[0071] The following examples are provided to further explain the embodiments of the present invention. It goes without saying that the present invention is not limited to the following examples, and various modifications are possible in detail. Furthermore, the present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed herein are also included in the technical scope of the present invention. Furthermore, all of the documents cited in this specification are incorporated by reference.

[0072] Example 1 211 Preparation of labeled precursors incorporating At 211 A labeled precursor (compound 5) incorporating At was prepared according to the following procedure.

[0073] (Synthesis of Compound 3)

[0074] Compound 1 (500 mg, 2.44 mmol) was dissolved in dichloromethane (7 mL), and DMF (3 drops) was added dropwise. The mixture was stirred at 0°C for 5 minutes. Oxalyl chloride (315 mL, 3.66 mmol) was added dropwise at room temperature (1°C to 30°C), followed by stirring for 4 hours. The solvent was then evaporated. To the residue, toluene (15 mL), triethylamine (1.02 mL, 7.32 mmol), and compound 2 (synthesized using the method described in Fujinaga M., Zhang MR., et al., J. Med. Chem., 2012, pp. 2342-2352) were added sequentially, and the mixture was stirred at 100°C for 5 hours. Water (50 mL) was added to the reaction mixture, and the reaction product was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated brine (50 mL x 3) and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using silica gel column chromatography (hexane:ethyl acetate=5:1 + triethylamine (0.1%)) to give white crystals (260 mg, 26%).

[0075] NMR analysis of compound 3 gave the following results: 1H NMR (CDCl3): d 3.76 (3H, s), 8.06 (1H, s), 8.13 (1H, s), 8.95 (1H, s)

[0076] (Synthesis of Compound 4)

[0077] To compound 3 (260 mg, 0.63 mmol), potassium carbonate (131 mg, 0.95 mmol) and 1,4-dioxane (10 mL) were added, followed by isopropylamine (1 mL). The reaction solution was heated to 80°C, and isopropylamine (1 mL) was added every 3 hours. The mixture was stirred for 10 hours. Water (50 mL) was added to the reaction mixture, and the reaction product was extracted with dichloromethane (30 mL x 3). The organic layer was washed with saturated brine (30 mL x 3) and then dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using silica gel column chromatography (hexane:ethyl acetate = 1:2 + triethylamine (0.1%)) to obtain cream-colored crystals (225 mg, 82%).

[0078] NMR analysis of compound 4 gave the following results: 1H NMR (CDCl3): d 1.29 (6H, d, J = 6.6 Hz), 3.74 (3H, s), 4.12 (1H, br), 4.87 (1H, br), 7.05 (1H, s), 7.92 (1H, s), 8.57 (1H, s).

[0079] (Synthesis of Compound 5)

[0080] Compound 4 (218 mg, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) were added to the reaction vessel, which was then purged with nitrogen. Bis(tributyltin) (348 mg, 0.6 mmol) and 1,4-dioxane (7 mL) were added, and the mixture was heated and stirred at 100°C for 8 hours. Water (30 mL) was added to the reaction mixture, which was then extracted with dichloromethane (30 mL x 3). The organic layer was washed with saturated brine (30 mL x 3) and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using silica gel column chromatography (hexane:ethyl acetate = 1:2 + triethylamine (0.1%)) to obtain an oil (46 mg, 14%).

[0081] NMR analysis of compound 5 gave the following results: 1H NMR (CDCl3): d 0.90 (9H, t, J = 7.4 Hz), 1.10 (6H, t, J = 7.7 Hz), 1.29 (6H, t, J = 6.2 Hz), 1.28-1.42 (6H, m), 1.50-1.61 (6H, m), 3.77 (3H, s), 4.13 (1H, br), 4.92 (1H, br), 7.07 (1H, s), 7.95 (1H, s), 8.58 (1H, s).

[0082] Example 2 211 Preparation of At-AITM-D4 Examination of reaction temperature for compound 5 211 Compounds with At introduced ( 211 The conditions for preparing At-AITM-D4 were investigated. 211 At was extracted with 460 μL of a 2 mg / mL N-chlorosuccinimide / methanol solution. Compound 5 was extracted with 100 μL of a 3% acetic acid / methanol solution containing 1 mg / mL of compound 5. 211 Two reaction mixtures were prepared by adding 200 μL of At solution. Each was left to stand at room temperature (1°C to 30°C) and 70°C for 20 minutes, and then the reaction was terminated by adding 50 μL of 2 mg / mL aqueous sodium sulfite solution. Labeling efficiency was measured by RadioHPLC.

[0083] The HPLC conditions were set as follows: Flow rate: 1 mL / min Mobile phase A: 0.1% TEA acetonitrile / water mixed solution (acetonitrile:water = 50:50) Mobile phase B: 0.1% TEA acetonitrile solution (acetonitrile 100%) Elution conditions: Mobile phase A 100% (start 0 min) → Mobile phase B 100% (start 20 min) Column temperature: Room temperature Column: CAPCELL PAK UG80, 5 mm, 4.6 mm ID 250 mm

[0084] The HPLC chart is shown in Figure 1. The labeling efficiencies at room temperature (1°C to 30°C) and 70°C were calculated from the HPLC area ratio and were 39% and 88%, respectively. 211 The reaction temperature of At-AITM-D4 was preferably 70°C.

[0085] Example 3 211 Labeled synthesis of At-AITM-D4 in a glass vial 211 To At, 200 μL of a 2 mg / mL N-chlorosuccinimide / methanol solution and 100 μL of a 3% acetic acid / methanol solution containing compound 5 at a concentration of 1 mg / mL were added. The reaction mixture was left standing at 70°C for 20 minutes, and then 50 μL of a 2 mg / mL aqueous sodium sulfite solution was added to terminate the reaction. Then, 1 mL of distilled water was added. Purification was performed by Radio HPLC, and a fraction with a retention time of approximately 16 minutes was collected. The collected solution was concentrated and then redissolved in 200-300 μL of saline: 2 mg / mL aqueous sodium ascorbate: Tween 80 (85:14:1). 211 The At-AITM-D4 injection was obtained. The total process time was 1.5 hours, the radiochemical yield was 42.2±2.7% (at the end of synthesis, n=5), and the radiochemical purity was 99% or more. 211 The RadioHPLC and RadioTLC charts of At-AITM-D4 are shown in Figure 2 and Figure 3, respectively. The HPLC conditions were set to the same conditions as in Example 2.

[0086] Example 4 211 Stability test of At-AITM-D4 prepared in Example 3 211 The stability in serum was measured using At-AITM-D4. 211 2 MBq of At-AITM-D4 was mixed with 30 μL of mouse serum and allowed to stand at 37°C for 24 hours. 1 μL of serum was loaded onto a TLC column and developed using ethyl acetate as a solvent. After drying, detection was performed using a RadioTLC scanner. The results are shown in Figure 4. 211 The proportion of unchanged At-AITM-D4 was 90.6±1.3% (n=5). 211 The proportion of unchanged At-AITM was 78.5±1.0% (n=3). 211Statistical analysis of the comparison with At-AITM showed a p<0.0001 result, with serum stability improved by 11%. This indicates that the proportion of unchanged form was significantly increased due to the effect of deuterium-modifying the aromatic ring.

[0087] Example 5 211 Cellular uptake and distribution of At-AITM-D4. Transplantable B16F10 melanoma cells in C57BL / 6J mice were obtained from the American Type Culture Collection. B16F10 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 × 10 4 The cells (number of cells) were seeded on a 24-well plate and subjected to adhesion culture for 24 hours. 211 At-AITM-D4 (18.5 kBq / mL) and the binding inhibitor FITM (4-fluoro-N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide) were added to the cells at a concentration of 10 mmol / L and incubated at 37°C for 1 hour. After removing the supernatant, the cells were washed with phosphate-buffered saline (PBS) and then lysed with 0.2 mol / L NaOH. Radioactivity was measured using a γ-counter (PerkinElmer), and the protein content of the cell lysate was quantified using a protein assay kit (Bio-RAD). The amount of radioactivity taken up into the cells was calculated per mg of protein (%ICD / mg protein). The results of the measurement of the amount of radioactivity taken up into the cells are shown in Figure 5. The amount of cellular uptake was 211 In the case of At-AITM, the %ICD was 20.64±2.97 (%ICD / mg protein) after 1 hour. 211 The %ICD / mg protein of At-AITM-D4 was 57.61±8.38 (%ICD / mg protein), which indicates a 2.5-fold increase in cellular uptake. The results of measuring cellular distribution are shown in Figure 6. The cellular distribution and internalization rate were also significantly higher. 211It was also confirmed that At-AITM-D4 had a greater increase.

[0088] Example 6 123 Preparation of I-Py[D4]Na 123 I was purchased from PDR Pharma. 1 mg of 3-pyridine-d4-boronic acid was mixed with 40 μL of acetonitrile, 15 μL of a methanol solution containing 1 mg of Cu(OTf)2(Py)4 and 355 μg of 3,4,7,8-tetramethyl-1,10-phenanthroline, and the Na prepared above. 123 50 μL of methanol solution was added and the mixture was left to stand at 70°C for 20 minutes. The reaction mixture was added to 10 mL of water and collected on a Sep-PAK C18 light column. The column was washed with 10 mL of water and the target product was recovered with 300 μL of ethanol. After the EtOH was evaporated to dryness, the target product was redissolved in saline to obtain the target product ( 123 I-Py[D4]) was obtained. 123 I-Py[D4] is a pyridine in which four hydrogen atoms on the pyridine ring are replaced with deuterium atoms. 123 The compound was labeled with I. 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.

[0089] Example 7 123 Preparation of I-Py in the same manner as in Example 6 123 I-Py was synthesized 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 123 I-labeled pyridine.

[0090] Example 8 211 Preparation of At-Py[D4] in a glass vial 211 50 μL of 0.1 mol / L Na2CO3 was added to At, and after standing for 1 minute, 300 μL of methanol was added. 1 mg of 3-pyridine-d4-boronic acid was added to 40 μL of acetonitrile, 15 μL of a methanol solution containing 1 mg of Cu(OTf)2(Py)4 and 355 μg of 3,4,7,8-tetramethyl-1,10-phenanthroline, and the above-prepared solution. 211150 μL of At solution was added and the mixture was left to stand at 70°C for 20 minutes. The reaction mixture was added to 10 mL of water and collected on a Sep-PAK C18 light column. The column was washed with 10 mL of water and then the target compound ( 211 At-Py[D4]) was collected. 211 At-Py[D4] is a pyridine in which four hydrogen atoms on the pyridine ring are replaced with deuterium atoms. 211 This compound was labeled with At. After the EtOH was evaporated to dryness, the target compound was redissolved in saline to obtain the desired 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.

[0091] Example 9 211 Preparation of At-Py in the same manner as in Example 8 211 At-Py was synthesized 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 211 It is pyridine labeled with At.

[0092] Example 10 123 I-Py[D4] and 211 Stability test of At-Py[D4] The stability in serum was measured using deuterated pyridines and pyridines containing radioactive halogens prepared in Examples 6 to 9. 2 MBq of the radioactive compound was mixed with 10 μL of mouse serum and allowed to stand at 37°C for 24 hours. 1 μL of the serum mixture was loaded onto a TLC column and developed using ethyl acetate as the solvent. After drying, detection was performed using a RadioTLC scanner. The results are shown in Figure 9. The proportion of unchanged substance in the serum after 24 hours was 123 I-Py[D4] was 96.9±0.1% (n=3), 211 At-Py[D4] was 95.1±0.6% (n=3), whereas 123 I-Py was 93.4±0.9% (n=3); 211The percentage of At-Py was 92.2±0.6% (n=3). The statistical analysis for the iodoform was ns (Figure 9, left), and the statistical analysis for the astatineform was p=0.0008 (Figure 9, right). The effect of deuterium addition to the pyridine ring increased the proportion of the unchanged form, demonstrating its effectiveness against astatine compounds.

[0093] [Summary of Examples] A radioactive halogen compound having a radioactive halogen nuclide and deuterium on an aromatic ring. 211 At-AITM-D4 has high metabolic stability and has been found to be useful as a radioactive diagnostic or therapeutic agent.

[0094] The present invention is applicable to the medical field, and in particular to the diagnosis or treatment of diseases involving cells expressing mGluR1.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof: In formula (I), X １ and X ２ are each independently a radioactive halogen nuclide, hydrogen or deuterium, R １ , R ２ and R ３ are each independently hydrogen or deuterium, X １ , X ２ 、 R １ , R ２ and R ３ at least one of which is deuterium, X １ and X ２ at least one of which is a radioactive halogen nuclide, and Y is a methyl group and an isopropyl group.

2. The radioactive halogen nuclide is ２１１ At, the compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. X １ and X ２ one of which ２１１ is At and the other is deuterium, and R １ , R ２ and R ３ are each deuterium, the compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. A radiotherapeutic agent or a radiodiagnostic agent comprising, as an active ingredient, the compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or a solvate thereof.

5. A method for producing a radioactively labeled deuterated aromatic carbonyl compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising a labeling step of subjecting an aromatic carbonyl compound in which at least one hydrogen on an aromatic ring or a heteroaromatic ring is substituted with deuterium and a radiohalogen nuclide to an aromatic electrophilic substitution reaction or an aromatic nucleophilic substitution reaction at 50°C or higher and 220°C or lower to label the aromatic ring or the heteroaromatic ring of the aromatic carbonyl compound with the radiohalogen nuclide.

6. The production method according to claim 5, wherein the labeling step is carried out in the presence of an acid and an oxidizing agent.

7. The aromatic carbonyl compound has a radiohalogen nuclide-introducing group on an aromatic ring or a heteroaromatic ring, and the radiohalogen nuclide-introducing group is selected from a boronic acid, a boronic acid ester, a trialkylstannyl group, a trialkylsilyl group, a trialkylgermyl group, chloro, bromo, iodo, a nitro group, a trimethylammonium trifluoromethanesulfonate, a sulfonic acid group, an iodonium salt, or an iodonium ylide group. The production method according to claim 5 or 6.

8. The production method according to any one of claims 5 to 7, wherein the aromatic carbonyl compound is a compound of the following formula (II): In formula (II), X １１ and X １２ are each independently a radioactive halogen nuclide-introducing group, hydrogen or deuterium, and R １１ , R １２ , and R １３ are each independently hydrogen or deuterium, and at least one of X １１ , X １２ 、 R １１ , R １２ and R １３ is deuterium, and at least one of X １１ and X １２ is a radioactive halogen nuclide-introducing group, Y is a methyl group and an isopropyl group, and the radioactive halogen nuclide-introducing group is a boronic acid, a boronic acid ester, a trialkylstannyl group, a trialkylsilyl group, a trialkylgermyl group, chloro, bromo, iodo, a nitro group, trimethylammonium trifluoromethanesulfonate, a sulfonic acid group, an iodonium salt, an iodonium ylide group.

9. X １１ and Xs １２ One of them is the radioactive halogen nuclide-introducing group, and the other is deuterium, and R １１ , R １２ and R １３ are each deuterium. The production method according to claim 8 10. A method for producing a radiotherapeutic agent or a radiodiagnostic agent, comprising a step of producing a radioactively labeled deuterated aromatic carbonyl compound, a pharmaceutically acceptable salt thereof, or a solvate thereof by the production method according to any one of claims 5 to 9.

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