JP7373151B2 - New compounds and their uses - Google Patents

Description

The present invention relates to a novel compound and its use.

In recent years, research has been conducted on various techniques for obtaining information inside living organisms, and in particular, "molecular imaging", which is a technology that can investigate the behavior of target molecules, has been attracting attention. Molecular imaging is considered to be useful for early detection of various diseases and for developing effective medicines with few side effects in a short period of time.

Positron emission tomography (PET) is well known as molecular imaging for obtaining information inside a living body. PET is a technology that takes tomographic images using gamma rays emitted when positrons collide with electrons. Specifically, when a molecule labeled with a radionuclide that emits positrons (so-called PET molecular probe) is administered into a living body, and the positrons released during the decay of the radionuclide collide with nearby electrons, the emission of 511 KeV Two gamma rays with energy of 180 degrees are emitted in the direction of 180 degrees. By detecting this γ-ray, the location of the PET molecular probe in the living body and the amount of the substance can be quantitatively determined. Currently, the PET method is widely used as a molecular imaging technique for diagnosing diseases and promoting drug discovery research.

In the field of pain treatment, palliative care is the mainstream, and no radical treatment exists. Although there are subjective indicators for evaluating the pain relief effect, there are no more accurate objective indicators or surrogate markers, and the evaluation of the pain relief effect is limited to qualitative methods such as interview, visual inspection, and palpation. There is. Image diagnosis is one means for objectively evaluating the pain relief effect, and in recent years, attempts have been made to use image diagnosis, particularly PET, to evaluate the pain relief effect. This is because PET has good resolution, a variety of drugs can be used for PET, and functional diagnosis is possible using PET. If PET can be used to evaluate pain relief effects, it will be possible to significantly improve medical technology related to the diagnosis and/or treatment of pain for which there is no radical treatment.

The TRPV1 (Transient Receptor Potential Vanilloid 1) receptor is known as a nociceptor, and one of its functions is as a pain receptor. Therefore, TRPV1 receptor antagonists are expected to lead to the development of analgesics, and pharmaceutical companies are proceeding with the development of candidate compounds for TRPV1 receptor antagonists. Moreover, the application of a radioisotope-labeled TRPV1 receptor antagonist as a PET probe has also been proposed. As a PET probe using a TRPV1 receptor antagonist that has been reported so far, for example, Non-Patent Document 1 describes a ¹¹ C-labeled PET probe of SB-366791 ([ ¹¹ C]SB-366791 ) are disclosed.

Daisy van Veghel et al., Nuclear Medicine and Biology, 40, 141-147, 2013

When imaging the TRPV1 receptor in the brain using the above-mentioned [ ¹¹ C]SB-366791, it was not possible to effectively image the TRPV1 receptor, which is known to exist in the brain. Ta.

One aspect of the present invention aims to provide a compound suitable for imaging TRPV1 receptors in the brain, and use of the compound.

［式（Ｉ）中、
Ｒ^１は、水素または任意の有機基であり、
Ｒ^２は、Ｒ^１が水素の場合は炭素数２以上の有機基であり、Ｒ^１が水素以外である場合は任意の有機基であり、
Ｒ^１および／またはＲ^２は、放射性同位体を有するものである］。In order to solve the above-mentioned problems, a compound or a salt thereof according to one aspect of the present invention is characterized by being a compound represented by the following formula (I) or a salt thereof:

[In formula (I),
R ¹ is hydrogen or any organic group,
R ² is an organic group having 2 or more carbon atoms when R ¹ is hydrogen, and is any organic group when R ¹ is other than hydrogen,
R ¹ and/or R ² have a radioisotope].

In order to solve the above-mentioned problem, the TRPV1 receptor imaging agent according to one aspect of the present invention is characterized by containing the compound according to one aspect of the present invention or a salt thereof as an active ingredient.

［式（Ｉ）中、
Ｒ^１は、水素または任意の有機基であり、
Ｒ^２は、Ｒ^１が水素の場合は炭素数２以上の有機基であり、Ｒ^１が水素以外である場合は任意の有機基であり、
Ｒ^１および／またはＲ^２は、放射性同位体を有するものである］。In order to solve the above problems, a TRPV1 receptor imaging kit according to one aspect of the present invention is characterized by comprising a compound represented by the following formula (I) or a salt thereof:

[In formula (I),
R ¹ is hydrogen or any organic group,
R ² is an organic group having 2 or more carbon atoms when R ¹ is hydrogen, and is any organic group when R ¹ is other than hydrogen,
R ¹ and/or R ² have a radioisotope].

According to one aspect of the present invention, TRPV1 receptors in the brain can be imaged.

These are images of the brain (A) and the whole body (B) obtained by PET measurement when Compound (14) according to the prior art is used. FIG. 2 shows images of the brain (A) and the whole body (B) obtained by PET measurement when compound (15) according to one embodiment of the present invention is used. FIG. 2 shows images of the brain (A) and the whole body (B) obtained by PET measurement when compound (16) according to one embodiment of the present invention is used. FIG. 2 is an image of the brain (A) and whole body (B) obtained by PET measurement when compound (17) according to one embodiment of the present invention is used. FIG. FIG. 2 is an image of the brain (A) and the whole body (B) obtained by PET measurement when compound (18) according to one embodiment of the present invention is used. FIG. 2 is an image of the brain (A) and whole body (B) obtained by PET measurement when compound (19) according to one embodiment of the present invention is used. FIG. 1 is a graph showing changes in SUV over time in PET measurements in the brain when using a compound according to one embodiment of the present invention and a compound according to the prior art. 2 is a graph showing changes in SUV over time in PET measurement of the body surface when using a compound according to one embodiment of the present invention and a compound according to the prior art.

An embodiment of the present invention will be described below, but the present invention is not limited thereto. The present invention is not limited to each configuration described below, and various changes can be made within the scope of the claims, and technical means disclosed in different embodiments and examples can be applied. Embodiments and examples obtained by appropriately combining them are also included in the technical scope of the present invention. Additionally, all documents mentioned herein are incorporated by reference herein.

［式（Ｉ）中、
Ｒ^１は、水素または任意の有機基であり、
Ｒ^２は、Ｒ^１が水素の場合は炭素数２以上の有機基であり、Ｒ^１が水素以外である場合は任意の有機基であり、
Ｒ^１および／またはＲ^２は、放射性同位体を有するものである］。[Embodiment 1]
The compound or a salt thereof according to this embodiment is a compound represented by the following formula (I) or a salt thereof:

[In formula (I),
R ¹ is hydrogen or any organic group,
R ² is an organic group having 2 or more carbon atoms when R ¹ is hydrogen, and is any organic group when R ¹ is other than hydrogen,
R ¹ and/or R ² have a radioisotope].

The compound represented by formula (I) or a salt thereof is a partial structure within SB-366791, and has a partial structure necessary for binding between SB-366791 and the TRPV1 receptor. Therefore, said compounds exhibit selective affinity for the TRPV1 receptor. The compound also has a radioisotope (eg, a short-lived radioisotope) at a metabolically stable site. Therefore, the above compound not only allows visualization of the distribution of TRPV1 receptors, but also enables highly accurate quantification of TRPV1 receptors. Furthermore, the compound has high metabolic stability in vivo. Therefore, the compound is suitable for administration to living organisms. Furthermore, the above compounds tend to accumulate in the brain. The compounds are therefore suitable for imaging the central nervous system, including the brain.

Here, R ¹ in formula (I) is hydrogen or any organic group, and R ² in formula (I) is an organic group having 2 or more carbon atoms when R ¹ is hydrogen; When ¹ is other than hydrogen, it is any organic group. In addition, in this specification, a substituent consisting only of hydrogen is not included in the "organic group".

The organic group in R ¹ and/or R ² is not particularly limited, but includes, for example, an aryl group, a heterocyclic group, an alkyl group, a fluoroalkyl group, an alkenyl group, a fluoroalkenyl group, an alkynyl group, a fluoroalkynyl group. , an alkoxyl group, a fluoroalkoxyl group, an acetyl group, a carboxyalkyl group, and an alkylamido group.

The organic group in R ¹ is preferably an alkyl group, especially one having 20 or less carbon atoms, more preferably 10 or less carbon atoms, more preferably 5 or less carbon atoms, It is more preferable that the number of carbon atoms is 3 or less, and a methyl group is particularly preferable. When R ¹ is such an organic group, the structure of the compound represented by formula (I) and its salt is stabilized, and the metabolic stability in vivo is improved.

The organic group in R ² is preferably an alkyl group, especially one having 20 or less carbon atoms, more preferably 10 or less carbon atoms, more preferably 5 or less carbon atoms, More preferably, the number of carbon atoms is 3 or less. The organic group in R ² is preferably a fluoroalkyl group, and specific examples include a fluoroethyl group, a fluoropropyl group, and a fluorobutyl group. Furthermore, when R ¹ is hydrogen, R ² may be a methyl group. When R ² is such an organic group, the structure of the compound represented by formula (I) and its salt is stabilized, and the metabolic stability in vivo is improved.

Any atom in R ¹ and/or R ² may be a radioactive isotope. The radioisotope is not particularly limited, but a short-lived radioisotope is preferred. Examples of short-lived radioisotopes include carbon radioisotopes and fluorine radioisotopes, with ¹¹ C and ¹⁸ F being particularly preferred. ¹⁴ C is preferred as a long-lived radioisotope.

Since ¹¹ C (half-life: 20.4 minutes) has a short half-life, exposure to radiation when administered to patients can be minimized. Since the half-life of ¹⁸ F (half-life: 109.8 minutes) is longer than that of ¹¹ C, patient exposure will be slightly higher, but the time from synthesis of a compound containing ¹⁸ F to its use will be shorter. You can get some leeway. Since it is not necessarily possible to prepare the compound according to the present embodiment at the site where it will be used, the compound having ¹⁸ F may be synthesized at a dedicated synthesis facility, etc., and then prepared at the site where the compound is used. It is excellent in that it can be ordered and used.

The salt of the compound represented by the above formula (I) is not particularly limited and may be any salt. Examples of the salt include metal salts (sodium salt, magnesium salt, calcium salt, and potassium salt).

[Embodiment 2]
The TRPV1 receptor imaging agent according to the present embodiment contains the compound or its salt according to Embodiment 1 of the present invention as an active ingredient. The TRPV1 receptor imaging agent according to the present embodiment may be used to visualize the brain (eg, visualize a specific region of the brain) regardless of the TRPV1 receptor. In this case, the TRPV1 receptor imaging agent according to this embodiment may be a brain imaging agent.

The imaging agent according to the present embodiment can be used to evaluate pathological conditions that affect the expression level of the TRPV1 receptor (in other words, have a correlation with the expression level of the TRPV1 receptor). Examples of the pathological conditions include pain, cancer, osteoarthritis, postherpetic neuralgia, lung diseases (e.g., cough attacks and bronchial asthma), inflammatory bowel disease, and irritable bowel syndrome. This includes, but is not limited to, any pathological condition that is accompanied by pain. The cancers include all solid cancers and hematological cancers. Such cancers include cancers that occur in the bones, such as osteosarcoma and cancers that have metastasized to the bones, as examples that are accompanied by particularly severe pain.

The imaging agent according to this embodiment can quantitatively image the TRPV1 receptor. Therefore, with the imaging agent according to this embodiment, the severity of the disease state can be quantitatively diagnosed.

Although PET is preferred as a method for evaluating the pathological condition, it is not limited thereto, and, for example, SPECT (Single photon emission computed tomography) may also be used. In addition, when the compound or salt thereof used is a ¹³ C-labeled compound, metabolite amount analysis by LC-MS (Liquid chromatography-mass spectrometry) is performed to determine if the compound or salt thereof used is a ¹⁴ C-labeled compound. In this case, analysis of the amount of metabolites by AMS (Accelerator Mass Spectrometry) can be used as a method for evaluating the pathological condition.

The imaging agent according to this embodiment can be used for PET imaging. When an imaging agent is used in PET, only a small amount of imaging agent is administered to the subject, so the pharmacological effects (pain relief, induction of burn sensation, etc.) due to inhibition of the TRPV1 receptor do not appear in the subject. , is safe. Furthermore, with the imaging agent according to this embodiment, exposure to radioactive isotopes can be minimized.

The method of administering the imaging agent is not particularly limited. Specifically, examples of the administration method include injection administration (for example, intravenous administration and transarterial administration), oral administration, nasal administration, oral mucosal administration, and transdermal administration. Therefore, the TRPV1 receptor imaging agent according to this embodiment may be an injection, an internal medicine, a nasal medicine, or an external medicine. The imaging agent may be prepared as a liquid formulation, either in solution or suspension, or as a solid formulation suitable for dissolution or suspension in a liquid (e.g., a buffer). good.

Since the TRPV1 receptor functions as a pain receptor, it is known as a target molecule for analgesics and the like. Therefore, the imaging agent can be utilized in screening for drugs that target the TRPV1 receptor. As the screening method, for example, a method can be considered in which the TRPV1 receptor is visualized using the imaging agent and a drug candidate substance whose expression level of the TRPV1 receptor changes upon administration is screened as a drug. The drug candidate substances and drugs include, but are not limited to, low molecular weight compounds, nucleic acids, peptides, and proteins such as antibodies. The screening can be performed either in vitro or in vivo.

The amount of the active ingredient in the imaging agent of this embodiment is not particularly limited, and may be, for example, 0.001% to 100% by weight, or 0.01% to 100% by weight based on the imaging agent. %, 0.1% to 100% by weight, 0.1% to 95% by weight, 0.1% to 90% by weight Often, it may be 0.1% to 80% by weight, 0.1% to 70% by weight, 0.1% to 60% by weight, 0.1% by weight It may be from 0.1% to 40% by weight, from 0.1% to 30% by weight, and from 0.1% to 20% by weight. % or 0.1% to 10% by weight.

The imaging agent of this embodiment may contain components other than the active ingredient (pharmaceutically acceptable carrier). When the imaging agent of this embodiment is provided as a solid preparation, ingredients other than the active ingredient include excipients, lubricants, binders, and disintegrants; When the agent is provided as a liquid formulation, mention may be made of solvents, solubilizing agents, suspending agents, tonicity agents, buffers and soothing agents. Other ingredients other than the active ingredient include preservatives, antioxidants, and stabilizers.

Examples of the above-mentioned "excipients" include, but are not limited to, lactose, sucrose, D-mannitol, xylitol, sorbitol, erythritol, starch, and crystalline cellulose.

Examples of the above-mentioned "lubricants" include, but are not limited to, magnesium stearate, calcium stearate, wax, talc, and colloidal silica.

Examples of the "binder" include, but are not limited to, pregelatinized starch, methylcellulose, crystalline cellulose, white sugar, D-mannitol, trehalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

Examples of the above-mentioned "disintegrant" include, but are not limited to, starch, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, and carboxymethyl starch sodium.

Examples of the "solvent" include, but are not limited to, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and tricaprylin.

Examples of the above-mentioned "solubilizing agent" include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate. Not limited to these.

Examples of the above-mentioned "suspending agent" include surfactants (e.g., stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate) and highly hydrophilic glyceryl monostearate. Non-limiting examples include molecules such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose.

Examples of the above-mentioned "tonicity agent" include, but are not limited to, sodium chloride, glycerin, and D-mannitol.

Examples of the above-mentioned "buffers" include, but are not limited to, phosphates, acetates, carbonates, and citrates.

Examples of the above-mentioned "alleviating agent" include, but are not limited to, benzyl alcohol.

Examples of the above-mentioned "preservatives" include, but are not limited to, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

Examples of the above-mentioned "antioxidant" include, but are not limited to, sulfites and ascorbic acid.

The above-mentioned "stabilizer" is not particularly limited as long as it is commonly used in the pharmaceutical field.

The amount of components other than the active ingredient in the imaging agent of the present embodiment is not particularly limited, and may be, for example, 0% to 99.999% by weight, 0% to 99% by weight based on the imaging agent. 99% by weight, 0% to 99.9% by weight, 5% to 99.9% by weight, 10% to 99.9% by weight. 20% to 99.9% by weight, 30% to 99.9% by weight, 40% to 99.9% by weight, It may be 50% to 99.9% by weight, 60% to 99.9% by weight, 70% to 99.9% by weight, 80% to 99% by weight. It may be .9% by weight, or it may be from 90% to 99.9% by weight.

[Embodiment 3]
The TRPV1 receptor imaging kit according to the present embodiment includes the compound described in [Embodiment 1] above or a salt thereof. The TRPV1 receptor imaging kit according to the present embodiment may be used to visualize the brain (for example, visualize a specific region of the brain) regardless of the TRPV1 receptor. In this case, the TRPV1 receptor imaging kit according to this embodiment may be a brain imaging kit.

Using the TRPV1 receptor imaging kit according to the present embodiment, the TRPV1 receptor imaging agent can be easily prepared and/or the TRPV1 receptor imaging agent can be easily administered to a subject.

The compounds and their salts included in the kit of this embodiment have been explained in [Embodiment 1], so their explanation will be omitted here.

The imaging kit may include components other than the compound described in [Embodiment 1] or a salt thereof (in other words, the active ingredient in the TRPV1 receptor imaging agent).

Examples of the above-mentioned components include excipients, lubricants, binders, and disintegrants. In this case, using the imaging kit of the present embodiment, a TRPV1 receptor imaging agent that is a solid preparation can be easily prepared. Further, such components may include a solvent, a solubilizing agent, a suspending agent, a tonicity agent, a buffering agent, and a soothing agent. In this case, the imaging kit of the present embodiment can be used to easily prepare a liquid preparation of an imaging agent for the TRPV1 receptor. Further, such components may include preservatives, antioxidants, and stabilizers. In this case, using the imaging kit of the present embodiment, a TRPV1 receptor imaging agent that can be stored for a long period of time can be easily prepared.

Moreover, a syringe can be mentioned as the above-mentioned structure. In this case, using the imaging kit of this embodiment, the TRPV1 receptor imaging agent can be easily administered to the subject.

［式（Ｉ）中、
Ｒ^１は、水素または任意の有機基であり、
Ｒ^２は、Ｒ^１が水素の場合は炭素数２以上の有機基であり、Ｒ^１が水素以外である場合は任意の有機基であり、
Ｒ^１および／またはＲ^２は、放射性同位体を有するものである］。〔summary〕
In order to solve the above-mentioned problems, a compound or a salt thereof according to one aspect of the present invention is characterized by being a compound represented by the following formula (I) or a salt thereof:

[In formula (I),
R ¹ is hydrogen or any organic group,
R ² is an organic group having 2 or more carbon atoms when R ¹ is hydrogen, and is any organic group when R ¹ is other than hydrogen,
R ¹ and/or R ² have a radioisotope].

In order to solve the above-mentioned problem, the TRPV1 receptor imaging agent according to one aspect of the present invention is characterized by containing the compound according to one aspect of the present invention or a salt thereof as an active ingredient.

The TRPV1 receptor imaging agent according to one aspect of the present invention is preferably used for PET imaging or evaluation of pathological conditions that affect the expression level of the TRPV1 receptor.

In the TRPV1 receptor imaging agent according to one aspect of the present invention, the pathological condition may be pain, cancer, osteoarthritis, postherpetic neuralgia, pulmonary disease, inflammatory bowel disease, or irritable bowel syndrome. preferable.

［式（Ｉ）中、
Ｒ^１は、水素または任意の有機基であり、
Ｒ^２は、Ｒ^１が水素の場合は炭素数２以上の有機基であり、Ｒ^１が水素以外である場合は任意の有機基であり、
Ｒ^１および／またはＲ^２は、放射性同位体を有するものである］。In order to solve the above problems, a TRPV1 receptor imaging kit according to one aspect of the present invention is characterized by comprising a compound represented by the following formula (I) or a salt thereof:

[In formula (I),
R ¹ is hydrogen or any organic group,
R ² is an organic group having 2 or more carbon atoms when R ¹ is hydrogen, and is any organic group when R ¹ is other than hydrogen,
R ¹ and/or R ² have a radioisotope].

EXAMPLES Hereinafter, the present invention will be explained in more detail based on Examples, but the present invention is not limited to the following Examples.

化合物（７）（(2E)-3-(4-Chlorophenyl)-N-[4-(tetrahydropyran-2-yl)oxyphenyl]-2-propenamide）、化合物（８）（(2E)-3-(4-Chlorophenyl)-N-[4-(hydroxyphenyl)-N-methyl-2-propenamide）、化合物（９）（2-Fluoroethyl methanesulfonate）、化合物（１０）（3-Fluoropropyl methanesulfonate）、化合物（１１）（(2E)-3-(4-Chlorophenyl)-N-(4-methoxyphenyl)-N-methyl-2-propenamide）、化合物（１２）（(2E)-3-(4-Chlorophenyl)-N-[4-(3-fluoroethoxyphenyl)-N-methyl-2-propenamide）、化合物（１３）（(2E)- 3-(4-Chlorophenyl)-N-[4-(3-fluoropropoxyphenyl)-N-methyl-2-propenamide）は、以下の合成スキームに従って合成した。

以下に、各化合物についての合成方法について具体的に説明する。[Synthesis of compounds]
(I) Synthesis of labeled precursor Compound (4) ((2E)-3-(4-Chlorophenyl)-N-(4-methoxyphenyl)-2-propenamide) (SB366791), Compound (5) ((2E)- Compound (6) ((2E)-3-(4-Chlorophenyl)-N-[4-( 3-fluoropropoxy)-phenyl]-2-propenamide) was synthesized according to the following synthetic scheme.

Compound (7) ((2E)-3-(4-Chlorophenyl)-N-[4-(tetrahydropyran-2-yl)oxyphenyl]-2-propenamide), Compound (8) ((2E)-3-(4 -Chlorophenyl)-N-[4-(hydroxyphenyl)-N-methyl-2-propenamide), Compound (9) (2-Fluoroethyl methanesulfonate), Compound (10) (3-Fluoropropyl methanesulfonate), Compound (11) (( Compound (12) ((2E)-3-(4-Chlorophenyl)-N-[4- (3-fluoroethoxyphenyl)-N-methyl-2-propenamide), Compound (13) ((2E)- 3-(4-Chlorophenyl)-N-[4-(3-fluoropropoxyphenyl)-N-methyl-2-propenamide ) was synthesized according to the following synthetic scheme.

The synthesis method for each compound will be specifically explained below.

乾燥したナスフラスコ（２００ｍＬ）に、4-chlorocinnamic acid（３．１ｇ，１７ｍｍｏｌ）を加え、更に、無水ＤＭＦ（７０ｍＬ）を加えた。このナスフラスコを氷水冷しながら、ＷＳＣＩ ＨＣＬ（Water Soluble Carbodiimide hydrochloride: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride）（３．６ｇ，１９ｍｍｏｌ）を、更に加えた。約１０分同温でナスフラスコ内の溶液を撹拌した後、ナスフラスコを氷水浴から取り出し、当該ナスフラスコへ、ＨＯＢｔ（２．５ｇ，１９ｍｍｏｌ）、および、ＤＭＡＰ（２．３ｇ，１８．７ｍｍｏｌ）を加えた。添加後、ナスフラスコ内の溶液を約２０分撹拌し、続いて、当該ナスフラスコへ3-hydroxyaniline（２．５ｇ，１９ｍｍｏｌ）を加え、ナスフラスコ内の溶液を室温で終夜撹拌し、反応させた。この反応混合物を精製水（２００ｍＬ）に投入し、酢酸エチルを用いて抽出した。抽出液を精製水および飽和食塩水で洗浄し、当該抽出液を無水硫酸マグネシウムで乾燥させた後、減圧濃縮し、粗生成物を得た。当該粗生成物を酢酸エチル：ｎ－ヘキサンを用いて再結晶化させ、化合物（１）（２．８ｇ，６１％）を得た。(i) Synthesis of compound (1) ((2E)-3-(4-Chlorophenyl)-N-(4-hydroxyphenyl-2-propenamide) Compound (1) was synthesized according to the following synthesis scheme.

4-chlorocinnamic acid (3.1 g, 17 mmol) was added to a dry eggplant flask (200 mL), and further, anhydrous DMF (70 mL) was added. While cooling the eggplant flask with ice water, WSCI HCL (Water Soluble Carbodiimide hydrochloride: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) (3.6 g, 19 mmol) was further added. After stirring the solution in the eggplant flask at the same temperature for about 10 minutes, take out the eggplant flask from the ice water bath and add HOBt (2.5 g, 19 mmol) and DMAP (2.3 g, 18.7 mmol) to the eggplant flask. added. After the addition, the solution in the eggplant flask was stirred for about 20 minutes, and then 3-hydroxyaniline (2.5 g, 19 mmol) was added to the eggplant flask, and the solution in the eggplant flask was stirred at room temperature overnight to react. . This reaction mixture was poured into purified water (200 mL) and extracted using ethyl acetate. The extract was washed with purified water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized using ethyl acetate:n-hexane to obtain compound (1) (2.8 g, 61%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.09 (1H, br. s), 9.43 (1H, s), 7.65 (2H d, J = 8.8 Hz, 4 Hz), 7.56 (1H, d, J = 14.8 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.30 (1H, t, J = 2 Hz), 7.09 (1H, dd, J = 8.0 Hz, 7.6 Hz), 7.05 (1H, dt, J ^13C -NMR (DMSO-d ₆ ) δ: 163. 1 , 157.6, 140.2, 138.5, 134.1, 133.7, 129.4, 129.3, 129.0, 123.3, 110.6, 110.0, 106.4.:.

氷水冷下に攪拌した、2-Fluoroethanol（１．０ｇ，１５ｍｍｏｌ）を含むＣＨＣＬ_３（１０ｍＬ）溶液に、Ｅｔ_３Ｎ（２．３８ｍＬ，１７ｍｍｏｌ）を加えた。当該溶液を同温にて暫く攪拌し、続いて、撹拌後の溶液にｐ－ＴｓＣｌ（p-Toluenesulfonyl chloride）（３．３ｇ，１７ｍｍｏｌ）を約５０分かけて加えた。添加完了後、当該溶液を室温で終夜攪拌し、反応させた。反応混合物を減圧濃縮し、残渣を酢酸エチル（２０ｍＬ）に再溶解し、溶解液を、精製水および飽和食塩水を用いて洗浄し、次いで無水ＭｇＳＯ_４を用いて乾燥させた後、この溶解液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶離液；ＡｃＯＥｔ：ｎ－ヘキサン）を用いて精製し、油状の化合物（２）（２．１ｇ，６３％）を得た。(ii) Synthesis of compound (2) (2-Fluoroethyl p-toluenesulfonate) Compound (2) was synthesized according to the following synthesis scheme.

Et ₃ N (2.38 mL, 17 mmol) was added to a CHCL ₃ (10 mL) solution containing 2-Fluoroethanol (1.0 g, 15 mmol) that was stirred under ice-water cooling. The solution was stirred for a while at the same temperature, and then p-TsCl (p-Toluenesulfonyl chloride) (3.3 g, 17 mmol) was added to the stirred solution over about 50 minutes. After the addition was complete, the solution was stirred at room temperature overnight to allow reaction. The reaction mixture was concentrated under reduced pressure, the residue was redissolved in ethyl acetate (20 mL), the solution was washed with purified water and saturated brine, and then dried with anhydrous _MgSO4 , and then the solution was washed with purified water and saturated brine. was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: AcOEt:n-hexane) to obtain oily compound (2) (2.1 g, 63%).

¹ H-NMR (CDCl ₃ ) δ: 7.8 (2H, d, J = 8.4 Hz), 7.36 (2H, d, J = 8.4 Hz), 4.65-4.61 (1H, m), 4.53-4.49 (1H, m ), 4.32-4.28 (1H, m), 4.25-4.21 (1H, m), 2.46 (3H, s):.

氷水冷下に攪拌した、3-fluoropropanol（１．６ｇ，２０ｍｍｏｌ）を含む塩化メチレン（１３ｍＬ）溶液に、Ｅｔ_３Ｎ（３．１７ｍＬ，２３ｍｍｏｌ）を加えた。当該溶液を同温にて暫く攪拌し、続いて、撹拌後の溶液にｐ－ＴｓＣｌ（４．２ｇ，２２ｍｍｏｌ）を約５０分かけて加えた。添加完了後、当該溶液を室温で終夜攪拌し、反応させた。反応混合物を減圧濃縮し、残渣を酢酸エチル（５０ｍＬ）に再溶解し、溶解液を、精製水および飽和食塩水を用いて洗浄し、次いで無水ＭｇＳＯ_４を用いて乾燥させた後、この溶解液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶離液；酢酸エチル：ｎ－ヘキサン）を用いて精製し、油状の化合物（３）（２．１ｇ，６３％）を得た。(iii) Synthesis of compound (3) (3-Fluoropropyl p-toluenesulfonate) Compound (3) was synthesized according to the following synthesis scheme.

Et ₃ N (3.17 mL, 23 mmol) was added to a methylene chloride (13 mL) solution containing 3-fluoropropanol (1.6 g, 20 mmol), which was stirred under ice-water cooling. The solution was stirred for a while at the same temperature, and then p-TsCl (4.2 g, 22 mmol) was added to the stirred solution over about 50 minutes. After the addition was complete, the solution was stirred at room temperature overnight to allow reaction. The reaction mixture was concentrated under reduced pressure, the residue was redissolved in ethyl acetate (50 mL), the solution was washed with purified water and saturated brine, and then dried with anhydrous _MgSO4 , and then the solution was washed with purified water and saturated brine. was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (eluent: ethyl acetate: n-hexane) to obtain oily compound (3) (2.1 g, 63%).

¹ H-NMR (CDCl ₃ ) δ: 7.8 (2H, d, J = 8, 4 Hz), 7.36 (2H d, J = 8.4 Hz), 4.65-4.61 (1H, m), 4.53-4.49 (1H, m), 4.32-4.28 (1H, m), 4.25-4.21 (1H, m), 2.46 (3H, s).:.

乾燥したスクリューキャップバイアル（１０ｍＬ）に、化合物（１）（５００ｍｇ，１．８ｍｍｏｌ）と、Ｋ_２ＣＯ_３（１２７ｍｇ，０．９ｍｍｏｌ）と、無水ＤＭＦ（６．３ｍＬ）とを加えた。この懸濁液を、室温下、約２０分攪拌した後、当該懸濁液にＣＨ_３Ｉ（１２５μＬ，２ｍｍｏｌ）を加え、スクリューキャップバイアルを８０℃の油浴に入れ、１５．５時間攪拌反応させた。反応混合物を放冷後、冷精製水中に投じ、生じた固形物を濾取し、粗生成物を得た。粗生成物をシリカゲルカラムクロマトグラフィー（溶離液ＣＨＣＬ_３：ＣＨ_３ＯＨ＝１００：０→９５：５）に供し、目的とする化合物（４）（２１４ｍｇ，４０％）を得た。(iv) Synthesis of Compound (4) (SB366791) Compound (4) was synthesized according to the following synthesis scheme.

To a dry screw cap vial (10 mL) were added compound (1) (500 mg, 1.8 mmol), K ₂ CO ₃ (127 mg, 0.9 mmol), and anhydrous DMF (6.3 mL). After stirring this suspension at room temperature for about 20 minutes, CH ₃ I (125 μL, 2 mmol) was added to the suspension, the screw cap vial was placed in an 80° C. oil bath, and the reaction was stirred for 15.5 hours. I let it happen. After the reaction mixture was allowed to cool, it was poured into cold purified water, and the resulting solid matter was collected by filtration to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent CHCL ₃ :CH ₃ OH=100:0→95:5) to obtain the target compound (4) (214 mg, 40%).

¹ H-NMR (DMSO-d ₆ ) δ: 9.75 (1H, 7.49 H, d, J = 15. 6Hz), 7.45-7.37 (4H, m, Ar-H), 7.25 (1H, t, J= 7.8 Hz), 6.78 (1H, dq, J = 8 Hz, 2 Hz), 6.72 (1H, dq, J = 8 Hz, 2 Hz), 6.68 (1H, t, J = 2 Hz), 6.43 (1H, d , J = 15.6 Hz), 3.25 (3H, s); ¹³ C-NMR (DMSO-d ₆ ) δ: 164.4, 158.2, 144.2, 139.0, 134.0, 133.6, 130.2, 129.3, 129.0, 128.9, 119.9, 117.6, 114.6, 113.9.:.

スクリューキャップバイアル（１０ｍＬ）に、化合物（１）（４００ｍｇ，１．５ｍｍｏｌ）と、Ｋ_２ＣＯ_３（１１１ｍｇ，０．８ｍｍｏｌ）と、無水ＤＭＦ（４ｍＬ）とを入れて懸濁液とし、この懸濁液を室温下約２０分攪拌した後、当該懸濁液に化合物（２）（３４９ｍｇ，１．６ｍｍｏｌ）を含む無水ＤＭＦ（１ｍＬ）溶液を加え、当該懸濁液を８０℃の油浴中にて２６時間攪拌して反応させた。反応混合物を放冷後、冷水中に投じ、生じた固形物を濾取し、粗生成物を得た。粗生成物をシリカゲルカラムクロマトグラフィー（溶離液ＣＨＣｌ_３：ＣＨ_３ＯＨ１００：０→９９：１）に供し、目的とする化合物（５）（２１４ｍｇ，４５％）を得た。(v) Synthesis of compound (5) Compound (5) was synthesized according to the following synthesis scheme.

Compound (1) (400 mg, 1.5 mmol), K ₂ CO ₃ (111 mg, 0.8 mmol), and anhydrous DMF (4 mL) were put into a screw cap vial (10 mL) to make a suspension. After stirring the suspension at room temperature for about 20 minutes, a solution of compound (2) (349 mg, 1.6 mmol) in anhydrous DMF (1 mL) was added to the suspension, and the suspension was placed in an oil bath at 80°C. The mixture was stirred for 26 hours to react. After cooling the reaction mixture, it was poured into cold water, and the resulting solid matter was collected by filtration to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent CHCl ₃ :CH ₃ OH 100:0→99:1) to obtain the target compound (5) (214 mg, 45%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.21 (1H, br. s), 7.66 (2H, d, J = 15.6 Hz ), 7.58 (1H, d, J = 15.6 Hz), 7.51 (2H, m ) 7.46 (1H, m), 4.21 (dt, 30 Hz, 4 Hz), 4.75 (dt, 48 Hz, 4 Hz). ¹³ C-NMR (DMSO-d ₆ ) δ: 163.3, 158.4, 140.3, 138.8, 134.2, 133.6, 129. 7, 123.0, 112.0, 109.3, 105.8, 82.9, 81.3, 67.1, 66.9.:.

スクリューキャップバイアル（１０ｍＬ）に、化合物（１）（４００ｍｇ，１．５ｍｍｏｌ）と、Ｋ_２ＣＯ_３（１１１ｍｇ，０．８ｍｍｏｌ）と、無水ＤＭＦ（５ｍＬ）とを加えた。この懸濁液を室温下にて約２０分攪拌した後、当該懸濁液に化合物（３）（３７１ｍｇ，１．６ｍｍｏｌ）を含む無水ＤＭＦ（１ｍＬ）溶液を加え、当該懸濁液を８０℃の油浴中にて２４時間攪拌して反応させた。なお原料の残留が認められたので、3-fluoropropyl tosylate（１２３ｍｇ，０．５ｍｍｏｌ）、および、Ｋ_２ＣＯ_３（３７ｍｇ，０．２７ｍｍｏｌ）を追加し、反応を続けた（２０時間）。反応混合物を放冷後、冷精製水中に投じ、生じた固形物を濾取し、粗生成物を得た。粗生成物をシリカゲルカラムクロマトグラフィー（溶離液；ＣＨＣｌ_３：ＣＨ_３ＯＨ＝１００：０→８０：２０）に供し、目的とする化合物（６）（１４５ｍｇ，３０％）を得た。(vi) Synthesis of compound (6) Compound (6) was synthesized according to the following synthesis scheme.

Compound (1) (400 mg, 1.5 mmol), K ₂ CO ₃ (111 mg, 0.8 mmol), and anhydrous DMF (5 mL) were added to a screw cap vial (10 mL). After stirring this suspension at room temperature for about 20 minutes, a solution of compound (3) (371 mg, 1.6 mmol) in anhydrous DMF (1 mL) was added to the suspension, and the suspension was stirred at 80°C. The reaction mixture was stirred for 24 hours in an oil bath. Since residual raw materials were observed, 3-fluoropropyl tosylate (123 mg, 0.5 mmol) and K ₂ CO ₃ (37 mg, 0.27 mmol) were added and the reaction was continued (20 hours). After the reaction mixture was allowed to cool, it was poured into cold purified water, and the resulting solid matter was collected by filtration to obtain a crude product. The crude product was subjected to silica gel column chromatography (eluent; CHCl ₃ :CH ₃ OH=100:0→80:20) to obtain the target compound (6) (145 mg, 30%).

¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, br. s), 7.67-7.63 (2H, m, Ar-H), 7.56 (1H, d, J = 5. 6 Hz), 7.53- 7.49 (2H, m, Ar-H), 7.45 (1H, m), 7.26-7.17 (2H, m, Ar-H), 6.82 (1H, d, J = 15.6 Hz), 6.70-6.66 (1H, m ), 4.62 (2H, dt, J _HF = 47.2 Hz, J _HH = 6.0 Hz), 4.06 (1H, t, J = 6Hz), 2.12 (2H, dq, J _HF = 26 Hz, J _HH = 6 Hz, ); ¹³ C-NMR (DMSO-d ₆ ) δ: 163.3, 158.4, 140.3, 138.8, 134.2, 133.6, 129.4, 129.0, 123.0, 112.0, 109.3, 105.8, 82.9, 81.3, 67.0, 66.9.:.

化合物（１）（２．０ｇ，７．３ｍｍｏｌ）とＤＨＰ（dihydropyrane）（１．５ｇ，１７．８ｍｍｏｌ）との混合溶液（ＣＨ_２Ｃｌ_２，２５ｍＬ）に、ＰＰＴＳ（Pyridinium p-toluenesulfonate）（８０ｍｇ，０．３ｍｍｏｌ）を加え、室温下にて２４時間攪拌して反応させた。なお原料の残留が認められたので、さらに２４時間攪拌して反応させた。反応溶液をＣＨ_２Ｃｌ_２（７５ｍＬ）にて希釈し、当該反応溶液をＮａＯＨ ａｑ．（１ｍｏｌ／Ｌ）、精製水、および、飽和食塩水にて洗浄し、無水ＭｇＳＯ_４にて乾燥させた後、減圧濃縮することにより、粗生成物（２．３ｇ）を得た。粗成生物を酢酸エチルとｎ－ヘキサンとを用いて再結晶化させることにより、化合物（７）（１．８ｇ，６８％）を得た。(vii) Synthesis of compound (7) Compound (7) was synthesized according to the following synthesis scheme.

PPTS (Pyridinium p-toluenesulfonate) (80 mg) was added to a mixed solution (CH ₂ Cl ₂ , 25 mL) of compound (1) (2.0 g, 7.3 mmol) and DHP (dihydropyrane) (1.5 g, 17.8 mmol). , 0.3 mmol) and stirred at room temperature for 24 hours to react. Since some raw material remained, the mixture was stirred for an additional 24 hours to react. The reaction solution was diluted with CH ₂ Cl ₂ (75 mL), and the reaction solution was treated with NaOH aq. (1 mol/L), purified water, and saturated brine, dried over anhydrous MgSO ₄ , and concentrated under reduced pressure to obtain a crude product (2.3 g). Compound (7) (1.8 g, 68%) was obtained by recrystallizing the crude product using ethyl acetate and n-hexane.

¹ H-NMR (DMSO-d ₆ ) δ: 10.20 (1H, br. s), 7.67-7.63 (2H, m, Ar-H), 7.56 (1H, d, 16 Hz), 7.53-7.45 (3H, m), 7.32-7.18 (3H, m, Ar-H), 6.81 (1H, d, J = 16 Hz), 6.76-6.69 (1H, m, Ar-H), 3.82-3.70 (1H, m), 3.61-3.49 (1h, m), 1.94-1.44 (6H, m), ¹³ C-NMR (DMSO-D ₆ ) δ: 163.3, 156.9, 140.2, 138.7, 133.2, 133.7, 129.0, 129.0, 129.1, 112.5 111.4, 107.5, 95.9, 61.6, 29.9, 24.6, 18.6.：.

アルゴンが封入された、風船付き三方コック、セプタムラバー、および、攪拌子を装着した二径フラスコに、化合物（７）（５００ｍｇ，１．４ｍｍｏｌ）、および、ＫＯＨ（２３５ｍｇ，４ｍｍｏｌ／乳鉢粉砕品）を加え、当該二径フラスコを氷水浴に浸けた状態にて、更に、無水ＤＭＦ（６ｍＬ）をシリンジにて加えた。同温で約１０分攪拌した後、ＣＨ_３Ｉ（２６３μＬ，４．２ｍｍｏｌ）を加えた。同温で約１０分、室温で３０分攪拌した後、二径フラスコを６０℃の油浴に移し、１５．５時間反応させた。反応混合物を室温にまで放冷し、当該反応混合物を精製水中に投入し、酢酸エチルにて抽出した。抽出液を、精製水および飽和食塩水を用いて洗浄した後、無水ＭｇＳＯ_４を用いて乾燥させた。この抽出液を濃縮乾固して得られたペースト状の粗生成物（４１４ｍｇ）を、シリカゲルカラムクロマトグラフィー（溶離液ＣＨＣｌ_３：ＣＨ_３ＯＨ＝１００：１→５０：１）に供し、化合物（８）を３６５ｍｇ（９０％）得た。(viii) Synthesis of Compound (8) Compound (8) was synthesized by the method shown in the scheme below.

Compound (7) (500 mg, 1.4 mmol) and KOH (235 mg, 4 mmol/mortar-pulverized product) were placed in a two-diameter flask filled with argon and equipped with a three-way cock with a balloon, a septum rubber, and a stirrer. was added, and while the two-diameter flask was immersed in an ice water bath, anhydrous DMF (6 mL) was further added using a syringe. After stirring at the same temperature for about 10 minutes, CH ₃ I (263 μL, 4.2 mmol) was added. After stirring at the same temperature for about 10 minutes and at room temperature for 30 minutes, the two-diameter flask was transferred to a 60° C. oil bath and reacted for 15.5 hours. The reaction mixture was allowed to cool to room temperature, poured into purified water, and extracted with ethyl acetate. The extract was washed with purified water and saturated saline, and then dried with anhydrous MgSO ₄ . The paste-like crude product (414 mg) obtained by concentrating this extract to dryness was subjected to silica gel column chromatography (eluent CHCl ₃ :CH ₃ OH=100:1 → 50:1), and the compound ( 8) was obtained in an amount of 365 mg (90%).

¹ H-NMR (DMSO-d ₆ ) δ: 9.75 (1H, s), 7.49 (1H, d, J = 15.6 Hz), 7.45-6.37 (4H, m, Ar-H), 7.25 (1H, m) , 6.81-6.75 (1H, m), 6.74-6.69 (1H, m), 6.68-6.67 (1H, m), 6.43 (1H, d, J = 15.6 Hz), 3.25 (2H, s); ¹³ C- NMR (DMSO-d ₆ ) δ: 164.4, 158.2, 144.2, 139.0, 134.0, 133.6, 130.2, 129.3, 128.8, 119.9, 117.6, 114.6, 113.9.:.

氷水冷下にて攪拌した、2-fluoroethanol（１．０ｇ，１５ｍｍｏｌ）を含むＣＨ_２Ｃｌ_２（２０ｍＬ）溶液に、Ｅｔ_３Ｎ（２．６ｍＬ，１８．７ｍｍｏｌ）を加えた。当該溶液を同温で暫く攪拌し、続いて、当該溶液に、methanesulfonyl chloride（２．１ｇ，１９ｍｍｏｌ）を含む塩化メチレン（１０ｍＬ）溶液を、約５分をかけて滴下した。滴下後、当該溶液を室温にて終夜攪拌して反応させた。反応終了後、反応混合物を、希塩酸（０．１ｍｏｌ／Ｌ）、精製水、および、飽和食塩水を用いて洗浄し、無水ＭｇＳＯ_４を用いて乾燥させた。この溶液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶離液；ＡｃＯＥｔ：ｎ－ヘキサン）に供し、淡褐色油状の化合物（９）（１．８ｇ，８０％）を得た。本法で得られた化合物（９）は、更なる精製をすることなく、次工程（Ｏ－アルキル化反応）に使用できた。(ix) Synthesis of compound (9) Compound (9) was synthesized according to the following synthesis scheme.

Et ₃ N (2.6 mL, 18.7 mmol) was added to a CH ₂ Cl ₂ (20 mL) solution containing 2-fluoroethanol (1.0 g, 15 mmol), which was stirred under ice-water cooling. The solution was stirred for a while at the same temperature, and then a methylene chloride (10 mL) solution containing methanesulfonyl chloride (2.1 g, 19 mmol) was added dropwise to the solution over about 5 minutes. After the dropwise addition, the solution was stirred at room temperature overnight to react. After the reaction was completed, the reaction mixture was washed with dilute hydrochloric acid (0.1 mol/L), purified water, and saturated brine, and dried using anhydrous MgSO ₄ . This solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: AcOEt:n-hexane) to obtain compound (9) (1.8 g, 80%) as a pale brown oil. Compound (9) obtained by this method could be used in the next step (O-alkylation reaction) without further purification.

¹ H-NMR (CDCl ₃ ) δ: 4.61 (2H, dm, J _HF = 47.6 Hz), 4.35 (2H, dm, J _HF = 28.4 Hz), 3.01 (3H, S):.

氷水冷下にて攪拌した、3-Fluoropropanol（１．２ｇ，１５ｍｍｏｌ）を含むＣＨ_２Ｃｌ_２（２０ｍＬ）溶液に、Ｅｔ_３Ｎ（１．９ｍＬ，１９ｍｍｏｌ）を加えた。当該溶液を同温で暫く攪拌し、続いて、当該溶液に、ｐ－ＭｓＣｌ（２．１ｇ，１９ｍｍｏｌ）を、約５０分かけて加えた。添加後、当該溶液を室温にて終夜攪拌して反応させた。反応混合物を減圧濃縮し、残渣を酢酸エチル（２０ｍＬ）に再溶解し、当該溶解液を、精製水および飽和食塩水を用いて洗浄し、無水ＭｇＳＯ_４を用いて乾燥させた後、この抽出液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶離液 ＡｃＯＥｔ／ｎ－ヘキサン）に供し、定量的収量にて、油状の化合物（１０）（２．０ｇ，８３％）を得た。(x) Synthesis of Compound (10) Compound (10) was synthesized according to the following synthesis scheme.

Et ₃ N (1.9 mL, 19 mmol) was added to a CH ₂ Cl ₂ (20 mL) solution containing 3-Fluoropropanol (1.2 g, 15 mmol), which was stirred under ice-water cooling. The solution was stirred for a while at the same temperature, and then p-MsCl (2.1 g, 19 mmol) was added to the solution over about 50 minutes. After the addition, the solution was stirred and reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was redissolved in ethyl acetate (20 mL), the solution was washed with purified water and saturated brine, dried over anhydrous MgSO ₄ , and the extract was was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: AcOEt/n-hexane) to obtain oily compound (10) (2.0 g, 83%) in quantitative yield.

¹ H-NMR (CDCl ₃ ) δ: 4.59 (2H, dt, J _HF = 46.8 Hz, J _HH = 6.0 Hz), 4.38 (2H, d, J = 6.0 Hz), 3.04 (3H, s), 2.15 ( 2H, dq, J _H,F = 25.6 Hz, J _H,H = 6.0 Hz):.

スクリューキャップバイアル（１０ｍＬ）に、化合物（８）（２００ｍｇ，０．７ｍｍｏｌ）と、ＫＯＨ（６２ｍｇ，１．１ｍｍｏｌ）と、乾燥ＤＭＦとを加え、乾燥ＤＭＦ中に化合物（８）とＫＯＨとを懸濁させた。この溶液を氷水冷下にて攪拌しながら、当該溶液にmethyl iodide（１５６ｍｇ，１．１ｍｍｏｌ）を加えた。当該溶液を同温度にて暫時攪拌した後、６０℃の油浴中にて１６時間攪拌して反応させた。反応混合物を、放冷し、精製水中に投入し、酢酸エチルにて抽出した。この抽出液を、精製水および飽和食塩水を用いて洗浄し、硫酸マグネシウムを用いて乾燥させた後、減圧濃縮し、ペースト状の粗生成物を得た。粗成生物をシリカゲルカラムクロマトグラフィー（溶離液 酢酸エチル：ｎ－ヘキサン）に供し、化合物（１１）（１７８ｍｇ，８４％）を得た。(xi) Synthesis of Compound (11) Compound (11) was synthesized according to the following synthesis scheme.

Compound (8) (200 mg, 0.7 mmol), KOH (62 mg, 1.1 mmol), and dry DMF were added to a screw cap vial (10 mL), and the compound (8) and KOH were suspended in dry DMF. Made it muddy. While stirring this solution under ice-water cooling, methyl iodide (156 mg, 1.1 mmol) was added to the solution. The solution was stirred for a while at the same temperature, and then stirred in an oil bath at 60° C. for 16 hours to react. The reaction mixture was allowed to cool, poured into purified water, and extracted with ethyl acetate. This extract was washed with purified water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a paste-like crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate: n-hexane) to obtain compound (11) (178 mg, 84%).

¹ H-NMR (DMSO-d ₆ ) δ: 7.49 (1H, d, J = 15.6 Hz), 7.46-7.33 (4H, m, Ar-H), 6.97-6.92 (2H, m, Ar-H), 6.88-6.85 (1H, m, Ar-H), 6.44 (1H, d, J = 15.6 Hz), 3.77 (3H, s), 3.28 (3H, s), ; ¹³ C-NMR (DMSO-d ₆ ) δ : 164.4, 160.0, 144.4, 139.1, 134.0, 133.6, 130.2, 129.3, 128.9, 119.9, 113.2, 112.7, 55.3, 37.0.:.

スクリューキャップバイアル（１０ｍＬ）中にて、化合物（８）（１５０ｍｇ，０．５５ｍｍｏｌ）)、化合物（９）（８５ｍｇ，０．６ｍｍｏｌ）、および、tetrabutyl ammonium hydroxide（１Ｍ ｓｏｌｎ．６６０μＬ，０．６ｍｍｏｌ）を乾燥ＤＭＦ中に溶解させた溶液を調製した。この溶液を６０℃の油浴中で約２４時間攪拌して反応させた。反応混合物を、放冷し、精製水中に投入し、酢酸エチルを用いて抽出した。この抽出液を、精製水および飽和食塩水を用いて洗浄し、硫酸マグネシウムを用いて乾燥させた後、減圧濃縮し、ペースト状の粗生成物を得た。粗生成物をシリカゲルカラムクロマトグラフィー（溶離液 酢酸エチル：ｎ－ヘキサン）に供し、化合物（１２）（１２０ｍｇ，６８％）を得た。併せて、未反応原料１９ｍｇも回収した。(xii) Synthesis of compound (12) Compound (12) was synthesized according to the following synthesis scheme.

In a screw cap vial (10 mL), compound (8) (150 mg, 0.55 mmol)), compound (9) (85 mg, 0.6 mmol), and tetrabutyl ammonium hydroxide (1M soln. 660 μL, 0.6 mmol). A solution was prepared in dry DMF. This solution was stirred in an oil bath at 60° C. for about 24 hours to react. The reaction mixture was allowed to cool, poured into purified water, and extracted using ethyl acetate. This extract was washed with purified water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a paste-like crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate: n-hexane) to obtain compound (12) (120 mg, 68%). In addition, 19 mg of unreacted raw material was also recovered.

¹ H-NMR (DMSO-d ₆ ) δ: 7.49 (1H, d, J = 15.6 Hz), 7.46-7.34 (4H, m, Ar-H), 7.02-6.96 (2H, m, Ar-H), 6.91-6.86 (1H, m, Ar-H), 6.44 (1H, br.d, J = 12.8 Hz), 4.73 (2H, dm, J _HF = 48 Hz), 4.26 (2H, dm, J _HF = 30.4 Hz), 3.28 (3H, s); ¹³ C-NMR (DMSO-d ₆ ) δ: 164.4, 158.9, 144.4, 139.1, 134.0, 133.6, 130.2, 129.3, 128.9, 119.9, 119.8, 113.8, 11 3.3, 82.8, 81.2, 67.3, 67.1, 37.0.:.

スクリューキャップバイアル（１０ｍＬ）に、化合物（８）（２００ｍｇ，０．７ｍｍｏｌ）と、tetrabutyl ammonium hydroxide（６２ｍｇ，１．１ｍｍｏｌ）と、乾燥ＤＭＦとを加え、乾燥ＤＭＦに化合物（８）とtetrabutyl ammonium hydroxideとを懸濁させた。この溶液を氷水冷下にて攪拌しながら、当該溶液に化合物（１０）（１６４ｍｇ，１．１ｍｍｏｌ）を加えた。当該溶液を同温度にて暫時攪拌した後、６０℃の油浴中にて約１６時間攪拌して反応させた。反応混合物を、放冷し、精製水中に投入し、酢酸エチルを用いて抽出した。この抽出液を、精製水および飽和食塩水を用いて洗浄し、硫酸マグネシウムを用いて乾燥させた後、減圧濃縮し、ペースト状の粗生成物を得た。粗生成物をシリカゲルカラムクロマトグラフィー（溶離液；酢酸エチル：ｎ－ヘキサン）に供し、化合物（１３）（１０４ｍｇ，４３％）を得た。併せて、未反応原料５９ｍｇも回収した。(xiii) Synthesis of Compound (13) Compound (13) was synthesized according to the following synthesis scheme.

Add compound (8) (200 mg, 0.7 mmol), tetrabutyl ammonium hydroxide (62 mg, 1.1 mmol), and dry DMF to a screw cap vial (10 mL), and add compound (8) and tetrabutyl ammonium hydroxide to dry DMF. were suspended. Compound (10) (164 mg, 1.1 mmol) was added to the solution while stirring the solution under ice-water cooling. The solution was stirred for a while at the same temperature, and then stirred in an oil bath at 60° C. for about 16 hours to react. The reaction mixture was allowed to cool, poured into purified water, and extracted using ethyl acetate. This extract was washed with purified water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a paste-like crude product. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate: n-hexane) to obtain compound (13) (104 mg, 43%). In addition, 59 mg of unreacted raw material was also recovered.

¹ H-NMR (DMSO-d ₆ ) δ: 7.52 (1H, d, J = 15.6 Hz), 7.46-7.33 (4H, m, Ar-H), 6.97-6.92 (2H, m, Ar-H), 6.88-6.85 (1H, m, Ar-H), 6.44 (1H, d, J = 15.6 Hz), 3.77 (3H, s), 3.28 (3H, s); ¹³ C-NMR (DMSO-d ₆ ) δ : 164.4, 160.0, 144.4, 139.1, 134.0, 133.6, 130.2, 129.3, 128.9, 119.9, 113.2, 112.7, 55.3, 37.0.:.

^１１Ｃ核の製造は、住友重機械工業社製サイクロトロンCYPRIS HM-12Sを使用した^１４Ｎ（ｐ，α）^１１Ｃの核合成反応（電流値５０μＡ、照射時間５１分）にて行った。［^１１Ｃ］ヨウ化メチルの合成は、専用の標識用合成装置（住友重機械工業株式会社製）を用いて行った。具体的に、^１１ＣＯ_２ガスを出発物質として用い、第１反応容器内にて、^１１ＣＯ_２、^１１ＣＨ_３ＯＨ、^１１ＣＨ_３Ｉの順にて材料を変換して、^１１ＣＨ_３Ｉを合成した。第２反応容器内にあらかじめフェノール前駆体（０．４ｍｇ，１．５μｍｏｌ）と、炭酸セシウム（Ｃｓ_２ＣＯ_３）（４．０ｍｇ，１２．３μｍｏｌ）と、ＤＭＦ（３００μＬ）とを入れ、次いで、第１反応容器内にて合成された^１１ＣＨ_３Ｉを第２反応容器内に、蒸留移送した。続いて、第２反応容器内の溶液を９０℃、４分間加熱して反応を行った。加熱反応後、第２反応容器を室温にまで冷却し、反応物をＨＰＬＣ（Ｈｉｇｈ ｐｅｒｆｏｒｍａｎｃｅ ｌｉｑｕｉｄ ｃｈｒｏｍａｔｏｇｒａｐｈｙ）に供した。ＨＰＬＣにおける分取条件は、カラム：COSMOSIL 5-C₁₈ AR-II 10×20 mm, 10×250 mm、展開溶媒：ＣＨ_３ＣＮ：Ｈ_２Ｏ＝６０：４０、流速：６．０ｍＬ／ｍｉｎ、保持時間：８．７ｍｉｎ、検出：ＵＶ２５４ｎｍ，ＲＩとした。分取した溶液をエバポレーターにて濃縮した後、当該溶液を希釈した後、メンブレンフィルターに通し、目的の化合物（１４）（４２４ＭＢｑ，６２ＧＢｑ／μｍｏｌ）をバイアル中に回収した。(II) Synthesis of labeled compound (i) Synthesis of compound (14) ([ ¹¹ C]SB366791) Compound (14) was synthesized according to the following synthesis scheme.

^{The 11} C nucleus was produced by ^{a 14} N(p,α) ¹¹ C nucleus synthesis reaction using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. (current value 50 μA, irradiation time 51 minutes). [ ¹¹ C] Methyl iodide was synthesized using a dedicated labeling synthesizer (manufactured by Sumitomo Heavy Industries, Ltd.). Specifically, using ¹¹ CO ₂ gas as a starting material, the materials are converted in the order of ¹¹ CO ₂ , ¹¹ CH ₃ OH, and ¹¹ CH ₃ I in the first reaction vessel to synthesize ¹¹ CH ₃ I. did. A phenol precursor (0.4 mg, 1.5 μmol), cesium carbonate (Cs ₂ CO ₃ ) (4.0 mg, 12.3 μmol), and DMF (300 μL) were placed in advance in a second reaction vessel, and then, ¹¹ CH ₃ I synthesized in the first reaction vessel was distilled and transferred into the second reaction vessel. Subsequently, the solution in the second reaction vessel was heated at 90° C. for 4 minutes to perform a reaction. After the heating reaction, the second reaction vessel was cooled to room temperature, and the reaction product was subjected to HPLC (High performance liquid chromatography). The preparative conditions for HPLC were: Column: COSMOSIL 5-C ₁₈ AR-II 10 x 20 mm, 10 x 250 mm, developing solvent: CH ₃ CN: H ₂ O = 60:40, flow rate: 6.0 mL/min, Retention time: 8.7 min, detection: UV 254 nm, RI. After concentrating the separated solution using an evaporator, the solution was diluted and passed through a membrane filter, and the target compound (14) (424 MBq, 62 GBq/μmol) was collected in a vial.

［^１８Ｆ］フッ素イオンは、住友重機械工業株式社製サイクロトロンCYPRIS HM-12Sを使用して、１２ＭｅＶの電子ビームを［^１８Ｏ］水（太陽日酸株式会社、約２ｍＬ）に照射し（電流値３５μＡ、照射時間４０分）、^１８Ｏ（ｐ，ｎ）^１８Ｆの核合成反応により、製造した。約４０ＧＢｑの［^１８Ｆ］フッ素イオンを含む［^１８Ｏ］水溶液を、ホットセル内に設置した標識用合成装置（住友重機械工業株式会社製）に移送し、陰イオン交換樹脂カートリッジ（Sep-Pak light QMA, Waters製）に［^１８Ｆ］フッ素イオンを吸着させた。このカートリッジに、クリプトフィックス２２２（Ｋ_２２２）（１４ｍｇ，３７μｍｏｌ）と炭酸カリウム（５．８ ｍｇ，４２μｍｏｌ）とを含むアセトニトリル水溶液（アセトニトリル：水＝７００μＬ：２００μＬ溶液，９００μＬ）を通し、［^１８Ｆ］ＫＦを溶出し、当該［^１８Ｆ］ＫＦを含む溶液を第１反応容器内に加えた。この溶液を、減圧下、Ｈｅガスを流しながら１２０℃にて加熱して、乾固させた。続いて、第１反応容器にアセトニトリル（１ｍＬ）を加え、残存する水とアセトニトリルとを共沸させて除去した。(ii) Synthesis of compound (15) ([ ¹⁸ F] (2E)-3-(4-Chlorophenyl)-N-[4-(2-fluoroethoxy)-phenyl]-2-propenamide) Compound (15) is It was synthesized according to the following synthesis scheme.

[ ¹⁸ F] fluorine ions were generated by irradiating [ ¹⁸ O] water (Taiyo Nippon Sanso Co., Ltd., approximately 2 mL) with a 12 MeV electron beam using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. (current It was produced by a nuclear synthesis reaction of ¹⁸ O(p,n) ¹⁸ F (value: 35 μA, irradiation time: 40 minutes). [ ¹⁸ O] aqueous solution containing about 40 GBq of [ ¹⁸ F] fluorine ions was transferred to a label synthesis device (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and an anion exchange resin cartridge (Sep-Pak light [ ¹⁸ F]fluorine ions were adsorbed onto QMA (manufactured by Waters). An acetonitrile aqueous solution (acetonitrile: water = 700 μL: 200 μL solution, 900 μL) containing Cryptofix 222 (K ₂₂₂ ) (14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through this cartridge, and [ ¹⁸ F ]KF was eluted, and the solution containing the [ ¹⁸ F]KF was added into the first reaction vessel. This solution was heated to dryness at 120° C. under reduced pressure while flowing He gas. Subsequently, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were azeotropically removed.

2-bromoethyl tosylate (10 μL, 36 μmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, heated at 150°C for 4 minutes, and the distillate was collected in the second reaction vessel. . Phenol precursor (1.7 mg, 6.2 μmol), tetrabutylammonium hydroxide (2.5 μL of 1M methanol solution, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further 2-[ ¹⁸ F]fluoroethyl bromide was distilled and transferred to a second reaction vessel, and the second reaction vessel was heated at 130° C. for 7 minutes. The second reaction vessel was cooled to room temperature and the reaction was subjected to HPLC. The HPLC preparative separation conditions were: Column: COSMOSIL 5C ₁₈ -AR-II 10 x 20 mm, 10 x 250 mm, developing solvent: CH ₃ CN: H ₂ O = 57:43, retention time: 10 minutes, flow rate: 6 mL. /min, detection: UV 254 nm, RI. The separated solution was concentrated using an evaporator, the solution was diluted, and then passed through a membrane filter to collect the target compound (15) (2.04 GBq, 317 GBq/μmol) in a vial.

［^１８Ｆ］フッ素イオンは、住友重機械工業株式社製サイクロトロンCYPRIS HM-12Sを使用して、１２ＭｅＶの電子ビームを［^１８Ｏ］水（太陽日酸株式会社、約２ｍＬ）に照射し（電流値３５μＡ、照射時間４０分）、^１８Ｏ（ｐ，ｎ）^１８Ｆの核合成反応により、製造した。約４０ＧＢｑの［^１８Ｆ］フッ素イオンを含む［^１８Ｏ］水溶液を、ホットセル内に設置した標識用合成装置（住友重機械工業株式会社製）に移送し、陰イオン交換樹脂カートリッジ（Sep-Pak light QMA, Waters製）に［^１８Ｆ］フッ素イオンを吸着させた。このカートリッジに、クリプトフィックス２２２（Ｋ_２２２）（１４ｍｇ，３７μｍｏｌ）と炭酸カリウム（５．８ｍｇ，４２μｍｏｌ）とを含むアセトニトリル水溶液（アセトニトリル：水＝７００μＬ：２００μＬ溶液，９００μＬ）を通し、［^１８Ｆ］ＫＦを溶出し、当該［^１８Ｆ］ＫＦを含む溶液を第１反応容器内に加えた。この溶液を、減圧下、Ｈｅガスを流しながら１２０℃にて加熱して、乾固させた。続いて、第１反応容器にアセトニトリル（１ｍＬ）を加え、残存する水とアセトニトリルとを共沸させて除去した。(iii) Synthesis of compound (16) ([ ¹⁸ F](2E)-3-(4-Chlorophenyl)-N-[4-(3-fluoropropoxy)- phenyl]-2-propenamide) Compound (16) is It was synthesized according to the following synthesis scheme.

[ ¹⁸ F] fluorine ions were generated by irradiating [ ¹⁸ O] water (Taiyo Nippon Sanso Co., Ltd., approximately 2 mL) with a 12 MeV electron beam using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. (current It was produced by a nuclear synthesis reaction of ¹⁸ O(p,n) ¹⁸ F (value: 35 μA, irradiation time: 40 minutes). [ ¹⁸ O] aqueous solution containing about 40 GBq of [ ¹⁸ F] fluorine ions was transferred to a label synthesis device (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and an anion exchange resin cartridge (Sep-Pak light [ ¹⁸ F]fluorine ions were adsorbed onto QMA (manufactured by Waters). An acetonitrile aqueous solution (acetonitrile: water = 700 μL: 200 μL solution, 900 μL) containing Kryptofix 222 (K ₂₂₂ ) (14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through this cartridge, and [ ¹⁸ F] KF was eluted, and the solution containing the [ ¹⁸ F]KF was added into the first reaction vessel. This solution was heated to dryness at 120° C. under reduced pressure while flowing He gas. Subsequently, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were azeotropically removed.

3-bromopropyl tosylate (10 μL, 34 mmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, heated at 150°C for 4 minutes, and the distillate was collected in the second reaction vessel. . Phenol precursor (2.0 mg, 7.3 μmol), tetrabutylammonium hydroxide (2.5 μL of 1M methanol solution, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further 3-[ ¹⁸ F]fluoropropyl bromide was distilled and transferred to a second reaction vessel, and the second reaction vessel was heated at 130° C. for 7 minutes. The second reaction vessel was cooled to room temperature and the reaction was subjected to HPLC. The HPLC preparative separation conditions were: Column: COSMOSIL 5C ₁₈ -AR-II 10 x 20 mm, 10 x 250 mm, developing solvent: CH ₃ CN: H ₂ O = 57:43, retention time: 13 minutes, flow rate: 6 mL. /min, detection: UV 254 nm, RI. The separated solution was concentrated using an evaporator, diluted, and then passed through a membrane filter to collect the target compound (16) (1.18 GBq, 247 GBq/μmol) in a vial.

^１１Ｃ核の製造は、住友重機械工業社製サイクロトロンCYPRIS HM-12Sを使用した^１４Ｎ（ｐ，α）^１１Ｃの核合成反応（電流値５０μＡ、照射時間５２分）にて行った。［^１１Ｃ］ヨウ化メチルの合成は、専用の標識用合成装置（住友重機械工業株式会社製）を用いて行った。具体的に、^１１ＣＯ_２ガスを出発物質として用い、第１反応容器にて^１１ＣＯ_２、^１１ＣＨ_３ＯＨ、^１１ＣＨ_３Ｉの順にて材料を変換して、^１１ＣＨ_３Ｉを合成した。第２反応容器内にあらかじめフェノール前駆体（０．８６ｍｇ，３．０μｍｏｌ）と、炭酸セシウム（Ｃｓ_２ＣＯ_３）（２．０ｍｇ，６．１μｍｏｌ）と、ＤＭＦ（３００μＬ）とを入れ、次いで、第１反応容器内で合成された^１１ＣＨ_３Ｉを第２反応容器内に、蒸留移送した。続いて、第２反応容器内の溶液を９０℃、４分間加熱して反応を行った。加熱反応後、第２反応容器を室温にまで冷却し、反応物をＨＰＬＣに供した。ＨＰＬＣにおける分取条件は、カラム：COSMOSIL 5-C₁₈ AR-II 10×20 mm, 10×250 mm、展開溶媒：ＣＨ_３ＣＮ：Ｈ_２Ｏ＝６０：４０、流速：６．０ｍＬ／ｍｉｎ、保持時間：１０．２ｍｉｎ、検出：ＵＶ２５４ｎｍ，ＲＩとした。分取した溶液をエバポレーターにて濃縮した後、当該溶液を希釈した後、メンブレンフィルターに通し、目的の化合物（１７）（４０６０ＭＢｑ，４８ＧＢｑ／μｍｏｌ）をバイアル中に回収した。(iv) Synthesis of compound (17) ([ ¹¹ C](2E)-3-(4-Chlorophenyl)-N-(4-methoxyphenyl)-N-methyl-2-propenamide) Compound (17) can be synthesized using the following method. It was synthesized according to the synthetic scheme.

^{The 11} C nucleus was produced by ^{a 14} N(p,α) ¹¹ C nucleus synthesis reaction using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. (current value 50 μA, irradiation time 52 minutes). [ ¹¹ C] Methyl iodide was synthesized using a dedicated labeling synthesizer (manufactured by Sumitomo Heavy Industries, Ltd.). Specifically, using ¹¹ CO ₂ gas as a starting material, ¹¹ CH 3 I was synthesized by converting the materials in the order of ¹¹ CO _{2 ,} ¹¹ CH ₃ OH, and ¹¹ CH ₃ I in the first reaction vessel. A phenol precursor (0.86 mg, 3.0 μmol), cesium carbonate (Cs ₂ CO ₃ ) (2.0 mg, 6.1 μmol), and DMF (300 μL) were placed in advance in a second reaction vessel, and then, ¹¹ CH ₃ I synthesized in the first reaction vessel was distilled and transferred into the second reaction vessel. Subsequently, the solution in the second reaction vessel was heated at 90° C. for 4 minutes to perform a reaction. After the heating reaction, the second reaction vessel was cooled to room temperature, and the reaction product was subjected to HPLC. The preparative conditions for HPLC were: Column: COSMOSIL 5-C ₁₈ AR-II 10 x 20 mm, 10 x 250 mm, developing solvent: CH ₃ CN: H ₂ O = 60:40, flow rate: 6.0 mL/min, Retention time: 10.2 min, detection: UV 254 nm, RI. After concentrating the separated solution using an evaporator, the solution was diluted and passed through a membrane filter, and the target compound (17) (4060 MBq, 48 GBq/μmol) was recovered in a vial.

［^１８Ｆ］フッ素イオンは、住友重機械工業株式社製サイクロトロンCYPRIS HM-12Sを使用して、１２ＭｅＶの電子ビームを［^１８Ｏ］水（太陽日酸株式会社、約２ｍＬ）に照射し（電流値３５μＡ、照射時間４０分）、^１８Ｏ（ｐ，ｎ）^１８Ｆの核合成反応により、製造した。約４０ＧＢｑの［^１８Ｆ］フッ素イオンを含む［^１８Ｏ］水溶液を、ホットセル内に設置した標識用合成装置（住友重機械工業株式会社製）に移送し、陰イオン交換樹脂カートリッジ（Sep-Pak light QMA, Waters製）に［^１８Ｆ］フッ素イオンを吸着させた。このカートリッジに、クリプトフィックス２２２（Ｋ_２２２）（１４ｍｇ，３７μｍｏｌ）と炭酸カリウム（５．８ｍｇ，４２μｍｏｌ）とを含むアセトニトリル水溶液（アセトニトリル：水＝７００μＬ：２００μＬ溶液，９００μＬ）を通し、［^１８Ｆ］ＫＦを溶出し、当該［^１８Ｆ］ＫＦを含む溶液を第１反応容器内に加えた。この溶液を、減圧下、Ｈｅガスを流しながら１２０℃にて加熱して、乾固させた。続いて、第１反応容器にアセトニトリル（１ｍＬ）を加え、残存する水とアセトニトリルとを共沸させて除去した。(v) Synthesis of compound (18) ([ ¹⁸ F](2E)-3-(4-Chlorophenyl)-N-[4-(3-fluoroethoxyphenyl) -N-methyl-2-propenamide) Compound (18) is , was synthesized according to the following synthetic scheme.

[ ¹⁸ F] fluorine ions were generated by irradiating [ ¹⁸ O] water (Taiyo Nippon Sanso Co., Ltd., approximately 2 mL) with a 12 MeV electron beam using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. (current It was produced by a nuclear synthesis reaction of ¹⁸ O(p,n) ¹⁸ F (value: 35 μA, irradiation time: 40 minutes). [ ¹⁸ O] aqueous solution containing about 40 GBq of [ ¹⁸ F] fluorine ions was transferred to a label synthesis device (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and an anion exchange resin cartridge (Sep-Pak light [ ¹⁸ F]fluorine ions were adsorbed onto QMA (manufactured by Waters). An acetonitrile aqueous solution (acetonitrile: water = 700 μL: 200 μL solution, 900 μL) containing Kryptofix 222 (K ₂₂₂ ) (14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through this cartridge, and [ ¹⁸ F] KF was eluted, and the solution containing the [ ¹⁸ F]KF was added into the first reaction vessel. This solution was heated to dryness at 120° C. under reduced pressure while flowing He gas. Subsequently, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were azeotropically removed.

2-bromoethyl tosylate (10 μL, 36 μmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, heated at 150°C for 4 minutes, and the distillate was collected in the second reaction vessel. . Phenol precursor (1.4 mg, 4.7 μmol), tetrabutylammonium hydroxide (2.5 μL of 1M methanol solution, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further 2-[ ¹⁸ F]fluoroethyl bromide was distilled and transferred to a second reaction vessel, and the second reaction vessel was heated at 130° C. for 7 minutes. The second reaction vessel was cooled to room temperature and the reaction was subjected to HPLC. The HPLC preparative separation conditions were: Column: COSMOSIL 5C ₁₈ -AR-II 10 x 20 mm, 10 x 250 mm, developing solvent: CH ₃ CN: H ₂ O = 57:43, retention time: 10 minutes, flow rate: 6 mL. /min, detection: UV 254 nm, RI. The separated solution was concentrated using an evaporator, the solution was diluted, and then passed through a membrane filter to collect the target compound (18) (2.81 GBq, 669 GBq/μmol) in a vial.

［^１８Ｆ］フッ素イオンは、住友重機械工業株式社製サイクロトロンCYPRIS HM-12Sを使用して、１２ＭｅＶの電子ビームを［^１８Ｏ］水（太陽日酸株式会社、約２ｍＬ）に照射し（電流値３５μＡ、照射時間４０分）、^１８Ｏ（ｐ，ｎ）^１８Ｆの核合成反応により、製造した。約４０ＧＢｑの［^１８Ｆ］フッ素イオンを含む［^１８Ｏ］水溶液を、ホットセル内に設置した標識用合成装置（住友重機械工業株式会社製）に移送し、陰イオン交換樹脂カートリッジ（Sep-Pak light QMA, Waters製）に［^１８Ｆ］フッ素イオンを吸着させた。このカートリッジに、クリプトフィックス２２２（Ｋ_２２２）（１４ｍｇ，３７μｍｏｌ）と炭酸カリウム（５．８ｍｇ，４２μｍｏｌ）とを含むアセトニトリル水溶液（アセトニトリル：水＝７００μＬ：２００μＬ溶液，９００μＬ）を通し、［^１８Ｆ］ＫＦを溶出し、当該［^１８Ｆ］ＫＦを含む溶液を第１反応容器内に加えた。この溶液を、減圧下、Ｈｅガスを流しながら１２０℃にて加熱して、乾固させた。続いて、第１反応容器にアセトニトリル（１ｍＬ）を加え、残存する水とアセトニトリルとを共沸させて除去した。(vi) Synthesis of compound (19) ([ ¹⁸ F](2E)-3-(4-Chlorophenyl)-N-[4-(3-fluoropropoxyphenyl)-N-methyl-2-propenamide) Compound (19) is , was synthesized according to the following synthetic scheme.

[ ¹⁸ F] fluorine ions were generated by irradiating [ ¹⁸ O] water (Taiyo Nippon Sanso Co., Ltd., approximately 2 mL) with a 12 MeV electron beam using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. (current It was produced by a nuclear synthesis reaction of ¹⁸ O(p,n) ¹⁸ F (value: 35 μA, irradiation time: 40 minutes). [ ¹⁸ O] aqueous solution containing about 40 GBq of [ ¹⁸ F] fluorine ions was transferred to a label synthesis device (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and an anion exchange resin cartridge (Sep-Pak light [ ¹⁸ F]fluorine ions were adsorbed onto QMA (manufactured by Waters). An acetonitrile aqueous solution (acetonitrile: water = 700 μL: 200 μL solution, 900 μL) containing Kryptofix 222 (K ₂₂₂ ) (14 mg, 37 μmol) and potassium carbonate (5.8 mg, 42 μmol) was passed through this cartridge, and [ ¹⁸ F] KF was eluted, and the solution containing the [ ¹⁸ F]KF was added into the first reaction vessel. This solution was heated to dryness at 120° C. under reduced pressure while flowing He gas. Subsequently, acetonitrile (1 mL) was added to the first reaction vessel, and the remaining water and acetonitrile were azeotropically removed.

3-bromopropyl tosylate (10 μL, 34 mmol) and 1,2-dichlorobenzene (400 μL) were added to the first reaction vessel, heated at 150°C for 4 minutes, and the distillate was collected in the second reaction vessel. . Phenol precursor (1.9 mg, 6.6 μmol), tetrabutylammonium hydroxide (2.5 μL of 1M methanol solution, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further 3-[ ¹⁸ F]fluoropropyl bromide was distilled and transferred to a second reaction vessel, and the second reaction vessel was heated at 130° C. for 7 minutes. The second reaction vessel was cooled to room temperature and the reaction was subjected to HPLC. The HPLC preparative separation conditions were: Column: COSMOSIL 5C ₁₈ -AR-II 10 x 20 mm, 10 x 250 mm, developing solvent: CH ₃ CN: H ₂ O = 57:43, retention time: 15 minutes, flow rate: 6 mL. /min, detection: UV 254 nm, RI. The separated solution was concentrated using an evaporator, the solution was diluted, and then passed through a membrane filter to collect the target compound (19) (1.93 GBq, 410 GBq/μmol) in a vial.

[Compound evaluation]
(PET measurement)
PET measurements were performed using 9-week-old male SD rats. The device used was (microPET F220, manufactured by Siemens).

脳内における各化合物の集積は、ＭＡＰ（Maximum a posterior）を用いて、３－２０分の積算画像により評価した。全身における各化合物の集積は、ＭＩＰ（Minimum intensity projection）を用いて、０－９０分の積算画像により評価した。In the PET measurement, after a 30-minute transmission scan, one of the test substances of compounds (14) to (19) was intravenously injected into the tail vein, and a 90-minute scan was performed. Table 1 shows the administration conditions for each compound.

The accumulation of each compound in the brain was evaluated using MAP (Maximum a posterior) by integrating images for 3 to 20 minutes. The accumulation of each compound in the whole body was evaluated using integrated images from 0 to 90 minutes using MIP (Minimum Intensity Projection).

(Test results)
1 to 6 respectively show control labeled compounds [ ¹¹ C]SB366791 (compound (14)), compound (15), compound (16), compound (17), compound (18) and compound (compound (14)) according to the prior art. 19) is an image showing the results of PET measurement using 19). More specifically, (A) in each figure is an image showing the result of PET measurement in the brain, and (B) in each figure is an image showing the result of PET measurement in the whole body.

As is clear from each figure (A), compounds (15) to (19) all showed improved accumulation in the brain compared to compound (14).

As is clear from each figure (B), the accumulation of compounds in the whole body was significantly improved, especially for compounds (17) to (19). This is thought to be due to the fact that by introducing a methyl group into R ¹ , an amide group that is easily decomposed in vivo was converted to a methylamide group, and metabolic stability was improved. In addition, accumulation in the liver, intestinal tract, and bladder (kidney) was observed for all compounds. This is thought to be due to the fact that in vivo, the localization changed to the intestinal tract and bladder (kidney) via the liver, and further reabsorption was observed.

Furthermore, compounds (15) to (19) were found to accumulate on the body surface and in areas sensitive to touch such as the neck, axilla, and thigh. Since these sites are considered to be sites where TRPV1 receptor is highly expressed, this is considered to be a result of accurate imaging of TRPV1 receptor.

Figures 7 and 8 show the results of calculating the SUV (standard uptake alue) in the brain and skin for compounds (14) to (19) and drawing time-radioactivity curves. SUV was calculated by normalizing by animal weight and administered radioactivity according to the following formula:
SUV=(tissue radioactivity (Bq)/tissue weight (g))/(administered radioactivity (Bq)/body weight (g)).

As is clear from FIG. 7, Compounds (15), (16), and (19) showed improved accumulation in the brain compared to the control Compound (14). As is clear from FIG. 8, compared to the control compound (14), compounds (16) to (19) showed improved accumulation on the body surface.

Thus, by using the present invention, it is possible not only to visualize the distribution of TRPV1 receptors, but also to quantify TRPV1 receptors with high accuracy. The present invention has enabled highly accurate imaging and quantification of TRPV1 receptors with improved accumulation in the brain and throughout the body such as the skin.

The present invention can be used for imaging TRPV1 receptors.

Claims (6)

A compound represented by the following formula (IA) or a salt thereof.
A compound represented by the following formula (IB) or a salt thereof.
An imaging agent for the TRPV1 receptor, comprising the compound according to claim 1 or 2 or a salt thereof as an active ingredient. The TRPV1 receptor imaging agent according to claim 3 , which is used for PET imaging or evaluation of pathological conditions that affect the expression level of the TRPV1 receptor. The TRPV1 receptor imaging agent according to claim 4 , wherein the pathological condition is pain, cancer, osteoarthritis, postherpetic neuralgia, pulmonary disease, inflammatory bowel disease, or irritable bowel syndrome. An imaging kit for TRPV1 receptor, comprising the compound according to claim 1 or 2 , or a salt thereof.

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