Fluorine-containing compounds and contrast agents

Abstract

To provide a fluorine-containing compound that is used as a material for a contrast agent to give a high-sensitivity magnetic resonance image, and also has high in vivo stability.SOLUTION: This fluorine-containing compound is represented by formula (1). R1, R2, R3, and R4 each represent an alkyl group that has 1-10 carbon atoms and that is unsubstituted or substituted with a substituent group not including a fluorine atom. X represents -(CH2)- or -(CH2)m-O-(CH2)-, Y represents -CZ3 or -C(CH3)Z2, and Z represents -CH2-O-C(CF3)3).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a fluorine-containing compound and a contrast agent. [Background technology]

[0002] Magnetic resonance imaging (hereinafter sometimes referred to as "MRI") diagnosis is one of the imaging diagnostic methods, along with X-ray diagnosis and ultrasound (US) diagnosis, and is widely used in the medical field in both basic research and clinical applications.

[0003] Currently, medical MRI uses proton ( 1 H) is used as the detection nucleus. 1 H-MRI is used. 1 H-MRI captures and images the magnetic environment of water molecules present in the body. There is a difference in the magnetic environment of protons between diseased tissue and normal tissue in the body. This is 1 This appears as a difference in H-MRI and provides diagnostic information. Water molecules are present almost everywhere in the body. 1 H-MRI can be used for whole-body imaging.

[0004] Nuclear isotopes that can be detected by MRI include: 1 In addition to H, 19 F, 23 Na, 31 P, 15 N, 13 C, etc. In MRI, which uses these elements as detection nuclei, 1 It provides different information than H-MRI. Among these, the detection nuclei are 19 MRI using F 1 It is expected to be used in the next generation of diagnostic methods following H-MRI diagnosis. Fluorine is an inexpensive element with a natural abundance of 100%, 19 The detection sensitivity of F 1 High at 83% of H. 19 Since the gyromagnetic ratio of F is close to that of the proton, 1 This is because it can be imaged using an H-MRI device.

[0005] Also, MRI detectable 19 F is hardly present in the body. Therefore, by using a compound containing a fluorine atom as a contrast agent, 19 F was used as a tracer 19 F-MRI diagnosis is possible. For example, by using a fluorine compound as a contrast agent that recognizes and accumulates in the tissue due to disease, 19 F-MRI provides location information for lesions, which is useful for diagnosing lesions that do not cause morphological changes and cannot be detected by conventional imaging diagnostic methods.

[0006] Currently, nuclear medicine techniques are used to obtain imaging information specific to lesions. Nuclear medicine techniques use radiopharmaceuticals that utilize radioisotopes. Specifically, nuclear medicine techniques include Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT). However, nuclear medicine techniques have problems such as the large scale equipment required to synthesize radioisotopes and the risk of radiation exposure.

[0007] 19 F-MRI diagnosis does not have the above problems that occur with nuclear medicine techniques. 19 In F-MRI diagnosis, by extracting information such as chemical shift, diffusion, and relaxation time, not only the location of the lesion but also many other diagnostic information can be obtained. 19 F-MRI and 1 By simultaneously capturing 1H-MRI images and superimposing the images, it is possible to obtain useful diagnostic information that combines anatomical and functional information.

[0008] Contrast agents for MRI diagnosis that use fluorine as a detection nucleus include those described in Patent Documents 1 and 2, for example. Patent Document 1 describes polylactic acid-co-glycolic acid (PLGA) particles containing a perfluorocrown ether and a gadolinium complex, while Patent Document 2 describes a fluorine-containing porphyrin complex and a contrast agent compound that can be used in MRI using fluorine as a detection nucleus. However, the contrast agents described in Patent Documents 1 and 2 contain metal ions, which raises concerns about their safety in vivo.

[0009] Furthermore, Patent Document 3 describes a compound having a nitroxide covalently bonded to a fluorine-containing compound. However, the fluorine-containing compound described in Patent Document 3 is easily reduced by a reducing agent such as ascorbic acid (see, for example, Non-Patent Document 1), and therefore has a problem with stability in vivo. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Special Publication No. 2015-534549 [Patent Document 2] Japanese Patent Application Publication No. 11-217385 [Patent Document 3] U.S. Patent No. 5,362,477 [Non-patent literature]

[0011] [Non-Patent Document 1] ACS Central Science,2017,3,800-811. Summary of the Invention [Problem to be solved by the invention]

[0012] Conventional MRI contrast agents that use fluorine as a detection nucleus were not able to provide highly sensitive MRI images and were not stable in vivo. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a fluorine-containing compound that can be used as a material for a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, thereby providing highly sensitive magnetic resonance images and having high stability in vivo. Another object of the present invention is to provide a contrast agent for magnetic resonance imaging diagnosis that contains the fluorine-containing compound of the present invention, has high stability in vivo, and can provide highly sensitive images, and uses fluorine as a detection nucleus. [Means for solving the problem]

[0013] [1] A fluorine-containing compound represented by the following general formula (1):

[0014] [ka] (In general formula (1), R 1 , R 2 , R 3 , R 4 are each independently an alkyl group having 1 to 10 carbon atoms, which is unsubstituted or substituted with a substituent not containing a fluorine atom. X is represented by the following general formula (2-1) or (2-2). Y is represented by the following general formula (3-1) or (3-2).

[0015] -(CH2)- ···(2-1) -(CH2) m -O-(CH2)- (2-2) (In formula (2-2), m is an integer of 1 to 12. In formula (2-2), -(CH2) m - is bonded to the oxygen atom in formula (1). -CZ3···(3-1) (In formula (3-1), Z is —CH—OC(CF)). -C(CH3)Z2···(3-2) (In formula (3-2), Z is —CH—OC(CF).)

[0016] [2] R in the general formula (1) 1 , R2 , R 3 , R 4 and each independently represent an alkyl group having 1 to 5 carbon atoms which is unsubstituted or substituted with a substituent not containing a fluorine atom. [3] The fluorine-containing compound according to [1] or [2], wherein the Y is represented by the general formula (3-1). [4] The fluorine-containing compound according to any one of [1] to [3], wherein X is represented by the general formula (2-2). [5] R in the general formula (1) 1 , R 2 , R 3 , R 4 and each independently represent a methyl group or an ethyl group.

[0017] [6] The fluorine-containing compound according to any one of [1] to [5], which is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus. [7] A contrast agent for magnetic resonance imaging that uses fluorine as a detection nucleus. A contrast agent containing the fluorine-containing compound according to any one of [1] to [6]. [Effects of the Invention]

[0018] The fluorine-containing compound of the present invention is a compound represented by the above general formula (1). Therefore, it has high stability in vivo. Furthermore, when the fluorine-containing compound of the present invention is used as a material for a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, highly sensitive magnetic resonance images can be obtained. The contrast agent of the present invention contains the fluorine-containing compound of the present invention. Therefore, the contrast agent of the present invention has high stability in vivo. Furthermore, when the contrast agent of the present invention is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, highly sensitive magnetic resonance images can be obtained. [Brief explanation of the drawings]

[0019] [Figure 1]1 shows 19F spin-lattice relaxation time (T1) weighted images of 19F-MRI of Example 1 (Compound 11), Example 3 (Compound 13), and Comparative Example 1 (Compound A1). [Figure 2] 19F-MRI 19F spin-lattice relaxation time (T1) weighted images of Example 1 (Compound 11), Example 3 (Compound 13), and Comparative Example 1 (Compound A1), showing the positions of Examples 1, 3, and Comparative Example 1 on the image shown in FIG. DETAILED DESCRIPTION OF THE INVENTION

[0020] The fluorine-containing compound and contrast agent of the present invention will be described in detail below. [Fluorine-containing compounds] The fluorine-containing compound of the present embodiment is represented by the following general formula (1).

[0021] [ka] (In general formula (1), R 1 , R 2 , R 3 , R 4 are each independently an alkyl group having 1 to 10 carbon atoms, which is unsubstituted or substituted with a substituent not containing a fluorine atom. X is represented by the following general formula (2-1) or (2-2). Y is represented by the following general formula (3-1) or (3-2).

[0022] -(CH2)- ···(2-1) -(CH2) m -O-(CH2)- (2-2) (In formula (2-2), m is an integer of 1 to 12. In formula (2-2), -(CH2) m - is bonded to the oxygen atom in formula (1). -CZ3···(3-1) (In formula (3-1), Z is —CH—OC(CF)). -C(CH3)Z2···(3-2) (In formula (3-2), Z is —CH—OC(CF).)

[0023] Here, the reason why a contrast agent containing the fluorine-containing compound of this embodiment is highly stable in vivo and can provide highly sensitive magnetic resonance images (MRI) when used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus will be explained.

[0024] High sensitivity 19 In order to obtain F-MRI, the fluorine-containing compounds contained in the contrast agent are 19 It is preferable to use a compound having a short F spin-lattice relaxation time (T1). The shorter the T1 of the fluorine-containing compound, the shorter the repetition time can be set. This is because the amount of signal obtained per unit time increases, and a highly sensitive image can be obtained. On the other hand, 19 If the F spin-spin relaxation time (T2) is too short, the signal intensity will decrease.

[0025] Fluorine-containing compounds 19 F spin-lattice relaxation time (T1) and 19 The F spin-spin relaxation time (T2) is affected by the paramagnetic relaxation enhancement (PRE) effect, which is a phenomenon in which the unpaired electron spins of a paramagnetic material shorten the T1 and T2 of MRI observation nuclei near the unpaired electron spins.

[0026] The PRE effect is inversely proportional to the sixth power of the distance between the paramagnetic substance and the MRI observation nucleus (in this embodiment, a fluorine atom) that relaxes to the paramagnetic substance. Therefore, in the fluorine-containing compound represented by formula (1) of this embodiment, the shorter the distance between the nitroxide radical, which is a paramagnetic substance, and the fluorine atom, the shorter T1 and T2 become. In the fluorine-containing compound represented by formula (1), a substituent (XY in formula (1)) having a fluorine atom attached to its terminal is bonded to the carbon at the 4-position of the piperidine ring via an oxygen atom. Therefore, the distance between the nitroxide radical and the fluorine atom is appropriate, and T1 is sufficiently short and T2 can be sufficiently ensured. Therefore, by using the fluorine-containing compound represented by formula (1) as a contrast agent for MRI diagnosis using fluorine as the detection nucleus, highly sensitive magnetic resonance images can be obtained.

[0027] Furthermore, unlike closed-shell species, organic radicals have a half-occupied molecular orbital (SOMO) with an unpaired electron between their highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). The oxidation-reduction process of organic radicals corresponds to the process of electron transfer at the SOMO. The reduction reaction of organic radicals by reducing agents such as ascorbic acid is more likely to occur when the energy difference between the HOMO of the reducing agent and the SOMO of the organic radical is smaller. Therefore, the lower the energy level of the SOMO of an organic radical, the more easily it is reduced.

[0028] In the fluorine-containing compound represented by formula (1) of this embodiment, three carbon atoms are located between the nitrogen atom of the piperidine ring and the fluorine-containing substituent represented by XY in formula (1). Furthermore, five or more carbon atoms are located between the oxygen atom bonded to the substituent represented by XY and the fluorine atom. As a result, in the fluorine-containing compound represented by formula (1), the nitroxide radical and the fluorine atom are located at positions sufficiently distant from each other, making the nitroxide radical less susceptible to electronic influence from the fluorine atom. Therefore, in the fluorine-containing compound represented by formula (1), there is no decrease in the energy level of the SOMO of the nitroxide radical due to the fluorine atom, which is an electron-withdrawing group. Therefore, the SOMO of the nitroxide radical in the fluorine-containing compound of this embodiment has a sufficiently large energy difference from the HOMO of a reducing agent such as ascorbic acid. Therefore, the fluorine-containing compound represented by formula (1) is less likely to be reduced in vivo and is highly stable in vivo.

[0029] Furthermore, the fluorine-containing compound of this embodiment represented by formula (1) is a non-metallic compound that does not contain metals, and therefore is safer in vivo than contrast agents containing metal ions. Therefore, the fluorine-containing compound of this embodiment is suitable as a material for contrast agents for magnetic resonance imaging diagnosis that use fluorine as a detection nucleus. Furthermore, the fluorine-containing compound represented by formula (1) of this embodiment is a compound having a piperidine ring and has a structure similar to 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPOL), which is highly safe in vivo. Therefore, the fluorine-containing compound represented by formula (1) of this embodiment is presumed to be more stable in vivo than, for example, fluorine-containing compounds having a pyrrolidine ring.

[0030] In the fluorine-containing compound represented by formula (1) of this embodiment, R 1 , R 2 , R 3 , R 4 are each independently an alkyl group having 1 to 10 carbon atoms and substituted or unsubstituted with a substituent that does not contain a fluorine atom, and preferably an alkyl group having 1 to 5 carbon atoms and substituted or unsubstituted with a substituent that does not contain a fluorine atom. 1 , R 2 , R 3 , R 4 is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, the synthesis of the fluorine-containing compound represented by formula (1) is easy. 1 , R 2 , R 3 , R 4 When is a substituted or unsubstituted alkyl group having 2 to 10 carbon atoms, the alkyl group becomes suitably bulky and can prevent a reducing agent from approaching the nitroxide radical. When the alkyl group has 5 or less carbon atoms, the synthesis of the fluorine-containing compound represented by formula (1) becomes easier, which is preferable.

[0031] R contained in the fluorine-containing compound represented by formula (1) 1 , R 2 , R 3 , R 4 When has a substituent that does not contain a fluorine atom, the substituent can be, for example, a methyl group or an ethyl group. R in the fluorine-containing compound represented by formula (1) of this embodiment 1 , R 2 , R 3 , R 4Specifically, is preferably a methyl group or an ethyl group, and more preferably an ethyl group since the energy level of the SOMO is high.

[0032] R contained in the fluorine-containing compound represented by formula (1) 1 , R 2 , R 3 , R 4 may be different from each other, or some or all of them may be the same. 1 , R 2 , R 3 , R 4 are all the same, this is preferred because it facilitates the synthesis of the fluorine-containing compound represented by formula (1).

[0033] In the fluorine-containing compound represented by formula (1) of this embodiment, X is represented by the above general formula (2-1) or (2-2), and Y is represented by the above general formula (3-1) or (3-2). Therefore, the fluorine-containing compound represented by formula (1) has a sufficiently large number of fluorine atoms, the distance between the nitroxide radical and the fluorine atom is appropriate, T1 is sufficiently short, and T2 can be sufficiently ensured. Therefore, by using the fluorine-containing compound represented by formula (1) as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, highly sensitive images can be obtained. Furthermore, because the distance between the nitroxide radical and the fluorine atom is appropriate, the nitroxide radical is less susceptible to electronic influence from the fluorine atom. Moreover, because the substituents represented by XY are bulky, the approach of a reducing agent to the nitroxide radical is sterically shielded and prevented. Therefore, the fluorine-containing compound represented by formula (1) is less likely to be reduced in vivo and is highly stable in vivo.

[0034] In the fluorine-containing compound represented by formula (1), when X is represented by formula (2-1), the distance between the nitroxide radical and the fluorine atom is appropriate. As a result, the nitroxide radical is less susceptible to electronic influence from the fluorine atom, resulting in a fluorine-containing compound with high stability in vivo. Furthermore, since the distance between the nitroxide radical and the fluorine atom is not too great and T1 is sufficiently short, when the compound is used as an MRI contrast agent using fluorine as a detection nucleus, highly sensitive images can be obtained. Furthermore, when X is represented by formula (2-1), synthesis is easier and productivity is superior compared to when X is represented by formula (2-2), and this is preferable.

[0035] In the fluorine-containing compound represented by formula (1), when X is represented by formula (2-2), m in formula (2-2) is an integer of 1 to 12, so that the distance between the nitroxide radical and the fluorine atom is appropriate. As a result, the nitroxide radical is less susceptible to electronic influence from the fluorine atom, resulting in a fluorine-containing compound with higher stability in vivo. When m in formula (2-2) is an integer of 12 or less, the distance between the nitroxide radical and the fluorine atom is not too great, and T1 is sufficiently short, so that when used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, highly sensitive images can be obtained. It is more preferable that m in formula (2-2) is 2 or 3, so that the distance between the nitroxide radical and the fluorine atom is not too great, and T1 is shorter.

[0036] In the fluorine-containing compound represented by formula (1), Y is represented by formula (3-1) or (3-2). Therefore, Y contains two or three Z(-CH2-OC(CF3)3). Z has three trifluoromethyl groups (-CF3), and therefore contains nine fluorine atoms. Therefore, the fluorine-containing compound represented by formula (1) is a single 19The number of fluorine atoms that exhibits an F-MRI peak is sufficiently large, and when used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, strong signal intensity is obtained, resulting in highly sensitive images. When Y is formula (3-1), the number of fluorine atoms is even greater, making it easier to obtain highly sensitive images, which is preferable. Furthermore, when Y is formula (3-1), the fluorine-containing compound can be produced in fewer production steps than when Y is formula (3-2), which is preferable.

[0037] The combination of X and Y in the fluorine-containing compound represented by formula (1) of this embodiment is not particularly limited, but is preferably a combination in which X is formula (2-1) and Y is formula (3-1), a combination in which X is formula (2-1) and Y is formula (3-2), or a combination in which X is formula (2-2) and Y is formula (3-1). Among the above combinations, the combination in which Y is formula (3-1) is particularly preferred. This is because the fluorine-containing compound has a larger number of fluorine atoms, and therefore, when used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, more sensitive images can be obtained.

[0038] Specifically, the fluorine-containing compound represented by formula (1) is preferably any one of the fluorine-containing compounds represented by the following formulae (11) to (20). The compounds represented by formulas (11) and (12) are fluorine-containing compounds in which X is represented by formula (2-1) and Y is represented by formula (3-1). The compound represented by formula (13) is a fluorine-containing compound in which X is represented by formula (2-1) and Y is represented by formula (3-2). The compounds represented by formulas (14) to (20) are fluorine-containing compounds in which X is represented by formula (2-2) and Y is represented by formula (3-1).

[0039] [ka]

[0040] [Method of producing fluorine-containing compounds] Next, the method for producing the fluorine-containing compound of the present embodiment represented by formula (1) will be described with reference to an example. The method for producing the fluorine-containing compound of the present embodiment is not particularly limited, and the compound can be produced using a conventionally known production method. The fluorine-containing compound of the present embodiment represented by formula (1) can be produced, for example, by the production method shown below.

[0041] (When X is formula (2-1)) First, the 2- and 6-positions of the piperidine ring are each provided with R 1 , R 2 , R 3 , R 4 A compound having a nitroxide radical with a hydroxyl group bonded to the 4-position is prepared. This compound may be synthesized or a commercially available compound may be used. When synthesizing, for example, a known synthesis method can be used using 2,2,6,6-tetramethyl-4-piperidone as a raw material.

[0042] Also, a halogen compound having a group corresponding to XY in the fluorine-containing compound represented by formula (1) and a halogeno group is prepared. Specifically, a halogen compound having -CZ3 (where Z is -CH2-OC(CF3)3) or -C(CH3)Z2 (where Z is -CH2-OC(CF3)3) and a group represented by r-(CH2)- (where r is a halogeno group) is prepared. This halogen compound can be produced by known methods. For example, it can be produced by reacting a compound having two or three hydroxymethyl groups (-CH2OH) and a halogenated alkyl group with nonafluoro-tert-butanol.

[0043] Then, the halogeno group of the halogen compound is reacted with the hydroxyl group of the compound having the nitroxide radical, thereby bonding a group corresponding to XY to the oxygen atom bonded to the 4-position of the piperidine ring. By the above method, a fluorine-containing compound represented by formula (1) in which X is formula (2-1) can be obtained.

[0044] (When X is formula (2-2)) As in the case where X is formula (2-1), a compound having a nitroxide radical is prepared. Next, -(CH2) in formula (2-2) m A tetrahydropyranyl ether containing a group corresponding to r-(CH2) is prepared. m A compound having a group represented by —O— (wherein m is an integer of 1 to 12, and r is a halogeno group) is prepared. This compound can be produced by a known method. Next, the halogeno group of the tetrahydropyranyl ether is reacted with the hydroxyl group of the compound having the nitroxide radical to obtain a first intermediate compound. Then, tetrahydropyran is removed from the first intermediate compound by a known method. This results in the addition of -(CH2) to the oxygen atom bonded to the 4-position of the piperidine ring. m A second intermediate compound having a group having a hydroxyl group bonded to the end of a chain structure corresponding to the compound of formula (1).

[0045] Also, a halogen compound having -CZ3 (where Z is -CH2-OC(CF3)3) or -C(CH3)Z2 (where Z is -CH2-OC(CF3)3) and a group represented by r-(CH2)- (where r is a halogeno group) is prepared. This halogen compound can be produced by known methods. For example, it can be produced by reacting a compound having two or three hydroxymethyl groups (-CH2OH) and a halogenated methyl group with nonafluoro-tert-butanol. Thereafter, the halogeno group of the halogen compound is reacted with the hydroxyl group of the second intermediate compound, thereby bonding a group corresponding to XY to the oxygen atom bonded to the 4-position of the piperidine ring. By the above method, a fluorine-containing compound represented by formula (1) in which X is formula (2-2) can be obtained.

[0046] "Contrast agent" The contrast agent of this embodiment contains the fluorine-containing compound of this embodiment. The contrast agent of this embodiment is a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus. The contrast agent of this embodiment can be produced by formulating the fluorine-containing compound of this embodiment into a form such as a solid formulation, powder formulation, or liquid formulation using a known formulation technique. The contrast agent of the present embodiment may contain, in addition to the fluorine-containing compound of the present embodiment, one or more additives used in known pharmaceutical preparations, such as excipients, stabilizers, surfactants, buffers, and electrolytes, as necessary. The contrast agent of this embodiment contains the fluorine-containing compound of the present invention, and therefore has high stability in vivo. Furthermore, when the contrast agent of this embodiment is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, highly sensitive magnetic resonance images can be obtained.

[0047] The above describes the embodiments of the present invention in detail, but each configuration and combination thereof in each embodiment is an example, and additions, omissions, substitutions, and other modifications of the configurations are possible within the scope that does not deviate from the spirit of the present invention. [Example]

[0048] "Example 1" (Synthesis of Compound 11)

[0049] [ka]

[0050] Synthesis of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) Under an argon atmosphere, 5.000 g (25.1 mmol) of 2-(bromomethyl)-2-(hydroxymethyl)-1,3-propanediol, 27.777 g (105.9 mmol) of triphenylphosphine (PPh3), 10.000 g of molecular sieves (MS) 4A, and 130 ml of tetrahydrofuran (THF) were mixed and cooled in an ice bath. 20.6 ml (105.9 mmol) of diisopropyl azodicarboxylate (DIAD) was added dropwise over 10 minutes and stirred for 20 minutes. 25.000 g (105.9 mmol) of nonafluoro-tert-butanol was added all at once and stirred at 45°C for 72 hours.

[0051] The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) (yield: 16.055 g, 75%).

[0052] Synthesis of 4-(3-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (11) Under an argon atmosphere, 0.567 g (13.0 mmol) of 55% sodium hydride (NaH) was added to 10 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. To this was added dropwise a solution of 2.239 g (13.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl in 20 ml of dimethylformamide over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 8.258 g (9.68 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction and 60 ml of dimethylformamide were added in an ice bath, and the mixture was stirred at 60°C for 16 hours.

[0053] Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The mixture was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 4:1) to obtain the target compound, 4-(3-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (11) (yield: 7.503 g, 83%).

[0054] Mass spectrometry of the obtained compound revealed m / z=944 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (11). Furthermore, the purity of the compound represented by formula (11) was confirmed to be 98.1% by high performance liquid chromatography (HPLC).

[0055] "Example 2" (Synthesis of Compound 12)

[0056] [ka]

[0057] <Synthesis of 1,2,2,6,6-pentamethyl-4-piperidone (1-2)> Under an argon stream, 15.524 g (100 mmol) of 2,2,6,6-tetramethyl-4-piperidone, 23.288 g (150 mmol) of paraformaldehyde, and 100 ml of toluene were mixed and heated to 90°C. 5.70 ml (150 mmol) of formic acid was added dropwise over 30 minutes, and the mixture was heated at 100°C for 12 hours. The mixture was cooled to room temperature, and 2.000 g (50 mmol) of sodium hydroxide was added and stirred for one hour. The mixture was then suction filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrate was distilled under reduced pressure (70-72°C / 2 mmHg) to obtain the desired 1,2,2,6,6-pentamethyl-4-piperidone (1-2) (yield: 13.532 g, 80%).

[0058] Synthesis of 7-aza-3.11-dithiadispiro[5.1.5.3]hexadecan-15-one (1-3) Under an argon atmosphere, 12.373 g (73.1 mmol) of 1,2,2,6,6-pentamethyl-4-piperidone (1-2) synthesized by the above reaction and 25.000 g (215.2 mmol) of 4-oxothiane were dissolved in 100 ml of dimethyl sulfoxide (DMSO), 23.001 g (430.0 mmol) of ammonium chloride was added, followed by 14 ml of 40% aqueous benzyltrimethylammonium hydroxide solution (Triron B), and the mixture was stirred at 50°C for 10 hours.

[0059] Water was added to the reaction solution, the pH was adjusted to 1 with 5% hydrochloric acid, and the mixture was washed with diethyl ether. The aqueous layer was adjusted to pH 9 with 10% aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (hexane:ethyl acetate = 3:1 to 1:1) and then reprecipitated with hexane-ethyl acetate to obtain the desired 7-aza-3.11-dithiadispiro[5.1.5.3]hexadecan-15-one (1-3) (yield: 5.771 g, 29%).

[0060] <Synthesis of 4-hydroxy-2,2,6,6-tetraethylpiperidine (1-4)> Under an argon atmosphere, 5.500 g (20.3 mmol) of 7-aza-3.11-dithiadispiro[5.1.5.3]hexadecan-15-one (1-3) was added to 320 mL of ethanol (EtOH). 50.00 g of Raney-Ni (aqueous suspension, Ni>92.5%, Al<6.5%) was added while washing in with 60 mL of ethanol, and the mixture was stirred at 65°C for 72 hours.

[0061] The reaction solution was filtered through Celite and concentrated under reduced pressure. The concentrated solution was adjusted to pH 12 with saturated aqueous potassium carbonate, extracted with ethyl acetate, and washed with saturated aqueous sodium chloride. It was concentrated under reduced pressure, 7% hydrochloric acid was added, and the mixture was washed with diethyl ether. The pH was adjusted to 12 with 5 M aqueous potassium hydroxide, extracted with ethyl acetate, and washed with saturated aqueous sodium chloride. It was dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the desired 4-hydroxy-2,2,6,6-tetraethylpiperidine (1-4) (yield 2.599 g, 60%).

[0062] <Synthesis of 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-5)> Under an argon atmosphere, 2.599 g (12.2 mmol) of 4-hydroxy-2,2,6,6-tetraethylpiperidine (1-4) synthesized by the above reaction was dissolved in 400 mL of dichloromethane and cooled in an ice bath. 80 mL of a dichloromethane solution containing 24.4 mmol of metachloroperbenzoic acid (mCPBA) was added dropwise over 45 minutes, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was dissolved in diethyl ether. It was washed with saturated aqueous sodium carbonate and then saturated aqueous sodium chloride, and then dried over magnesium sulfate. After concentration under reduced pressure, the product was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to obtain the desired 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-5) (yield: 1.811 g, 65%).

[0063] Synthesis of 4-(3-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (12) Under an argon atmosphere, 0.349 g (8.00 mmol) of 55% sodium hydride was added to 5 mL of dimethylformamide and stirred at room temperature for 10 minutes. 20 mL of a dimethylformamide solution of 1.811 g (7.93 mmol) of 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-5) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 5.972 g (7.00 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added in an ice bath, and the mixture was stirred at 60 °C for 15 hours.

[0064] Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The mixture was then washed with water, and the organic layer was dried over magnesium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain the target compound, 4-(3-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (12) (yield: 2.101 g, 30%).

[0065] Mass spectrometry of the obtained compound revealed m / z=1000 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (12). Furthermore, the purity of the compound represented by formula (12) was confirmed to be 98.9% by high performance liquid chromatography (HPLC).

[0066] "Example 3" (Synthesis of Compound 13)

[0067] [ka]

[0068] <Synthesis of 2-(bromomethyl)-2-methyl-1,3-propanediol (1-6)> 5.450 g (53.4 mmol) of 3-methyl-3-octanemethanol was dissolved in 25 mL of 1,4-dioxane, and 7.20 mL (64.0 mmol) of 48% aqueous hydrogen bromide solution was added dropwise over 10 minutes. The mixture was stirred at 100°C for 4 hours. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The concentrate was dissolved in diethyl ether and washed with saturated aqueous sodium chloride and then aqueous sodium carbonate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure to obtain the desired 2-(bromomethyl)-2-methyl-1,3-propanediol (1-6) (yield: 8.993 g, 92%).

[0069] Synthesis of 2-(3-bromo-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)-2-methylpropoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-7) Under an argon atmosphere, 7.761 g (42.4 mmol) of 2-(bromomethyl)-2-methyl-1,3-propanediol (1-6) synthesized by the above reaction, 27.777 g (105.9 mmol) of triphenylphosphine (PPh3), 10.000 g of molecular sieves (MS) 4A, and 130 ml of tetrahydrofuran (THF) were mixed and cooled in an ice bath. 20.6 ml (105.9 mmol) of diisopropyl azodicarboxylate (DIAD) was added dropwise over 10 minutes and stirred for 20 minutes. 25.000 g (105.9 mmol) of nonafluoro-tert-butanol was added all at once and stirred at 45°C for 72 hours.

[0070] The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound 2-(3-bromo-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)-2-methylpropoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-7) (yield: 21.003 g, 80%).

[0071] Synthesis of 4-(3-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)-2-methylpropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (13) Under an argon atmosphere, 0.567 g (13.0 mmol) of 55% sodium hydride was added to 10 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution of 2.239 g (13.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 5.993 g (9.68 mmol) of 2-(3-bromo-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)-2-methylpropoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-7) synthesized by the above reaction and 60 ml of dimethylformamide were added in an ice bath, and the mixture was stirred at 60 °C for 16 hours.

[0072] Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The mixture was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 to 4:1) to obtain the target compound, 4-(3-((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)-2-(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)-2-methylpropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (13) (yield: 5.364 g, 78%).

[0073] Mass spectrometry of the obtained compound revealed m / z=701 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (13). Furthermore, the purity of the compound represented by formula (13) was confirmed to be 98.8% by high performance liquid chromatography (HPLC).

[0074] Example 4 (Synthesis of Compound 14)

[0075] [ka]

[0076] Synthesis of 2-(2-bromoethoxy)tetrahydro-2H-pyran (1-8) Under an argon atmosphere, 3.749 g (30.0 mmol) of 2-bromo-1-ethanol was dissolved in 150 mL of dichloromethane, 3.30 mL (36.0 mmol) of 3,4-dihydro-2H-pyran was added, and then 1.508 g (6.00 mmol) of pyridinium p-toluenesulfonate (PPTS) was added. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired 2-(2-bromoethoxy)tetrahydro-2H-pyran (1-8) (yield: 5.206 g, 83%).

[0077] Synthesis of 2,2,6,6-tetramethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)piperidine-1-oxyl (1-9) Under an argon atmosphere, 0.524 g (12.0 mmol) of 55% sodium hydride was added to 10 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution containing 1.723 g (10.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 10 ml of a dimethylformamide solution containing 2.927 g (14.0 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-pyran (1-8) synthesized by the above reaction was added in an ice bath, and the mixture was stirred at room temperature for 15 hours.

[0078] Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The mixture was then washed with water, and the organic layer was dried over magnesium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired 2,2,6,6-tetramethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)piperidine-1-oxyl (1-9) (yield: 1.382 g, 46%).

[0079] <Synthesis of 4-(2-hydroxyethoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-10)> 1.382 g (4.60 mmol) of 2,2,6,6-tetramethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)piperidine-1-oxyl (1-9) synthesized by the above reaction and 0.116 g (0.46 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 ml of ethanol (EtOH) and stirred at 78 °C for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the desired 4-(2-hydroxyethoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-10) (yield 0.895 g, 90%).

[0080] <Synthesis of compound (14)> Under an argon atmosphere, 0.218 g (5.00 mmol) of 55% sodium hydride was added to 5 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. To this was added dropwise 15 ml of a dimethylformamide solution of 0.895 g (4.14 mmol) of 4-(2-hydroxyethoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-10) synthesized by the above reaction over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, in an ice bath, 15 ml of a dimethylformamide solution containing 2.943 g (3.45 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60°C for 15 hours.

[0081] Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the extract was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound (14) (yield: 2.046 g, 60%).

[0082] Mass spectrometry of the obtained compound revealed m / z=988 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (14). Furthermore, the purity of the compound represented by formula (14) was confirmed to be 98.7% by high performance liquid chromatography (HPLC).

[0083] "Example 5" (Synthesis of Compound 15)

[0084] [ka]

[0085] Synthesis of 2,2,6,6-tetraethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)piperidine-1-oxyl (1-11) Under an argon atmosphere, 10 ml of dimethylformamide (DMF) was added to 0.524 g (12.0 mmol) of 55% sodium hydride and stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution containing 2.284 g (10.0 mmol) of 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-5) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 10 ml of a dimethylformamide solution containing 2.927 g (14.0 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-pyran (1-8) synthesized by the above reaction was added in an ice bath, and the mixture was stirred at room temperature for 15 hours.

[0086] Water was added to the reaction solution, which was then extracted with diethyl ether. The mixture was then washed with water, and the organic layer was dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired 2,2,6,6-tetraethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)piperidine-1-oxyl (1-11) (yield: 1.426 g, 40%).

[0087] <Synthesis of 4-(2-hydroxyethoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-12)> 1.426 g (4.00 mmol) of 2,2,6,6-tetraethyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)piperidine-1-oxyl (1-11) synthesized by the above reaction and 0.100 g (0.40 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 mL of ethanol (EtOH) and stirred at 78 °C for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the desired 4-(2-hydroxyethoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-12) (yield 1.002 g, 92%).

[0088] <Synthesis of compound (15)> Under an argon atmosphere, 0.193 g (4.42 mmol) of 55% sodium hydride was added to 5 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. To this was added dropwise 15 ml of a dimethylformamide solution of 1.002 g (3.68 mmol) of 4-(2-hydroxyethoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-12) synthesized by the above reaction over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, in an ice bath, 15 ml of a dimethylformamide solution containing 2.619 g (3.07 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60°C for 18 hours.

[0089] Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the extract was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound (15) (yield: 1.860 g, 58%).

[0090] Mass spectrometry of the obtained compound revealed m / z=1044 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (15). Furthermore, the purity of the compound represented by formula (15) was confirmed to be 98.3% by high performance liquid chromatography (HPLC).

[0091] "Example 6" (Synthesis of Compound 16)

[0092] [ka]

[0093] Synthesis of 2-(3-bromopropoxy)tetrahydro-2H-pyran (1-13) Under an argon atmosphere, 4.170 g (30.0 mmol) of 3-bromo-1-propanol was dissolved in 150 mL of dichloromethane, 3.30 mL (36.0 mmol) of 3,4-dihydro-2H-pyran was added, and then 1.508 g (6.00 mmol) of pyridinium p-toluenesulfonate (PPTS) was added. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired 2-(3-bromopropoxy)tetrahydro-2H-pyran (1-13) (yield: 5.355 g, 80%).

[0094] Synthesis of 2,2,6,6-tetramethyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidine-1-oxyl (1-14) Under an argon atmosphere, 10 ml of dimethylformamide (DMF) was added to 0.524 g (12.0 mmol) of 55% sodium hydride and stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution containing 1.723 g (10.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 10 ml of a dimethylformamide solution containing 3.124 g (14.0 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran (1-13) synthesized by the above reaction was added in an ice bath, and the mixture was stirred at room temperature for 15 hours.

[0095] Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The mixture was then washed with water, and the organic layer was dried over magnesium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired 2,2,6,6-tetramethyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidine-1-oxyl (1-14) (yield: 1.572 g, 50%).

[0096] <Synthesis of 4-(3-hydroxypropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-15)> 1.572 g (5.00 mmol) of 2,2,6,6-tetramethyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidine-1-oxyl (1-14) synthesized by the above reaction and 0.126 g (0.50 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 mL of ethanol (EtOH) and stirred at 78 °C for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the desired 4-(3-hydroxypropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-15) (yield 0.990 g, 86%).

[0097] <Synthesis of compound (16)> Under an argon atmosphere, 0.225 g (5.16 mmol) of 55% sodium hydride was added to 5 ml of dimethylformamide and stirred at room temperature for 10 minutes. To this was added dropwise 15 ml of a dimethylformamide solution of 0.990 g (4.30 mmol) of 4-(3-hydroxypropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-15) synthesized by the above reaction over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, in an ice bath, 15 ml of a dimethylformamide solution containing 3.057 g (3.58 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60°C for 13 hours.

[0098] Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the extract was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound (16) (yield: 2.716 g, 63%).

[0099] Mass spectrometry of the obtained compound revealed m / z=1002 (M +) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (16). Furthermore, the purity of the compound represented by formula (16) was confirmed to be 98.8% by high performance liquid chromatography (HPLC).

[0100] "Example 7" (Synthesis of Compound 17)

[0101] [ka]

[0102] Synthesis of 2,2,6,6-tetraethyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidine-1-oxyl (1-16) Under an argon atmosphere, 10 ml of dimethylformamide (DMF) was added to 0.524 g (12.0 mmol) of 55% sodium hydride and stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution containing 2.284 g (10.0 mmol) of 4-hydroxy-2,2,6,6-tetraethylpiperidine-1-oxyl (1-5) synthesized by the above reaction was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 10 ml of a dimethylformamide solution containing 3.124 g (14.0 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran (1-13) synthesized by the above reaction was added in an ice bath, and the mixture was stirred at room temperature for 15 hours.

[0103] Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The mixture was then washed with water, and the organic layer was dried over magnesium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired 2,2,6,6-tetraethyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidine-1-oxyl (1-16) (yield: 1.964 g, 53%).

[0104] <Synthesis of 4-(3-hydroxypropoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-17)> 1.964 g (5.30 mmol) of 2,2,6,6-tetraethyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)piperidine-1-oxyl (1-16) synthesized by the above reaction and 0.133 g (0.53 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 ml of ethanol (ErOH) and stirred at 78 °C for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the desired 4-(3-hydroxypropoxy)-2,2,6,6-tetraethylpiperidine-1-oxyl (1-17) (yield 1.230 g, 81%).

[0105] <Synthesis of compound (17)> Under an argon atmosphere, 0.225 g (5.16 mmol) of 55% sodium hydride was added to 5 ml of dimethylformamide and stirred at room temperature for 10 minutes. To this was added dropwise 15 ml of a dimethylformamide solution of 1.230 g (4.29 mmol) of 4-(3-hydroxypropoxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-17) synthesized by the above reaction over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, in an ice bath, 15 ml of a dimethylformamide solution containing 3.057 g (3.58 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60°C for 13 hours.

[0106] Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the extract was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound (17) (yield: 1.971 g, 52%).

[0107] Mass spectrometry of the obtained compound revealed m / z=1058 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (17). Furthermore, the purity of the compound represented by formula (17) was confirmed to be 98.0% by high performance liquid chromatography (HPLC).

[0108] "Example 8" (Synthesis of Compound 18)

[0109] [ka]

[0110] Synthesis of 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (1-18) Under an argon atmosphere, 5.432 g (30.0 mmol) of 6-bromo-1-hexanol was dissolved in 150 mL of dichloromethane, 3.30 mL (36.0 mmol) of 3,4-dihydro-2H-pyran was added, and then 1.508 g (6.00 mmol) of pyridinium p-toluenesulfonate (PPTS) was added. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (1-18) (yield: 6.762 g, 85%).

[0111] Synthesis of 2,2,6,6-tetramethyl-4-((6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)oxy)piperidine-1-oxyl (1-19) Under an argon atmosphere, 10 ml of dimethylformamide (DMF) was added to 0.524 g (12.0 mmol) of 55% sodium hydride and stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution containing 1.723 g (10.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 10 ml of a dimethylformamide solution containing 3.713 g (14.0 mmol) of 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (1-18) synthesized by the above reaction was added in an ice bath, and the mixture was stirred at room temperature for 18 hours.

[0112] Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The mixture was then washed with water, and the organic layer was dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired 2,2,6,6-tetramethyl-4-((6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)oxy)piperidine-1-oxyl (1-19) (yield: 1.426 g, 40%).

[0113] <Synthesis of 4-((6-hydroxyhexyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-20)> 1.426 g (4.00 mmol) of 2,2,6,6-tetramethyl-4-((6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)oxy)piperidine-1-oxyl (1-19) synthesized by the above reaction and 0.101 g (0.40 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 ml of ethanol (EtOH) and stirred at 78°C for 3 hours.

[0114] The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the desired 4-((6-hydroxyhexyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-20) (yield: 0.959 g, 88%).

[0115] <Synthesis of compound (18)> Under an argon atmosphere, 0.184 g (4.22 mmol) of 55% sodium hydride was added to 5 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. To this was added dropwise 15 ml of a dimethylformamide solution of 0.959 g (3.52 mmol) of 4-((6-hydroxyhexyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-20) synthesized by the above reaction over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, in an ice bath, 15 ml of a dimethylformamide solution containing 2.500 g (2.93 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60°C for 13 hours.

[0116] Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the extract was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound (18) (yield: 1.653 g, 54%).

[0117] Mass spectrometry of the obtained compound revealed m / z=1044 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (18). Furthermore, the purity of the compound represented by formula (18) was confirmed to be 98.8% by high performance liquid chromatography (HPLC).

[0118] "Example 9" (Synthesis of Compound 19)

[0119] [ka]

[0120] Synthesis of 2-((9-bromononyl)oxy)tetrahydro-2H-pyran (1-21) Under an argon atmosphere, 6.695 g (30.0 mmol) of 9-bromo-1-nonanol was dissolved in 150 mL of dichloromethane, 3.30 mL (36.0 mmol) of 3,4-dihydro-2H-pyran, and then 1.508 g (6.00 mmol) of pyridinium p-toluenesulfonate (PPTS) were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired 2-((9-bromononyl)oxy)tetrahydro-2H-pyran (1-21) (yield: 7.374 g, 80%).

[0121] Synthesis of 2,2,6,6-tetramethyl-4-((9-((tetrahydro-2H-pyran-2-yl)oxy)nonyl)oxy)piperidine-1-oxyl (1-22) Under an argon atmosphere, 0.524 g (12.0 mmol) of 55% sodium hydride was added to 10 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution containing 1.723 g (10.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 20 ml of a dimethylformamide solution containing 4.302 g (14.0 mmol) of 2-((9-bromononyl)oxy)tetrahydro-2H-pyran (1-21) synthesized by the above reaction was added in an ice bath, and the mixture was stirred at room temperature for 18 hours.

[0122] Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The mixture was then washed with water, and the organic layer was dried over magnesium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired 2,2,6,6-tetramethyl-4-((9-((tetrahydro-2H-pyran-2-yl)oxy)nonyl)oxy)piperidine-1-oxyl (1-22) (yield: 1.714 g, 43%).

[0123] <Synthesis of 4-((9-hydroxynonyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-23)> 1.714 g (4.30 mmol) of 2,2,6,6-tetramethyl-4-((9-((tetrahydro-2H-pyran-2-yl)oxy)nonyl)oxy)piperidine-1-oxyl (1-22) synthesized by the above reaction and 0.108 g (0.43 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 mL of ethanol (EtOH) and stirred at 78 °C for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the desired 4-((9-hydroxynonyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-23) (yield 1.190 g, 88%).

[0124] <Synthesis of compound (19)> Under an argon atmosphere, 0.198 g (4.54 mmol) of 55% sodium hydride was added to 5 mL of dimethylformamide and stirred at room temperature for 10 minutes. To this was added dropwise 15 mL of a dimethylformamide solution of 1.190 g (3.78 mmol) of 4-((9-hydroxynonyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-23) synthesized by the above reaction over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, in an ice bath, 15 ml of a dimethylformamide solution containing 2.687 g (3.15 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60°C for 20 hours.

[0125] Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the extract was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound (19) (yield: 1.540 g, 45%).

[0126] Mass spectrometry of the obtained compound revealed m / z=1086 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (19). Furthermore, the purity of the compound represented by formula (19) was confirmed to be 98.9% by high performance liquid chromatography (HPLC).

[0127] "Example 10" (Synthesis of Compound 20)

[0128] [ka]

[0129] Synthesis of 2-((12-bromododecyl)oxy)tetrahydro-2H-pyran (1-24) Under an argon atmosphere, 7.957 g (30.0 mmol) of 12-bromo-1-dodecanol was dissolved in 150 mL of dichloromethane, 3.30 mL (36.0 mmol) of 3,4-dihydro-2H-pyran was added, and then 1.508 g (6.00 mmol) of pyridinium p-toluenesulfonate (PPTS) was added. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired 2-((12-bromododecyl)oxy)tetrahydro-2H-pyran (1-24) (yield: 8.280 g, 79%).

[0130] Synthesis of 2,2,6,6-tetramethyl-4-((12-((tetrahydro-2H-pyran-2-yl)oxy)dodecyl)oxy)piperidine-1-oxyl (1-25) Under an argon atmosphere, 0.524 g (12.0 mmol) of 55% sodium hydride was added to 10 ml of dimethylformamide (DMF) and stirred at room temperature for 10 minutes. 20 ml of a dimethylformamide solution containing 1.723 g (10.0 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, 20 ml of a dimethylformamide solution containing 4.891 g (14.0 mmol) of 2-((12-bromododecyl)oxy)tetrahydro-2H-pyran (1-24) synthesized by the above reaction was added in an ice bath, and the mixture was stirred at room temperature for 18 hours.

[0131] Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The mixture was then washed with water, and the organic layer was dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired 2,2,6,6-tetramethyl-4-((12-((tetrahydro-2H-pyran-2-yl)oxy)dodecyl)oxy)piperidine-1-oxyl (1-25) (yield: 1.631 g, 37%).

[0132] <Synthesis of 4-((12-hydroxydodecyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-26)> 1.631 g (3.70 mmol) of 2,2,6,6-tetramethyl-4-((12-((tetrahydro-2H-pyran-2-yl)oxy)dodecyl)oxy)piperidine-1-oxyl (1-25) synthesized by the above reaction and 0.093 g (0.37 mmol) of pyridinium p-toluenesulfonate (PPTS) were dissolved in 200 mL of ethanol (EtOH) and stirred at 78 °C for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the desired 4-((12-hydroxydodecyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-26) (yield 1.108 g, 84%).

[0133] <Synthesis of compound (20)> Under an argon atmosphere, 0.163 g (3.73 mmol) of 55% sodium hydride was added to 5 mL of dimethylformamide and stirred at room temperature for 10 minutes. To this was added dropwise 15 mL of a dimethylformamide solution containing 1.108 g (3.11 mmol) of 4-((12-hydroxydodecyl)oxy)-2,2,6,6-tetramethylpiperidine-1-oxyl (1-26) synthesized by the above reaction over 10 minutes, and the mixture was stirred at room temperature for 3 hours. Furthermore, in an ice bath, 15 ml of a dimethylformamide solution containing 2.211 g (2.59 mmol) of 2-(3-bromo-2,2-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)propoxy)-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane (1-1) synthesized by the above reaction was added, and the mixture was stirred at 60°C for 20 hours.

[0134] Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was then washed with saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the extract was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the target compound (20) (yield: 1.374 g, 47%).

[0135] Mass spectrometry of the obtained compound revealed m / z=1128 (M + ) was confirmed. From this, it was confirmed that the synthesized compound was the compound represented by formula (20). Furthermore, the purity of the compound represented by formula (20) was confirmed to be 98.6% by high performance liquid chromatography (HPLC).

[0136] "Comparative Example 1" 1,3-bis(2,2,2-trifluoro-1,1-bis(trifluoromethyl(ethoxy)-2,2-bis((2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxy)methyl)propane (PERFECTA, manufactured by Aldrich) represented by the following formula (A1) was prepared.

[0137] "Comparative Example 2" Trifluoromethylbenzene represented by formula (A2) and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPOL, manufactured by Tokyo Chemical Industry Co., Ltd.) represented by the following formula (A3) were mixed in a molar ratio ((A1):(A2)) of 1:1 to prepare the compound of Comparative Example 2.

[0138] [ka]

[0139] The compounds of Examples 1 to 10, Comparative Examples 1 and 2 thus obtained were each purified by the following methods. 19 F spin-lattice relaxation time (T1) and 19 The F spin-spin relaxation time (T2) was measured, and the results are shown in Table 1.

[0140] ( 19 F spin-lattice relaxation time (T1) The compound was dissolved in a 5 mM concentration of deuterated chloroform solution, and the compound was analyzed by repeated rotation using a 500 MHz NMR apparatus under the following conditions: 19 The longitudinal relaxation time (T1) of F nuclei was measured. (Measurement conditions) NMR device: JNM-ECA500 (manufactured by JOEL) Measurement temperature: 36℃ Pulse sequence: double_pulse relaxation_delay:10[s] tau_interval:4,3,2,1,0.8,0.6,0.4,0.2,0.1[s],80,60,40,20,10,8,6,4,2[ms] Number of times accumulated: 128

[0141] ( 19 F spin-spin relaxation time (T2) The compound was dissolved in a 5 mM concentration of deuterated chloroform solution, and analyzed by the Carr-Purcell-Meiboom-Gill (CPMG) method using a 500 MHz NMR apparatus under the following conditions:19 The transverse relaxation time (T2) of F nuclei was measured. (Measurement conditions) NMR device: JNM-ECA500 (manufactured by JOEL) Measurement temperature: 36℃ relaxation_delay:10[s] tau_step:1[ms] relaxation_delay:1,2,3,4,5,6,8,9,10,25,50,75[ms],0.10,0.25,0.50,0.75,1.00,1.25,1.50,1.75,2.00[s] Number of times accumulated: 128

[0142] The half-occupied molecular orbital (SOMO) energy levels of the compounds of Examples 1 to 10 and the compound of Comparative Example 3 represented by formula (A4) were calculated by the method shown below. The results are shown in Table 1.

[0143] (Calculation of SOMO energy levels) Molecular orbital calculations for the compounds were performed using Gaussian09 manufactured by Gaussian Inc., USA. The energy levels of half-occupied molecular orbitals (SOMO) were calculated by geometry optimization calculations using density functional theory (DFT) with B3LYP as the functional and 6-31+G(d,p) as the basis set.

[0144] [Table 1]

[0145] As shown in Table 1, the compounds of Examples 1 to 10 have the following properties compared to the compounds of Comparative Examples 1 and 2: 19 The F spin-lattice relaxation time (T1) was short. In addition, the compounds of Examples 1 to 10 are 19 The F spin-spin relaxation time (T2) was within the appropriate range. 19 Compounds with F spin-spin relaxation times (T2) of milliseconds or less will result in rapid signal decay and low sensitivity.

[0146] Furthermore, the compounds of Examples 1 to 10 had higher half-occupied molecular orbitals (SOMO) energy levels than the compound of Comparative Example 3. This is because in Comparative Example 3 (Compound A4), there is only one carbon atom between the fluorine atom and the carbons at the 2- and 5-positions of the pyrrolidine ring, and the distance between the nitroxide radical and the fluorine atom is shorter than in the compounds of Examples 1 to 10. As a result, it is presumed that the nitroxide radical contained in Comparative Example 3 (Compound A4) is susceptible to electronic influence from the fluorine atom, and the effect of the fluorine atom as an electron-withdrawing group lowers the energy level of the SOMO.

[0147] Furthermore, 5 mM chloroform solutions were prepared for each of the compounds of Example 1 (compound 11), Example 3 (compound 13), and Comparative Example 1 (compound A1), and T1-weighted images (phantom images) were obtained under the following imaging conditions. (imaging conditions) Imaging device: MRI BioSpec117 / 11 (manufactured by Burker) Pulse Sequence: RAREVTR Repeat time: TR = 300 ms Echo time: TE=6ms Phase encoding number = 64 Number of Eco Trains = 1 Flip angle = 180° Accumulation count: 16 times Total imaging time: 5.1 minutes

[0148] FIG. 1 shows the results of Example 1 (compound 11), Example 3 (compound 13), and Comparative Example 1 (compound A1). 19 F-MRI 19 2 shows F spin-lattice relaxation time (T1) weighted images of Example 1 (Compound 11), Example 3 (Compound 13), and Comparative Example 1 (Compound A1). 19 F-MRI 19 2 is an F spin-lattice relaxation time (T1) weighted image, showing the positions of Examples 1 and 3 and Comparative Example 1 on the image shown in FIG. 1.

[0149] Furthermore, using image processing software (ImageJ), the SNR (signal-to-noise ratio) of Examples 1, 3, and Comparative Example 1 was calculated from the gray values ​​at the positions of Examples 1, 3, and Comparative Example 1 in the (T1)-weighted image shown in Figure 1. The results are shown in Table 2.

[0150] [Table 2]

[0151] As shown in FIGS. 1 and 2, the images of Example 1 (Compound 11) and Example 3 (Compound 13) were brighter than the image of Comparative Example 1 (Compound A1). Furthermore, as shown in Table 2, it was confirmed that Example 1 (Compound 11) and Example 3 (Compound 13) were able to obtain a large SNR even with a short imaging time of about 5 minutes, compared to Comparative Example 1 (Compound A1). These results demonstrate that by using Example 1 (Compound 11) and Example 3 (Compound 13) as contrast agents for MRI diagnosis using fluorine as the detection nucleus, images that are sufficiently suitable for clinical application can be obtained.

Claims

1. A fluorine-containing compound represented by the following general formula (1): 【Chemistry 1】 (In general formula (1), R １ , R ２ , R ３ , R ４ are each independently an unsubstituted alkyl group having 1 to 10 carbon atoms. X is represented by the following general formula (2-1) or (2-2). Y is represented by the following general formula (3-1) or (3-2). -(CH ２ )- ・・・(2-1) -(CH ２ ) ｍ -O-(CH ２ )- ・・・(22-22) (In formula (2-2), m is an integer of 1 to 12. In formula (2-2), -(CH ２ ) ｍ - is bonded to the oxygen atom in formula (1). -CZ ３ ・・・(3-1) (In formula (3-1), Z is —CH ２ -O-C(CF ３ ) ３ It is.) -C(CH ３ )Z ２ ・・・(3-2) (In formula (3-2), Z is —CH ２ -O-C(CF ３ ) ３ It is.)

2. R in the general formula (1) １ , R ２ , R ３ , R ４ and each independently represent an unsubstituted alkyl group having 1 to 5 carbon atoms.

3. 3. The fluorine-containing compound according to claim 1, wherein Y is represented by general formula (3-1).

4. The fluorine-containing compound according to any one of claims 1 to 3, wherein X is represented by general formula (2-2).

5. R in the general formula (1) １ , R ２ , R ３ , R ４ and each independently represent a methyl group or an ethyl group.

6. 6. The fluorine-containing compound according to claim 1, which is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus.

7. It is a contrast agent for magnetic resonance imaging diagnosis that uses fluorine as a detection nucleus. A contrast agent comprising the fluorine-containing compound according to any one of claims 1 to 6.

Images