JPWO2020017557A1 - New compounds and their use - Google Patents

Abstract

Provided are compounds suitable for imaging TRPV1 receptors in the brain, and their utilization. A compound represented by the following formula (I), or a salt thereof, is used: [Chemical formula 1] [In formula (I), R1 is hydrogen or any organic group; R2 is carbon when R1 is hydrogen. It is an organic group of number 2 or more, and is any organic group if R1 is other than hydrogen; R1 and / or R2 are those having a radioactive isotope].

Description

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

In recent years, various techniques for obtaining in-vivo information have been studied, and in particular, "molecular imaging", which is a technique for investigating a target molecular behavior, has attracted attention. Molecular imaging is considered to be useful for early detection of various diseases and for short-term development of drugs that are effective and have few side effects.

Positron Emission Tomography (PET) is well known as molecular imaging for obtaining in-vivo information. PET is a technique for taking a tomographic image using γ-rays emitted when a positron collides with an electron. Specifically, when a molecule labeled with a radionuclide that emits positrons (positrons) (so-called PET molecular probe) is administered in vivo and the positrons emitted during the decay of the radionuclide collide with nearby electrons, 511 KeV. Two γ-rays with the energy of are emitted in the direction of 180 degrees. By detecting this γ-ray, the position of the PET molecular probe in the living body and the amount of the substance thereof can be quantitatively investigated. 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 there is no curative treatment. Although there are subjective indicators for assessing pain relief, there are no more accurate objective indicators and surrogate markers, and assessment of pain relief is limited to qualitative methods such as interviews, inspections and palpation. There is. Diagnostic imaging is one of the means for objectively evaluating the pain-relieving effect, and in recent years, attempts have been made to use PET in particular for evaluating the pain-relieving effect. The reason is that the resolution of PET is good, the agents that can be used for PET are various, and the function can be diagnosed by PET. If PET can be used to evaluate the pain-relieving effect, it will be possible to significantly improve medical techniques involved in the diagnosis and / or treatment of pain for which there is no curative treatment.

The TRPV1 (Transient Receptor Potential Vanilloid 1) receptor is known as a nociceptor, and one of its functions is a function as a pain receptor. Therefore, TRPV1 receptor antagonists are expected to lead to the development of analgesics, and pharmaceutical companies are developing candidate compounds for TRPV1 receptor antagonists. In addition, application of a radioisotope-labeled TRPV1 receptor antagonist as a PET probe has also been proposed. As PET probes utilizing TRPV1 receptor antagonists have been reported so far, for example, Non-Patent Document 1, ¹¹ C-labeled PET probe SB-366 791 is a TRPV1 receptor antagonist ^([11 C] SB-366791 ) Is disclosed.

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

When the TRPV1 receptor in the brain was imaged using the above-mentioned [ ¹¹ C] SB-366791, the TRPV1 receptor known to be present in the brain could not be effectively imaged. rice field.

One aspect of the present invention is to provide a compound suitable for imaging TRPV1 receptors in the brain and utilization 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］。The compound according to one aspect of the present invention or a salt thereof is characterized in that it is a compound represented by the following formula (I) or a salt thereof in order to solve the above-mentioned problems:

[In formula (I),
R ¹ is hydrogen or any organic group and
R ^2, if R ¹ is hydrogen is the number 2 or more organic groups carbon, if R ¹ is other than hydrogen and any organic radical,
R ¹ and / or R ² have radioactive isotopes].

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 in order to solve the above-mentioned problems.

［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］。The 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 order to solve the above-mentioned problems:

[In formula (I),
R ¹ is hydrogen or any organic group and
R ^2, if R ¹ is hydrogen is the number 2 or more organic groups carbon, if R ¹ is other than hydrogen and any organic radical,
R ¹ and / or R ² have radioactive isotopes].

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

It is an image of the brain (A) and the whole body (B) by PET measurement when the compound (14) according to the prior art is used. It is an image of the brain (A) and the whole body (B) by PET measurement when the compound (15) according to one aspect of the present invention is used. It is an image of the brain (A) and the whole body (B) by PET measurement when the compound (16) according to one aspect of the present invention is used. It is an image of the brain (A) and the whole body (B) by PET measurement when the compound (17) according to one aspect of the present invention is used. It is an image of the brain (A) and the whole body (B) by PET measurement when the compound (18) according to one aspect of the present invention is used. It is an image of the brain (A) and the whole body (B) by PET measurement when the compound (19) according to one aspect of the present invention is used. It is a graph which shows the change of SUV with the passage of time by the PET measurement in the brain when the compound which concerns on one aspect of this invention and the compound which concerns on a prior art is used. It is a graph which shows the change of SUV with the passage of time in the PET measurement of the body surface in the case of using the compound which concerns on one aspect of this invention, and the compound which concerns on a 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 the configurations described below, and various modifications can be made within the scope of the claims, and the technical means disclosed in different embodiments and examples can be used. Embodiments and examples obtained in appropriate combinations are also included in the technical scope of the present invention. In addition, all of the documents described herein are incorporated herein by reference.

［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 according to the present embodiment or a salt thereof is a compound represented by the following formula (I) or a salt thereof:

[In formula (I),
R ¹ is hydrogen or any organic group and
R ^2, if R ¹ is hydrogen is the number 2 or more organic groups carbon, if R ¹ is other than hydrogen and any organic radical,
R ¹ and / or R ² have radioactive isotopes].

The compound represented by the formula (I), or a salt thereof, has a partial structure within SB-366791 and has a partial structure necessary for binding SB-366791 to the TRPV1 receptor. Therefore, the compound exhibits a selective affinity for the TRPV1 receptor. In addition, the compound has a radioisotope (for example, a short-lived radioisotope) at a site stable to metabolism. Therefore, the compound can not only visualize the distribution of TRPV1 receptor, but also accurately quantify the TRPV1 receptor. In addition, the compound has high metabolic stability in vivo. Therefore, the compound is suitable for administration to a living body. In addition, the compound easily accumulates in the brain. Therefore, the compound is suitable for imaging the central nervous system, including the brain.

^{Here, R 1} in the formula (I) is hydrogen or an arbitrary organic group, and R ² in the formula (I) is an organic group having 2 or more carbon atoms when R ^{1 is hydrogen, and R When 1} is other than hydrogen, it is an arbitrary organic group. 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 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. , Alkenyl group, Fluoroalkenyl group, acetyl group, carboxyalkyl group, and alkylamide group.

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

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

In R ¹ and / or R ² , any atom can be a radioisotope. The radioisotope is not particularly limited, but a short-lived radioisotope is preferable. Examples of short-lived radioisotopes include carbon radioisotopes and fluorine radioisotopes, with ¹¹ C and ¹⁸ F being preferred. As the long-lived radioisotope, ¹⁴ C is preferable.

^{Since 11} C (half-life: 20.4 minutes) has a short half-life, exposure to radiation when administered to patients can be minimized. ^{Since 18} F (half-life: 109.8 minutes) has ^{a longer half-life than 11} C, the patient's exposure to radiation is slightly increased, but the time from the synthesis of the compound having ^{18 F to its use.} You can get a margin. Since the compound according to this embodiment can not always be prepared for use in the place where it is used, the compound having ¹⁸ F is used in the place where the compound is used after being synthesized in a dedicated facility for synthesis or the like. It is excellent in that it can be ordered and used in.

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 a salt thereof according to the first embodiment of the present invention as an active ingredient. The TRPV1 receptor imaging agent according to this embodiment may be used for visualizing the brain (for example, visualizing a specific region of the brain) regardless of the TRPV1 receptor. In this case, the TRPV1 receptor imaging agent according to this embodiment can be a brain imaging agent.

The imaging agent according to the present embodiment can be used for evaluating a pathological condition that affects the expression level of TRPV1 receptor (in other words, has a correlation with the expression level of TRPV1 receptor). The pathological conditions include, for example, pain, cancer, osteoarthritis, postherpetic neuralgia, lung disease (eg, cough attack and bronchial asthma), inflammatory bowel disease, and irritable bowel syndrome. Not limited to these, all pathological conditions that are painful can be mentioned. The cancers include all solid and hematological cancers. Examples of such cancers include particularly severe painful cancers that occur in bone, such as osteosarcoma and cancers that have metastasized to bone.

The imaging agent according to this embodiment can quantitatively image the TRPV1 receptor. Therefore, the imaging agent according to the present embodiment can quantitatively diagnose the severity of the pathological condition.

PET is preferable as the method for evaluating the pathological condition, but the method is not limited to this, and for example, SPECT (Single photon emission computed tomography) may be used. When the compound or its salt used is a ¹³ C-labeled substance, the amount of metabolites analyzed by LC-MS (Liquid chromatography-mass spectrometry) shows that the compound or its salt used is a ¹⁴ C-labeled substance. If this is the 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 the imaging agent is used in PET, the dose of the imaging agent to the subject may be very small, so that the pharmacological action (pain relief, sensation of burns, etc.) due to the inhibition of the TRPV1 receptor does not appear in the subject. , Safe. Further, with the imaging agent according to the present 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 the present 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 of either a solution or a suspension, or as a solid formulation suitable for dissolving or suspending in a liquid (eg, 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 for screening pharmaceutical products targeting the TRPV1 receptor. As the screening method, for example, a method of visualizing the TRPV1 receptor with the imaging agent and screening a drug candidate substance whose expression level of the TRPV1 receptor changes with administration can be considered as a drug. Examples of the drug candidate substance and the drug include, but are not limited to, small molecule 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 the present embodiment is not particularly limited, and may be, for example, 0.001% by weight to 100% by weight, 0.01% by weight to 100% by weight, based on the imaging agent. %, 0.1% by weight to 100% by weight, 0.1% by weight to 95% by weight, 0.1% by weight to 90% by weight. It may be 0.1% by weight to 80% by weight, 0.1% by weight to 70% by weight, 0.1% by weight to 60% by weight, 0.1% by weight. It may be from% to 50% by weight, from 0.1% to 40% by weight, from 0.1% to 30% by weight, from 0.1% to 20% by weight. It may be%, and it may be 0.1% by weight to 10% by weight.

The imaging agent of the present embodiment may contain an ingredient (pharmaceutically acceptable carrier) other than the active ingredient. Examples of the component other than the active ingredient include excipients, lubricants, binders and disintegrants when the imaging agent of the present embodiment is provided as a solid preparation, and imaging of the embodiment. When the agent is provided as a liquid preparation, it may include a solvent, a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent and a pain-relieving agent. In addition, as ingredients other than the active ingredient, preservatives, antioxidants and stabilizers can also be mentioned.

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

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

Examples of the above-mentioned "binder" include, but are not limited to, pregelatinized starch, methyl cellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.

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

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

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 (for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate) and highly hydrophilic. The molecules (eg, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose) are not limited thereto.

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

Examples of the "buffering agent" include, but are not limited to, phosphates, acetates, carbonates and citrates.

The above-mentioned "painless agent" is not limited to, for example, benzyl alcohol.

Examples of the above-mentioned "preservative" 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" may be any one usually used in the pharmaceutical field and is not particularly limited.

The amount of the component other than the active component in the imaging agent of the present embodiment is not particularly limited, and may be, for example, 0% by weight to 99.999% by weight, or 0% by weight to 99% by weight, based on the imaging agent. It may be .99% by weight, 0% by weight to 99.9% by weight, 5% by weight to 99.9% by weight, or 10% by weight to 99.9% by weight. It may be 20% by weight to 99.9% by weight, 30% by weight to 99.9% by weight, 40% by weight to 99.9% by weight, and may be. It may be 50% by weight to 99.9% by weight, 60% by weight to 99.9% by weight, 70% by weight to 99.9% by weight, 80% by weight to 99% by weight. It may be 9.9% by weight, or 90% by weight to 99.9% by weight.

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

By 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 the subject.

Since the compounds and salts thereof provided in the kit of this embodiment have been described in [Embodiment 1], the description thereof will be omitted here.

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

Examples of the above composition include excipients, lubricants, binders and disintegrants. In this case, the imaging agent of TRPV1 receptor, which is a solid preparation, can be easily prepared by using the imaging kit of the present embodiment. In addition, examples of the constitution include a solvent, a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, and a pain-relieving agent. In this case, the imaging agent of TRPV1 receptor, which is a liquid preparation, can be easily prepared by using the imaging kit of the present embodiment. In addition, examples of the constitution include preservatives, antioxidants and stabilizers. In this case, the imaging kit of the present embodiment can be used to easily prepare an imaging agent for TRPV1 receptor that can be stored for a long period of time.

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

［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〕
The compound according to one aspect of the present invention or a salt thereof is characterized in that it is a compound represented by the following formula (I) or a salt thereof in order to solve the above-mentioned problems:

[In formula (I),
R ¹ is hydrogen or any organic group and
R ^2, if R ¹ is hydrogen is the number 2 or more organic groups carbon, if R ¹ is other than hydrogen and any organic radical,
R ¹ and / or R ² have radioactive isotopes].

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 in order to solve the above-mentioned problems.

The TRPV1 receptor imaging agent according to one aspect of the present invention is preferably used for PET imaging or evaluation of a pathological condition that affects the expression level of 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, lung 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］。The 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 order to solve the above-mentioned problems:

[In formula (I),
R ¹ is hydrogen or any organic group and
R ^2, if R ¹ is hydrogen is the number 2 or more organic groups carbon, if R ¹ is other than hydrogen and any organic radical,
R ¹ and / or R ² have radioactive isotopes].

Hereinafter, the present invention will be described 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。[Compound synthesis]
(I) Synthesis of Labeled Precursor Compound (4) ((2E) -3- (4-Chlorophenyl) -N- (4-methoxyphenyl) -2-propenamide) (SB366791), Compound (5) ((2E)- 3- (4-Chlorophenyl) -N- [4- (2-fluoroethoxy) -phenyl] -2-propenamide), compound (6) ((2E) -3- (4-Chlorophenyl) -N- [4- ( 3-fluoropropoxy) -phenyl] -2-propenamide) was synthesized according to the following synthesis 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) (( 2E) -3- (4-Chlorophenyl) -N- (4-methoxyphenyl) -N-methyl-2-propenamide), 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 synthesis scheme.

The synthetic method for each compound will be specifically described 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 dried eggplant flask (200 mL), and anhydrous DMF (70 mL) was further 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, the eggplant flask is taken out from the ice water bath, and HOBt (2.5 g, 19 mmol) and DMAP (2.3 g, 18.7 mmol) are added to the eggplant flask. Was added. After the addition, the solution in the eggplant flask was stirred for about 20 minutes, then 3-hydroxyaniline (2.5 g, 19 mmol) was added to the eggplant flask, and the solution in the eggplant flask was stirred overnight at room temperature to react. .. The reaction mixture was added to purified water (200 mL) and extracted with ethyl acetate. The extract was washed with purified water and saturated brine, the extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethyl acetate: n-hexane to give 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 = 8.4 Hz, 1.6 Hz), 6.88 (1H, d, J = 8.4 Hz), 6.47 (1H, dt, J = 8.0 Hz, 1.6 Hz), ¹³ C-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.

Was stirred under ice water cooling, 2-Fluoroethanol (1.0g, 15mmol ) in CHCl ₃ (10 mL) solution containing _was added Et 3 N (2.38mL, 17mmol) . The solution was stirred at the same temperature for a while, and then p-TsCl (p-Toluenesulfonyl chloride) (3.3 g, 17 mmol) was added to the stirred solution over about 50 minutes. After completion of the addition, the solution was stirred at room temperature overnight for reaction. The reaction mixture is concentrated under reduced pressure, the residue is redissolved in ethyl acetate (20 mL), the lysate is washed with purified water and saturated brine, then dried over anhydrous silica ₄ and then the lysate. Was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; AcOEt: n-hexane) to obtain an oily compound (2) (2.1 g, 63%).

^{1 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.

Was stirred under ice water cooling, 3-fluoropropanol (1.6g, 20mmol ) in methylene chloride (13 mL) solution containing _was added Et 3 N (3.17mL, 23mmol) . The solution was stirred at the same temperature for a while, and then p-TsCl (4.2 g, 22 mmol) was added to the stirred solution over about 50 minutes. After completion of the addition, the solution was stirred at room temperature overnight for reaction. The reaction mixture was concentrated under reduced pressure, the residue was redissolved in ethyl acetate (50 mL), the lysate was washed with purified water and saturated brine, then dried over anhydrous sulfonyl ₄ , and then this lysate. Was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane) to obtain an oily compound (3) (2.1 g, 63%).

^{1 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.

A dry screw-cap vials (10 mL), was added with the compound (1) (500mg, 1.8mmol) , K 2 CO 3 (127mg, 0.9mmol) and, of anhydrous DMF (6.3 mL). The suspension at room temperature, after stirring for about 20 _{minutes, CH 3 I (125μL, 2mmol} ) in this suspension was added, put the screw cap vial in an oil bath at 80 ° C., 15.5 h stirring the reaction I let you. After allowing the reaction mixture 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 desired 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 placed in a screw cap vial (10 mL) to form a suspension. After stirring the turbid solution at room temperature for about 20 minutes, an anhydrous DMF (1 mL) solution containing compound (2) (349 mg, 1.6 mmol) is added to the suspension, and the suspension is placed in an oil bath at 80 ° C. The mixture was stirred for 26 hours and reacted. After allowing the reaction mixture to cool, 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 desired compound (5) (214 mg, 45%).

^{1 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.

Screw cap vial (10 mL), was added with the compound (1) (400mg, 1.5mmol) , K 2 CO 3 (111mg, 0.8mmol) and, of anhydrous DMF (5 mL). After stirring this suspension at room temperature for about 20 minutes, an anhydrous DMF (1 mL) solution containing compound (3) (371 mg, 1.6 mmol) is added to the suspension, and the suspension is heated to 80 ° C. The reaction was carried out by stirring for 24 hours in the oil bath of. Note the residual raw material was observed, 3-fluoropropyl tosylate (123mg, 0.5mmol), _and add the _{K 2 CO 3 (37mg, 0.27mmol} ), and the reaction was continued (20 hours). After allowing the reaction mixture 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 desired compound (6) (145 mg, 30%).

^{1 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 _{= 6 Hz), 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 _{) in 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) was added, and the mixture was stirred and reacted at room temperature for 24 hours. Since residual raw material was observed, the mixture was further stirred for 24 hours for reaction. The reaction solution was _{diluted with CH 2} Cl ₂ (75 mL), and the reaction solution was prepared with NaOH aq. The crude product (2.3 g) was obtained by washing with (1 mol / L), purified water and saturated brine, _{drying over anhydrous sulfonyl 4, and concentrating under reduced pressure.} The crude product was recrystallized from ethyl acetate and n-hexane to give compound (7) (1.8 g, 68%).

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, br. S) 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, 134.2, 133.7, 129.3, 129.0, 123.1, 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。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 crushed product) in a two-diameter flask equipped with a three-way cock with a balloon, a septum rubber, and a stir bar filled with argon. Was added, and the anhydrous DMF (6 mL) was further added with a syringe while the two-diameter flask was immersed in an ice-water bath. 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 an oil bath at 60 ° C. and reacted for 15.5 hours. The reaction mixture was allowed to cool to room temperature, the reaction mixture was put into purified water, and the mixture was extracted with ethyl acetate. The extract was washed with purified water and saturated brine, and then dried with anhydrous water ₄ . The paste-like crude product (414 mg) obtained by concentrating and drying this extract was subjected to silica gel column chromatography (eluent CHCl ₃ : CH ₃ OH = 100: 1 → 50: 1) and subjected to compound (eluent CHCl 3: CH 3 OH = 100: 1 → 50: 1). 8) was obtained in 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.

Was stirred at under ice water cooling, 2-fluoroethanol (1.0g, 15mmol ) in _CH 2 _Cl 2 (20mL) solution containing _was added Et 3 N (2.6mL, 18.7mmol) . The solution was stirred at the same temperature for a while, and then a solution of methylene chloride (10 mL) containing methanesulfonyl chloride (2.1 g, 19 mmol) was added dropwise to the solution over about 5 minutes. After the dropping, the solution was stirred at room temperature overnight to react. After completion of the reaction, the reaction mixture, dilute hydrochloric acid (0.1 mol / L), purified water, and was washed with saturated brine, dried over anhydrous MgSO _4. This solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; AcOEt: n-hexane) to obtain a light brown oily compound (9) (1.8 g, 80%). The compound (9) obtained by this method could be used in the next step (O-alkylation reaction) without further purification.

^{1 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.

Was stirred at under ice water cooling, 3-Fluoropropanol (1.2g, 15mmol ) in _CH 2 _Cl 2 (20mL) solution containing _was added Et 3 N (1.9mL, 19mmol) . The solution was stirred at the same temperature for a while, 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 at room temperature overnight for 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, dried over anhydrous silica gel ₄ , and then this extract. Was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent AcOEt / n-hexane) to obtain an oily compound (10) (2.0 g, 83%) in a quantitative yield.

^{1 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 dried DMF are added to a screw cap vial (10 mL), and compound (8) and KOH are suspended in the dried DMF. Made muddy. Methyl iodide (156 mg, 1.1 mmol) was added to the solution while stirring the solution under ice-water cooling. The solution was stirred at the same temperature for a while, and then stirred and reacted in an oil bath at 60 ° C. for 16 hours. The reaction mixture was allowed to cool, put 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 give a crude paste 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.

Compound (8) (150 mg, 0.55 mmol)), compound (9) (85 mg, 0.6 mmol), and tetrabutyl ammonium hydroxide (1 M solution. 660 μL, 0.6 mmol) in a screw cap vial (10 mL). Was dissolved in dry DMF to prepare a solution. The solution was reacted by stirring in an oil bath at 60 ° C. for about 24 hours. The reaction mixture was allowed to cool, put 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 give a crude paste product. The crude product was subjected to silica gel column chromatography (eluent ethyl acetate: n-hexane) to give compound (12) (120 mg, 68%). At the same time, 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, 113.3, 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。Synthesis of Compound (13) Compound (13) was synthesized according to the following synthesis scheme.

Compound (8) (200 mg, 0.7 mmol), tetrabutyl ammonium hydroxide (62 mg, 1.1 mmol), and dried DMF are added to a screw cap vial (10 mL), and compound (8) and tetrabutyl ammonium hydroxide are added to the dried DMF. And was 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 at the same temperature for a while, and then stirred and reacted in an oil bath at 60 ° C. for about 16 hours. The reaction mixture was allowed to cool, put 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 give a crude paste product. The crude product was subjected to silica gel column chromatography (eluent; ethyl acetate: n-hexane) to give compound (13) (104 mg, 43%). At the same time, 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) Compound ⁽¹⁴⁾ ([11 C] SB366791) solution of compound (14) was synthesized according to the following synthesis scheme.

^{The 11 C nucleus was produced by a 14} N (p, α) ¹¹ C nuclear synthesis reaction (current value 50 μA, irradiation time 51 minutes) using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. [ 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. 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 the 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 carry out the 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 in HPLC are: column: COSMOSIL 5-C ₁₈ AR-II 10 × 20 mm, 10 × 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 with an evaporator, the solution was diluted and then passed through a membrane filter to recover the target compound (14) (424MBq, 62GBq / 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（５．８ 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) It was synthesized according to the following synthesis scheme.

[ ^{18 F] Fluorine ion irradiates [18} O] water (Solar Nissin Co., Ltd., about 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). ^{An aqueous solution of [18} O] containing about 40 GBq of [ ¹⁸ F] fluoride ion was transferred to a labeling synthesizer (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and an anion exchange resin cartridge (Sep-Pak light) was transferred. ^[18 F] Fluoride ion was adsorbed on QMA (manufactured by Waters). This cartridge, Kryptofix _{222 (K 222) (14mg,} 37μmol) and aqueous acetonitrile containing potassium carbonate (5.8 mg, 42μmol) (acetonitrile: water = 700 [mu] L: 200 [mu] L solution, 900 [mu] L) ^{through, [18} F ] KF was eluted, and the ^{solution containing the [18} F] KF was added into the first reaction vessel. This solution was heated at 120 ° C. under reduced pressure while flowing He gas to dryness. 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 recovered in the second reaction vessel. .. Phenol precursor (1.7 mg, 6.2 μmol), tetrabutylammonium hydroxide (1 M methanol solution 2.5 μL, 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 preparative conditions in HPLC are: column: COSMOSIL 5C ₁₈ -AR-II 10 × 20 mm, 10 × 250 mm, developing solvent: CH ₃ CN: H ₂ O = 57: 43, holding time: 10 minutes, flow rate: 6 mL. / Min, detection: UV 254 nm, RI. The separated solution was concentrated with an evaporator, the solution was diluted, and then passed through a membrane filter to recover 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) It was synthesized according to the following synthesis scheme.

[ ^{18 F] Fluorine ion irradiates [18} O] water (Solar Nissin Co., Ltd., about 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). ^{An aqueous solution of [18} O] containing about 40 GBq of [ ¹⁸ F] fluoride ion was transferred to a labeling synthesizer (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and an anion exchange resin cartridge (Sep-Pak light) was transferred. ^[18 F] Fluoride ion was adsorbed on QMA (manufactured by Waters). This cartridge, Kryptofix _{222 (K 222) (14mg,} 37μmol) and potassium carbonate (5.8mg, 42μmol) aqueous acetonitrile containing a (acetonitrile: water = 700 [mu] L: 200 [mu] L solution, 900 [mu] L) ^{through, [18} F] KF was eluted and a ^{solution containing the [18} F] KF was added into the first reaction vessel. This solution was heated at 120 ° C. under reduced pressure while flowing He gas to dryness. 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 recovered in the second reaction vessel. .. Phenol precursor (2.0 mg, 7.3 μmol), tetrabutylammonium hydroxide (1 M methanol solution 2.5 μL, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further 3-[ ¹⁸ F] Fluorpropyl 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 preparative conditions in HPLC are: column: COSMOSIL 5C ₁₈ -AR-II 10 × 20 mm, 10 × 250 mm, developing solvent: CH ₃ CN: H ₂ O = 57: 43, holding time: 13 minutes, flow rate: 6 mL. / Min, detection: UV 254 nm, RI. The separated solution was concentrated with an evaporator, the solution was diluted, and then passed through a membrane filter to recover 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) is as follows. It was synthesized according to the synthesis scheme.

^{The 11 C nucleus was produced by a 14} N (p, α) ¹¹ C nuclear synthesis reaction (current value 50 μA, irradiation time 52 minutes) using a cyclotron CYPRIS HM-12S manufactured by Sumitomo Heavy Industries, Ltd. [ ¹¹ C] Methyl iodide was synthesized using a dedicated labeling synthesizer (manufactured by Sumitomo Heavy Industries, Ltd.). Specifically, ¹¹ CO ₂ gas was used as a starting material, and the materials were 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. 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 the 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 carry out the 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 in HPLC are: column: COSMOSIL 5-C ₁₈ AR-II 10 × 20 mm, 10 × 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 with an evaporator, the solution was diluted and then passed through a membrane filter to recover the target compound (17) (4060 MBq, 48 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。(V) Synthesis of compound (18) ([ ¹⁸ F] (2E) -3- (4-Chlorophenyl) -N- [4- (3-fluoroethoxyphenyl) -N-methyl-2-propenamide) Compound (18) , Was synthesized according to the following synthesis scheme.

[ ^{18 F] Fluorine ion irradiates [18} O] water (Solar Nissin Co., Ltd., about 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). ^{An aqueous solution of [18} O] containing about 40 GBq of [ ¹⁸ F] fluoride ion was transferred to a labeling synthesizer (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and an anion exchange resin cartridge (Sep-Pak light) was transferred. ^[18 F] Fluoride ion was adsorbed on QMA (manufactured by Waters). This cartridge, Kryptofix _{222 (K 222) (14mg,} 37μmol) and potassium carbonate (5.8mg, 42μmol) aqueous acetonitrile containing a (acetonitrile: water = 700 [mu] L: 200 [mu] L solution, 900 [mu] L) ^{through, [18} F] KF was eluted and a ^{solution containing the [18} F] KF was added into the first reaction vessel. This solution was heated at 120 ° C. under reduced pressure while flowing He gas to dryness. 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 recovered in the second reaction vessel. .. Phenol precursor (1.4 mg, 4.7 μmol), tetrabutylammonium hydroxide (1 M methanol solution 2.5 μL, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and 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 preparative conditions in HPLC are: column: COSMOSIL 5C ₁₈ -AR-II 10 × 20 mm, 10 × 250 mm, developing solvent: CH ₃ CN: H ₂ O = 57: 43, holding time: 10 minutes, flow rate: 6 mL. / Min, detection: UV 254 nm, RI. The separated solution was concentrated with an evaporator, the solution was diluted, and then passed through a membrane filter to recover 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) , Was synthesized according to the following synthesis scheme.

[ ^{18 F] Fluorine ion irradiates [18} O] water (Solar Nissin Co., Ltd., about 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). ^{An aqueous solution of [18} O] containing about 40 GBq of [ ¹⁸ F] fluoride ion was transferred to a labeling synthesizer (manufactured by Sumitomo Heavy Industries, Ltd.) installed in a hot cell, and an anion exchange resin cartridge (Sep-Pak light) was transferred. ^[18 F] Fluoride ion was adsorbed on QMA (manufactured by Waters). This cartridge, Kryptofix _{222 (K 222) (14mg,} 37μmol) and potassium carbonate (5.8mg, 42μmol) aqueous acetonitrile containing a (acetonitrile: water = 700 [mu] L: 200 [mu] L solution, 900 [mu] L) ^{through, [18} F] KF was eluted and a ^{solution containing the [18} F] KF was added into the first reaction vessel. This solution was heated at 120 ° C. under reduced pressure while flowing He gas to dryness. 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 recovered in the second reaction vessel. .. Phenol precursor (1.9 mg, 6.6 μmol), tetrabutylammonium hydroxide (1 M methanol solution 2.5 μL, 2.5 μmol), and DMSO (500 μL) were added to the second reaction vessel, and further 3-[ ¹⁸ F] Fluorpropyl 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 preparative conditions in HPLC are: column: COSMOSIL 5C ₁₈ -AR-II 10 × 20 mm, 10 × 250 mm, developing solvent: CH ₃ CN: H ₂ O = 57: 43, holding time: 15 minutes, flow rate: 6 mL. / Min, detection: UV 254 nm, RI. The separated solution was concentrated with an evaporator, the solution was diluted, and then passed through a membrane filter to recover the target compound (19) (1.93 GBq, 410 GBq / μmol) in a vial.

[Evaluation of compounds]
(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 transmission scan for 30 minutes, a test substance of any one of compounds (14) to (19) was injected into the tail vein by intravenous injection, and the scan was performed for 90 minutes. Table 1 shows the administration conditions of each compound.

Accumulation of each compound in the brain was evaluated by a 3-20 minute integrated image using MAP (Maximum a posterior). Accumulation of each compound in the whole body was evaluated by a 0-90 minute integrated image using MIP (Minimum intensity projection).

(Test results)
Figures 1-6, respectively, the control labeled compound according to the prior art ^[11 C] SB366791 (Compound (14)), compound (15), compound (16), compound (17), compound (18) and compound ( It is an image which shows the result 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 (A) in each figure, all of the compounds (15) to (19) had improved accumulation in the brain as compared with the compound (14).

As is clear from (B) of each figure, the accumulation of the compound in the whole body was remarkably improved especially in the compounds (17) to (19). It is considered that the cause is that by introducing a methyl group into R ¹ , the amide group that is easily decomposed in the living body is converted into a methyl amide group, and the metabolic stability is improved. In addition, accumulation in the liver, intestinal tract, and bladder (kidney) was observed in all the compounds. It is considered that this was observed that the localization changed to the intestinal tract and the bladder (kidney) via the liver in the living body, and further reabsorption was observed.

In addition, compounds (15) to (19) were found to accumulate on the body surface and in tactilely sensitive sites such as the neck, axilla, and thigh. Since these sites are considered to be highly expressed sites of TRPV1 receptor, it is considered that the result was that TRPV1 receptor could be accurately imaged.

7 and 8 show the results of calculating the SUV (Standard uptake alue) in the brain and the skin of the compounds (14) to (19) and drawing a time radioactivity curve. SUVs were calculated by normalizing by animal body weight and administered radioactivity according to the formula below:
SUV = (tissue radioactivity (Bq) / tissue weight (g)) / (administered radioactivity (Bq) / body weight (g)).

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

As described above, according to the present invention, not only the distribution of TRPV1 receptor can be visualized, but also TRPV1 receptor can be quantified with high accuracy. INDUSTRIAL APPLICABILITY According to the present invention, highly accurate imaging and quantification of TRPV1 receptor with improved accumulation in the brain and whole body such as skin has become possible.

The present invention can be used for imaging TRPV1 receptors.

Claims (5)

A compound represented by the following formula (I) or a salt thereof;

[In formula (I),
R ¹ is hydrogen or any organic group and
R ^2, if R ¹ is hydrogen is the number 2 or more organic groups carbon, if R ¹ is other than hydrogen and any organic radical,
R ¹ and / or R ² have radioactive isotopes]. An imaging agent for a TRPV1 receptor, which comprises the compound according to claim 1 or a salt thereof as an active ingredient. The TRPV1 receptor imaging agent according to claim 2, which is used for PET imaging or evaluation of a pathological condition that affects the expression level of TRPV1 receptor. The TRPV1 receptor imaging agent according to claim 3, wherein the pathological condition is pain, cancer, osteoarthritis, postherpetic neuralgia, lung disease, inflammatory bowel disease, or irritable bowel syndrome. TRPV1 receptor imaging kit comprising the compound represented by the following formula (I) or a salt thereof;

[In formula (I),
R ¹ is hydrogen or any organic group and
R ^2, if R ¹ is hydrogen is the number 2 or more organic groups carbon, if R ¹ is other than hydrogen and any organic radical,
R ¹ and / or R ² have radioactive isotopes].

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