WO2022196523A1 - Fluorine-containing compound and contrast agent - Google Patents

Abstract

The present invention provides a fluorine-containing compound which is represented by formula (1) or formula (2). (In the formulae, R¹, R², R³ and R⁴ represent one of the groups (1-1) to (1-4) described below.) (1-1) an alkyl group having 1 to 10 carbon atoms (1-2) a cyclic alkyl group having 5 to 7 carbon atoms, the cyclic alkyl group being formed of R¹ and R² combined with each other, or R³ and R⁴ combined with each other (1-3) an alkyl group having one or more trifluoromethyl groups, while having 1 to 10 carbon atoms (1-4) a cyclic alkyl group having one or more trifluoromethyl groups, while having 5 to 7 carbon atoms, the cyclic alkyl group being formed of R¹ and R² combined with each other, or R³ and R⁴ combined with each other

Description

Fluorine-containing compounds and contrast agents

The present invention relates to fluorine-containing compounds and contrast agents.
This application claims priority based on Japanese Patent Application No. 2021-043736 filed in Japan on March 17, 2021, the contents of which are incorporated herein.

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

Currently, ¹ H-MRI using protons ( ¹ H) as detection nuclei is used for medical MRI. ¹ H-MRI captures and images the magnetic environment of water molecules present in vivo. A difference occurs in the magnetic environment of protons between diseased tissue and normal tissue in vivo. This appears as a difference in ¹ H-MRI and serves as diagnostic information. Moreover, water molecules are present almost everywhere in the living body. Therefore, ¹ H-MRI can be used for whole-body imaging.

Nuclides detectable by MRI include ¹⁹ F, ²³ Na, ³¹ P, ¹⁵ N, ¹³ C, etc., in addition to ¹ H. MRI using these elements as detection nuclei provides different information from ¹ H-MRI.
Among these, MRI using ¹⁹ F as a detection nucleus is expected to be used as a next-generation diagnostic method following ¹ H-MRI diagnosis. Fluorine is an inexpensive element with a natural abundance ratio of 100%, the detection sensitivity of ¹⁹ F is as high as 83% of ¹ H, and the gyromagnetic ^ratio of ¹⁹ F is close to that of protons. This is because imaging is possible.

In addition, ¹⁹ F detectable by MRI is almost non-existent in vivo. Therefore, by using a fluorine atom-containing compound as a contrast agent, ¹⁹ F-MRI diagnosis using ¹⁹ F as a tracer is possible. For example, positional information of lesions can be obtained from ¹⁹ F-MRI using a fluorine compound that recognizes and accumulates endogenous changes caused by a disease as a contrast medium. This method is useful for diagnosing lesions that do not cause morphological changes that could not be detected by conventional diagnostic imaging methods.

Currently, there is a nuclear medicine method as a method of obtaining image information specific to the lesion. Nuclear medicine techniques use radiopharmaceuticals that utilize radioactive isotopes. Specifically, nuclear medicine techniques include Positron Emission Tomography (PET) examination and Single Photon Emission Computed Tomography (SPECT) examination. However, the nuclear medicine technique has problems such as a large-scale apparatus for synthesizing radioisotopes and the risk of radiation exposure.

¹⁹ F-MRI diagnostics do not suffer from the above problems in nuclear medicine procedures. Further, in ¹⁹ F-MRI diagnosis, by extracting information such as chemical shift, diffusion, and relaxation time, more diagnostic information can be obtained in addition to the positional information of the lesion. In addition, ¹⁹ F-MRI and ¹ H-MRI are simultaneously imaged in one diagnosis, and useful diagnostic information in which anatomical information and functional information coexist can be obtained by superimposing the respective images. It is possible.

Contrast agents for MRI diagnosis using fluorine as a detection nucleus are disclosed, for example, in Patent Document 1 and Patent Document 2.
US Pat. No. 5,300,001 describes lactic acid-co-glycolic acid (PLGA) particles containing perfluorocrown ether and gadolinium complexes. Further, 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, since the contrast agents described in Patent Documents 1 and 2 contain metal ions, there are concerns about their in vivo safety.

In addition, 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), so there is a problem with in vivo stability.

Japanese special table 2015-534549 (A) Japanese Patent Laid-Open No. 11-217385 (A) U.S. Pat. No. 5,362,477 (B)

Conventional contrast agents for MRI diagnosis using fluorine as a detection nucleus do not provide high-sensitivity MRI and are not highly stable in vivo.
The present invention has been made in view of the above circumstances, and by using fluorine as a contrast agent material for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, a highly sensitive magnetic resonance image can be obtained, and in vivo An object of the present invention is to provide a fluorine-containing compound having high stability of
The present invention also provides a contrast agent for magnetic resonance imaging diagnosis, containing the fluorine-containing compound of the present invention, having high stability in vivo and capable of obtaining highly sensitive images, and having fluorine as a detection nucleus. for the purpose.

[1] A fluorine-containing compound represented by the following general formula (1) or (2).

(In general formula (1), R ¹ , R ² , R ³ and R ⁴ are any one of the following (1-1) to (1-4), and R ¹ , R ² , R ³ and R ⁴ is (1-3) below, or one or both of R ¹ and R ² , R ³ and R ⁴ are (1-4).)
(In general formula (2), R ¹ , R ² , R ³ and R ⁴ are any one of the following (1-1) to (1-4), and R ¹ , R ² , R ³ and R ⁴ is (1-3) below, or one or both of R ¹ and R ² , R ³ and R ⁴ are (1-4), X is a hydrogen atom or a fluorine atom It is either a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms with a substituent that does not contain
(1-1) an alkyl group having 1 to 10 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom;
(1-2) a cyclic alkyl group having 5 to 7 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; It is the basis of
(1-3) an alkyl group having 1 to 10 carbon atoms and having one or more trifluoromethyl groups;
(1-4) a cyclic alkyl group having 5 to 7 carbon atoms and having one or more trifluoromethyl groups, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; is.

[2] The fluorine-containing compound according to [1], wherein (1-1) is a chain alkyl group having 1 to 5 carbon atoms substituted or unsubstituted with a fluorine atom-free substituent.
[3] The above (1-2) is a cyclohexyl group substituted or unsubstituted with a substituent containing no fluorine atom, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; The fluorine-containing compound according to [1] or [2], which is a group.

[4] The fluorine-containing compound according to any one of [1] to [3], wherein (1-3) is a chain alkyl group having 1 to 5 carbon atoms and having one or more trifluoromethyl groups. .
[5] The above (1-4) is a cyclohexyl group having one or more trifluoromethyl groups, wherein R ¹ and R ² or R ³ and R ⁴ are combined to form The fluorine-containing compound according to any one of [1] to [4].

[6] Any one of [1] to [5], wherein R ¹ and R ³ in the general formula (1) or the general formula (2) are the same, and R ² and R ⁴ are the same The fluorine-containing compound according to 1.
[7] X in the general formula (2) is either a hydrogen atom or a chain alkyl group having 1 to 5 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom, [1] The fluorine-containing compound according to .

[8] The fluorine-containing compound according to any one of [1] to [7], which is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus.
[9] A contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus,
A contrast agent containing the fluorine-containing compound according to any one of [1] to [8].

The fluorine-containing compound of the present invention is a compound represented by the above general formula (1) or the following general formula (2). Therefore, the in vivo stability is high. In addition, the fluorine-containing compound of the present invention can be used as a contrast agent material for magnetic resonance imaging diagnosis using fluorine as a detection nucleus to obtain a highly sensitive magnetic resonance image.
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 in vivo stability. Further, the contrast agent of the present invention can be used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus to obtain a highly sensitive magnetic resonance image.

1 is a ¹⁹ F spin-lattice relaxation time (T1) weighted image of ¹⁹ F-MRI of Example 1 (compound 11). 19 is a ¹⁹ F spin-lattice relaxation time (T1)-enhanced image of ¹⁹ F-MRI of Comparative Example 1 (Compound A1).

The fluorine-containing compound and contrast agent of the present invention are described in detail below.
[Fluorine-containing compound]
The fluorine-containing compound of this embodiment is represented by the following general formula (1) or the following general formula (2).

(In general formula (1), R ¹ , R ² , R ³ and R ⁴ are any one of the following (1-1) to (1-4), and R ¹ , R ² , R ³ and R ⁴ is (1-3) below, or one or both of R ¹ and R ² , R ³ and R ⁴ are (1-4).)
(In general formula (2), R ¹ , R ² , R ³ and R ⁴ are any one of the following (1-1) to (1-4), and R ¹ , R ² , R ³ and R ⁴ is (1-3) below, or one or both of R ¹ and R ² , R ³ and R ⁴ are (1-4), X is a hydrogen atom or a fluorine atom It is either a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms with a substituent that does not contain
(1-1) an alkyl group having 1 to 10 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom;
(1-2) a cyclic alkyl group having 5 to 7 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; It is the basis of
(1-3) an alkyl group having 1 to 10 carbon atoms and having one or more trifluoromethyl groups;
(1-4) a cyclic alkyl group having 5 to 7 carbon atoms and having one or more trifluoromethyl groups, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; is.

Here, when the contrast agent containing the fluorine-containing compound of the present embodiment is used as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, high stability in vivo and high sensitivity magnetic resonance imaging ( MRI) is obtained.

In order to obtain ¹⁹ F-MRI with high sensitivity, it is preferable to use a fluorine-containing compound contained in the contrast agent having a short ¹⁹ F spin-lattice relaxation time (T1). The shorter the T1 of the fluorine-containing compound, the shorter the repetition time can be set. Therefore, the amount of signal obtained per unit time is increased, and a highly sensitive image can be obtained. On the other hand, if the ¹⁹ F spin-spin relaxation time (T2) of the fluorine-containing compound is too short, the signal intensity will decrease.

The ¹⁹ F spin-lattice relaxation time (T1) and ¹⁹ F spin-spin relaxation time (T2) of fluorine-containing compounds are affected by the paramagnetic relaxation enhancement (PRE) effect. The PRE effect is a phenomenon in which T1 and T2 of MRI observation nuclei in the vicinity of unpaired electron spins are shortened by unpaired electron spins possessed by a paramagnetic material.

The PRE effect is inversely proportional to the sixth power of the distance between the paramagnetic substance and the MRI observation nuclei (fluorine atoms in this embodiment) relaxed by the paramagnetic substance. Therefore, in the fluorine-containing compound represented by Formula (1) or Formula (2) of the present embodiment, T1 and T2 become shorter as the distance between the paramagnetic nitroxide radical and the fluorine atom becomes shorter. In the fluorine-containing compound represented by formula (1) or formula (2), at the 2- and / or 6-position carbon of the piperidine ring, one or more trifluoromethyl groups having 1 to 10 carbon atoms An alkyl group or a cyclic alkyl group having 5 to 7 carbon atoms having one or more trifluoromethyl groups is bonded. Therefore, the distance between the nitroxide radical and the fluorine atom is appropriate, T1 is sufficiently short, and T2 is sufficiently secured. Therefore, by using the fluorine-containing compound represented by formula (1) or formula (2) as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, a highly sensitive magnetic resonance image can be obtained.

In addition, unlike closed-shell species, organic radicals have a semi-occupied orbital (SOMO) containing an unpaired electron between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). The redox process of organic radicals corresponds to the electron transfer process in SOMO. The reduction reaction of organic radicals by a reducing agent 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 radicals is smaller. Therefore, the lower the SOMO energy level of the organic radical, the easier it is to be reduced.

In the fluorine-containing compound represented by formula (1) or formula (2) of the present embodiment, the nitrogen atom of the piperidine ring and one or more trifluoromethyl groups in formula (1) or formula (2) three or more carbon atoms are arranged between As a result, in the fluorine-containing compound represented by formula (1) or (2), the nitroxide radical and the fluorine atom are arranged at sufficiently distant positions, and the nitroxide radical is electronically affected by the fluorine atom. is considered to be difficult to receive. Therefore, in the fluorine-containing compound represented by formula (1) or (2), the SOMO energy level of the nitroxide radical does not decrease due to the fluorine atom, which is an electron-withdrawing group. Therefore, the SOMO of the nitroxide radical in the fluorine-containing compound of the present 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) or Formula (2) is less likely to be reduced in vivo and has high in vivo stability.

In addition, in the fluorine-containing compound represented by formula (1) or formula (2), sterically bulky substituents (formula (1) and formula (2 ) in which R ¹ , R ² , R ³ , and R ⁴ ) are bonded. Accordingly, in the fluorine-containing compound represented by formula (1) or (2), the approach of the reducing agent to the nitroxide radical is sterically blocked by R ¹ , R ² , R ³ and R ⁴ . Hindered. Therefore, the fluorine-containing compound represented by formula (1) or (2) is difficult to be reduced in vivo and has high stability in vivo.

Moreover, since the fluorine-containing compound represented by Formula (1) or Formula (2) of the present embodiment is a nonmetallic compound that does not contain metal, it is less effective in vivo than contrast agents containing metal ions. High safety. Therefore, the fluorine-containing compound of the present embodiment is suitable as a material for a contrast medium for magnetic resonance imaging using fluorine as a detection nucleus.
In addition, the fluorine-containing compound represented by formula (1) or formula (2) of the present embodiment is a compound having a piperidine ring and is highly safe in vivo. ,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPOL). Therefore, the fluorine-containing compound represented by formula (1) or formula (2) of the present embodiment is presumed to have higher in vivo stability than, for example, a fluorine-containing compound having a pyrrolidine ring. be done.

In the fluorine-containing compound represented by Formula (1) or Formula (2) of the present embodiment, R ¹ , R ² , R ³ and R ⁴ are any one of (1-1) to (1-4) be. one or more of R ¹ , R ² , R ³ and R ⁴ in formula (1) or formula (2) is (1-3), or one of R ¹ and R ² , R ³ and R ⁴ or Both are (1-4).

When one or more of R ¹ , R ² , R ³ and R ⁴ is (1-3), the number of fluorine atoms showing a single ¹⁹ F-MRI peak increases, so that R ¹ , R ² , Two or all of R ³ and R ⁴ are preferably (1-3). when two of R ¹ , R ² , R ³ and R ⁴ are (1-3), then one of R ¹ and R ² and one of R ³ and R ⁴ is (1-3) and, among R ¹ , R ² , R ³ and R ⁴ , those other than (1-3) are preferably (1-1).

When one or both of R ¹ and R ² and R ³ and R ⁴ are (1-4), the number of fluorine atoms showing a single ¹⁹ F-MRI peak increases, so that R ¹ and R ² and R It is preferred that both ³ and R ⁴ are (1-4). When only one of R ¹ and R ² , R ³ and R ⁴ is (1-4), R ¹ and R ² , R ³ and R ⁴ that are not (1-4) are (1- 1) or (1-2).

The (1-1) alkyl group having 1 to 10 carbon atoms substituted or unsubstituted with a fluorine atom-free substituent is moderately bulky. Therefore, it is possible to prevent the approach of the reducing agent to the nitroxide radical. In addition, since the alkyl group of (1-1) has 10 or less carbon atoms, synthesis of the fluorine-containing compound represented by formula (1) or formula (2) is facilitated. (1-1) is a chain alkyl group having 1 to 5 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom, a fluorine-containing compound represented by formula (1) or formula (2) is easier to synthesize, which is preferable. Specifically, (1-1) is preferably a methyl group or an ethyl group, and more preferably a methyl group for ease of synthesis.

When (1-1) is an alkyl group having 1 to 10 carbon atoms substituted with a substituent containing no fluorine atom, the substituent containing no fluorine atom may be, for example, a methyl group or an ethyl group. can be done.

(1-2), a cyclic alkyl group having 5 to 7 carbon atoms substituted or unsubstituted with a fluorine atom-free substituent, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; The group formed by is moderately bulky. Therefore, it is possible to prevent the approach of the reducing agent to the nitroxide radical. In (1-2), since the cyclic alkyl group has 5 to 7 carbon atoms, synthesis of the fluorine-containing compound represented by formula (1) or formula (2) is facilitated. The number of carbon atoms in the cyclic alkyl group (1-2) is preferably 5 or 6 for ease of synthesis. (1-2) is a cyclohexyl group substituted or unsubstituted with a substituent containing no fluorine atom, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; With this, the synthesis of the fluorine-containing compound represented by the formula (1) or (2) becomes easier, which is preferable. (1-2) is an unsubstituted cyclohexyl group, most preferably a group formed by bonding R ¹ and R ² or R ³ and R ⁴ together.

(1-2) is a cyclic alkyl group having 5 to 7 carbon atoms substituted with a substituent containing no fluorine atom, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; In the case of a group containing a fluorine atom, for example, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group can be used as the substituent containing no fluorine atom.

The fluorine atom of the alkyl group having 1 to 10 carbon atoms and having one or more trifluoromethyl groups (1-3) has an appropriate distance from the nitroxide radical. Therefore, the fluorine-containing compound represented by the formula (1) or (2) in which one or more of R ¹ , R ² , R ³ and R ⁴ is (1-3) has a sufficiently short T1. , and T2 can be sufficiently secured. Also, since the distance between the nitroxide radical and the fluorine atom is appropriate, the nitroxide radical is less likely to be electronically affected by the fluorine atom. Moreover, since the formula (1-3) is bulky, the approach of the reducing agent to the nitroxide radical is sterically blocked and prevented. Therefore, the fluorine-containing compound represented by Formula (1) or Formula (2) is less likely to be reduced in vivo and has high in vivo stability.

(1-3) facilitates the synthesis of the fluorine-containing compound represented by formula (1) or formula (2), so a chain alkyl having 1 to 5 carbon atoms and having one or more trifluoromethyl groups It is preferably a group. Further, the number of carbon atoms in the alkyl group (1-3) is preferably 1 or 2 for ease of synthesis.
The number of trifluoromethyl groups that (1-3) has is 1 or more, and a single ¹⁹ F-MRI peak is obtained, so it is preferably 1 to 3, more preferably 1 preferable. When (1-3) has one trifluoromethyl group, it is preferably located at the terminal because synthesis is easy.

(1-3) may have a substituent other than the trifluoromethyl group, if necessary. Substituents different from the trifluoromethyl group include, for example, a 2,2,2-trifluoroethoxy group, a (1,1,1,3,3,3-hexafluoropropan-2-yl)oxy group, A ((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy group can be used.

(1-4), a cyclic alkyl group having 5 to 7 carbon atoms and having one or more trifluoromethyl groups, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to form The fluorine atom possessed by the group is properly spaced from the nitroxide radical. Therefore, the fluorine-containing compound represented by the formula (1) or (2) in which one or both of R ¹ and R ² and R ³ and R ⁴ are (1-4) has a sufficiently short T1, And T2 can be sufficiently secured. Also, since the distance between the nitroxide radical and the fluorine atom is appropriate, the nitroxide radical is less likely to be electronically affected by the fluorine atom. Moreover, since the formula (1-4) is bulky, the approach of the reducing agent to the nitroxide radical is sterically blocked and prevented. Therefore, the fluorine-containing compound represented by Formula (1) or Formula (2) is less likely to be reduced in vivo and has high in vivo stability.

(1-4) preferably has a cyclic alkyl group with 5 or 6 carbon atoms, since it facilitates the synthesis of the fluorine-containing compound represented by formula (1) or formula (2). and R ¹ and R ² or R ³ and R ⁴ are more preferably a group formed by bonding with each other.
The number of trifluoromethyl groups that (1-4) has is 1 or more, and a single ¹⁹ F-MRI peak is obtained, so it is preferably 1 to 2, more preferably 1 preferable. When (1-4) has one trifluoromethyl group, the desired product can be obtained in good yield in the synthesis reaction, so the carbon at the 2-position and / or 6-position of the piperidine ring is farthest away. It is preferably attached to the other carbon.

In the fluorine-containing compound represented by Formula (1) or Formula (2) of the present embodiment, R ¹ and R ³ are preferably the same, and R ² and R ⁴ are preferably the same. Such a fluorine-containing compound exhibits a single ¹⁹ F-MRI peak when used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus. Therefore, high-quality ¹⁹ F-MRI with suppressed chemical shift artifacts can be obtained.

In the fluorine-containing compound represented by formula (2) of the present embodiment, X is either a hydrogen atom or an alkyl group having 1 to 10 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom. , a hydrogen atom, or a chain alkyl group having 1 to 5 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom.
X in the fluorine-containing compound represented by formula (2) is bonded to the 4-position of the piperidine ring via an ether bond (--O--). Since X in the fluorine-containing compound represented by formula (2) is bonded via an ether bond, it has higher stability against oxidation-reduction reaction than the fluorine-containing compound represented by formula (1) having a carbonyl group. high. Therefore, the fluorine-containing compound represented by formula (2) is presumed to have higher in vivo stability than the fluorine-containing compound represented by formula (1).
In addition, in the fluorine-containing compound represented by formula (2) of the present embodiment, the number of carbon atoms in the alkyl group of X is 10 or less, so synthesis of the fluorine-containing compound represented by formula (2) is easy. . When the number of carbon atoms in the alkyl group of X is 5 or less, synthesis of the fluorine-containing compound represented by formula (1) becomes easier, which is preferable.

Specifically, the fluorine-containing compound represented by formula (1) is preferably any fluorine-containing compound represented by the following formulas (11) to (16), (23), and (24).
Specifically, the fluorine-containing compound represented by the formula (2) is preferably any one of the fluorine-containing compounds represented by the following formulas (17) to (22) and (25).

[Method for producing fluorine-containing compound]
Next, the method for producing the fluorine-containing compound of the present embodiment represented by formula (1) or formula (2) will be described with examples.
The method for producing the fluorine-containing compound of the present embodiment is not particularly limited, and it 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, using the production method shown below.
First, a first intermediate compound is synthesized in which two methyl groups are bonded to each of the 2- and 6-positions of the piperidine ring, an oxygen atom is bonded to the 4-position, and a methyl group is bonded to the nitrogen atom. Next, the first intermediate compound is reacted with a compound having (1-1) to (1-4) corresponding to R ¹ , R ² , R ³ and R ⁴ . As a result, R ¹ , R ² , R ³ , and R ⁴ each of (1-1) to (1-4) are bound to the 2- and 6-positions of the piperidine ring, and piperidine A second intermediate compound in which a hydrogen atom is attached to a ring nitrogen atom. After that, the hydrogen atom attached to the nitrogen atom of the piperidine ring of the second intermediate compound is removed and converted to a nitroxide radical. By the above method, the fluorine-containing compound represented by formula (1) is obtained.

The fluorine-containing compound of the present embodiment represented by formula (2) can be produced, for example, using the production method shown below.
First, a second intermediate compound is synthesized in the same manner as in the method for producing the fluorine-containing compound represented by formula (1) described above. Next, the second intermediate compound and di-tert-butyl dicarbonate are reacted to bind a tertiary butoxycarbonyl group (t-Boc group) which is a protecting group to the nitrogen atom of the piperidine ring, 3 intermediate compounds. Next, sodium borohydride is used to reduce the third intermediate compound to give a fourth intermediate compound in which a hydroxyl group is bonded to the 4-position of the piperidine ring.

Next, a compound having a group corresponding to X in the fluorine-containing compound represented by formula (2) is reacted with the fourth intermediate compound to give X is a fifth intermediate compound to which a group corresponding to is bonded. Thereafter, using dichloromethane and trifluoroacetic acid, the nitrogen atom forming the piperidine ring of the fifth intermediate compound is converted to a nitroxide radical by removing the tertiary-butoxycarbonyl group as a protective group.
The fluorine-containing compound represented by Formula (2) is obtained by the above method.

When X is a hydrogen atom, the fluorine-containing compound of the present embodiment represented by formula (2) can be produced, for example, using the method shown below.
A fluorine-containing compound represented by formula (1) is produced by the method described above. Then, the fluorine-containing compound represented by formula (1) is reacted with sodium borohydride to obtain a fluorine-containing compound represented by formula (2) in which a hydroxyl group is bonded to the 4-position of the piperidine ring.

"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 the present embodiment can be produced by formulating the fluorine-containing compound of the present embodiment into a solid formulation, powder formulation, liquid formulation, or the like using a known formulation technique.
The contrast agent of the present embodiment includes, in addition to the fluorine-containing compound of the present embodiment, additives used in known formulations such as excipients, stabilizers, surfactants, buffers, electrolytes, etc. may contain one or more.
Since the contrast agent of this embodiment contains the fluorine-containing compound of the present invention, it has high in vivo stability. Further, by using the contrast agent of the present embodiment as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus, a highly sensitive magnetic resonance image can be obtained.

The embodiments of the present invention have been described in detail above, but each configuration and combination thereof in each embodiment are examples, and additions, omissions, replacements, and other modifications of the configuration can be made without departing from the scope of the present invention. can be changed.

"Example 1"
(Synthesis of Compound 11)
<Synthesis of 1,2,2,6,6-pentamethyl-4-piperidone (1-7)>
Under an argon stream, 15.524 g (100 mmol) of 2,2,6,6-tetramethylpiperidin-4-one, 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 heated at 100° C. for 12 hours to react.

The reaction solution was cooled to room temperature, 2.000 g (50 mmol) of sodium hydroxide was added, and after stirring for 1 hour, suction filtration was performed, 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 product, 1,2,2,6,6-pentamethyl-4-piperidone represented by formula (1-7) ( Yield 13.532 g, 80% yield).

<Synthesis of 3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane-15-one (2-1)>
1.695 g (10.0 mmol) of 1,2,2,6,6-pentamethyl-4-piperidone (1-7) obtained by the above reaction, 4-(trifluoromethyl)cyclohexanone4. 10 ml (30.0 mmol) was dissolved in 20 ml of dimethylsulfoxide (DMSO) and 3.209 g (60.0 mmol) of ammonium chloride was added over 20 minutes. The reaction mixture was stirred at 60° C. for 5 hours, cooled to room temperature, added with water, and neutralized with 1N-hydrochloric acid. After extraction with diethyl ether, the water bath was adjusted to pH 9 with a 10% potassium carbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.

The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product, 3,11-bis(trifluoromethyl)-7 represented by formula (2-1). -Azadispiro[5.1.5.3]hexadecan-15-one (yield 1.596 g, 43% yield).

<Synthesis of 3,11-bis(trifluoromethyl)-15-oxo-7-azadispiro[5.1.5.3]hexadec-7-yloxy (11)>
1.596 g (4.30 mmol) of 3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecan-15-one (2-1) obtained by the above reaction, tungsten 0.132 g (0.40 mmol) of sodium acid dihydrate and 5 ml of ethanol (EtOH) were mixed and cooled in an ice bath. 15 ml (143 mmol) of 30% hydrogen peroxide solution was slowly added, and the mixture was stirred at room temperature for 24 hours to react.

Potassium carbonate was added to the reaction solution, extracted with chloroform, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product, 3,11-bis(trifluoro Methyl)-15-oxo-7-azadispiro[5.1.5.3]hexadec-7-yloxy was obtained (yield 0.996 g, 60% yield).

Mass spectrometry of the obtained compound confirmed a peak at m/z=386 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (11). The purity of the compound represented by formula (11) confirmed by high performance liquid chromatography (HPLC) was 95.8%.

"Example 2"
(Synthesis of compound 12)
A target compound represented by formula (12) was synthesized in the same manner as in Example 1, except that 3-(trifluoromethyl)cyclohexanone was used instead of 4-(trifluoromethyl)cyclohexanone. .
Mass spectrometry of the obtained compound confirmed a peak at m/z=386 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (12). The purity of the compound represented by formula (12) confirmed by high performance liquid chromatography (HPLC) was 94.5%.

"Example 3"
(Synthesis of compound 13)
In the same manner as in Example 1, except that 3-(trifluoromethyl)cyclopentanone was used instead of 4-(trifluoromethyl)cyclohexanone, the target compound represented by formula (13) was obtained. Synthesized.
Mass spectrometry of the obtained compound confirmed a peak at m/z=358 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (13). The purity of the compound represented by formula (13) confirmed by high performance liquid chromatography (HPLC) was 95.3%.

"Example 4"
(Synthesis of compound 14)
In the same manner as in Example 1, except that 4,4,4-trifluoro-2-butanone was used instead of 4-(trifluoromethyl)cyclohexanone, the target product represented by formula (14) A compound was synthesized.
Mass spectrometry of the obtained compound confirmed a peak at m/z=306 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (14). The purity of the compound represented by formula (14) confirmed by high performance liquid chromatography (HPLC) was 95.2%.

"Example 5"
(Synthesis of compound 15)
In the same manner as in Example 1, except that 5,5,5-trifluoro-2-pentanone was used in place of 4-(trifluoromethyl)cyclohexanone, the target product represented by formula (15) A compound was synthesized.
Mass spectrometry of the obtained compound confirmed a peak at m/z=334 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (15). The purity of the compound represented by formula (15) confirmed by high performance liquid chromatography (HPLC) was 96.0%.

"Example 6"
(Synthesis of compound 16)
The target product of the formula A compound represented by (16) was synthesized.
Mass spectrometry of the obtained compound confirmed a peak at m/z=498 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (16). The purity of the compound represented by formula (16) confirmed by high performance liquid chromatography (HPLC) was 96.4%.

"Example 7"
(Synthesis of compound 17)
<Synthesis of 3,11-bis(trifluoromethyl)-15-hydroxy-7-azadispiro[5.1.5.3]hexadec-7-yloxy (17)>
Under an argon stream, 1.158 g (3 .00 mmol) was dissolved in 10 ml of ethanol (EtOH) and cooled in an ice bath. 0.057 g (1.50 mmol) of sodium borohydride was slowly added and stirred at room temperature for 6 hours to react.

Saturated saline was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the desired product, 3,11-bis(trifluoromethyl)-15-hydroxy- represented by formula (17). 7-Azadispiro[5.1.5.3]hexadec-7-yloxy was obtained (yield 0.909 g, 78% yield).

Mass spectrometry of the obtained compound confirmed a peak at m/z=388 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (17). The purity of the compound represented by formula (17) confirmed by high performance liquid chromatography (HPLC) was 96.0%.

"Example 8"
(Synthesis of compound 18)
A compound represented by formula (14) was used in place of 3,11-bis(trifluoromethyl)-15-oxo-7-azadispiro[5.1.5.3]hexadec-7-yloxy (11). In the same manner as in Example 7, except for the above, the target compound represented by formula (18) was synthesized.

Mass spectrometry of the obtained compound confirmed a peak at m/z=308 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (18). The purity of the compound represented by formula (18) confirmed by high performance liquid chromatography (HPLC) was 95.5%.

"Example 9"
(Synthesis of compound 19)
A compound represented by formula (16) was used in place of 3,11-bis(trifluoromethyl)-15-oxo-7-azadispiro[5.1.5.3]hexadec-7-yloxy (11) In the same manner as in Example 7, except for the above, the target compound represented by formula (19) was synthesized.

Mass spectrometry of the obtained compound confirmed a peak at m/z=500 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (19). The purity of the compound represented by formula (19) confirmed by high performance liquid chromatography (HPLC) was 96.4%.

"Example 10"
(Synthesis of compound 20)
<Synthesis of tert-butyl-15-oxo-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane-7-carboxylic acid ester (2-2)>
3.712 g (10.0 mmol) of 3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecan-15-one (2-1) synthesized by the above reaction was added to tetrahydrofuran ( THF) (10 ml) and cooled in an ice bath. 10 ml of a tetrahydrofuran solution of 2.92 ml (21.0 mmol) of triethylamine (Et ₃ N) and 2.292 g (10.5 mmol) of di-tert-butyl dicarbonate (Boc ₂ O) was added and stirred at room temperature for 2 hours to complete the reaction. let me

The reaction solution was concentrated under reduced pressure, and hexane was added. The resulting solid was separated by filtration, washed with hexane, and the desired product, tert-butyl-15-oxo-3,11-bis(trifluoromethyl)-7-azadispiro represented by formula (2-2) [ 5.1.5.3]Hexadecane-7-carboxylic acid ester was obtained (yield 3.819 g, yield 81%).

<Synthesis of tert-butyl-15-hydroxy-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane-7-carboxylic acid ester (2-3)>
Under an argon stream, tert-butyl-15-oxo-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane-7-carboxylic acid ester obtained by the above reaction ( 2-2) 3.819 g (8.10 mmol) was dissolved in 10 ml of ethanol (EtOH) and cooled in an ice bath. 0.153 g (4.05 mmol) of sodium borohydride was slowly added and stirred at room temperature for 6 hours to react.

Saturated saline was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. Concentrate under reduced pressure to obtain the desired product, tert-butyl-15-hydroxy-3,11-bis(trifluoromethyl)-7-azadispiro represented by formula (2-3) [5.1.5.3]. Hexadecane-7-carboxylic acid ester was obtained (yield 3.260 g, yield 85%).

<Synthesis of tert-butyl-15-methoxy-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane-7-carboxylic acid ester (2-4)>
Under an argon stream, 5 ml of tetrahydrofuran (THF) was added to 0.360 g (8.26 mmol) of 55% sodium hydride, and the mixture was cooled in an ice bath. tert-butyl-15-hydroxy-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane-7-carboxylic acid ester (2-3) obtained by the above reaction 10 ml of a tetrahydrofuran solution of 3.260 g (6.89 mmol) was added over 20 minutes and stirred for 30 minutes. Furthermore, 10 ml of a tetrahydrofuran solution of 1.172 g (8.26 mmol) of methyl iodide (MeI) was added over 10 minutes, and the mixture was stirred at room temperature for 12 hours to react.

Water was added to the reaction solution, extracted with diethyl ether, and dried over magnesium sulfate. After concentrating under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-4:1) to give the target product of formula (2-4), tert- Butyl-15-methoxy-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane-7-carboxylic acid ester was obtained (yield 2.537 g, yield 63%). .

<Synthesis of 15-methoxy-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane (2-5)>
tert-butyl-15-methoxy-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane-7-carboxylic acid ester (2-4) obtained by the above reaction 2.537 g (5.20 mmol) was dissolved in 15 ml of dichloromethane, 3.1 ml (40.0 mmol) of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 18 hours to react.

After concentrating the reaction solution under reduced pressure, water was added, and the organic layer was neutralized with an aqueous sodium hydrogencarbonate solution. After extraction with diethyl ether, the organic layer was washed with saturated brine and dried over magnesium sulfate. Concentration under reduced pressure gave the desired product, 15-methoxy-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane represented by formula (2-5). (Yield 1.793 g, 89% yield).

<Synthesis of 3,11-bis(trifluoromethyl)-15-methoxy-7-azadispiro[5.1.5.3]hexadec-7-yloxy (20)>
1.793 g (4.63 mmol) of 15-methoxy-3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecane (2-5) obtained by the above reaction, tungsten 0.165 g (0.50 mmol) of sodium acid dihydrate and 5 ml of ethanol (EtOH) were mixed and cooled in an ice bath. 15 ml (143 mmol) of 30% hydrogen peroxide solution was slowly added, and the mixture was stirred at room temperature for 24 hours to react.

Potassium carbonate was added to the reaction solution, extracted with chloroform, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product, 3,11-bis(trifluoro Methyl)-15-methoxy-7-azadispiro[5.1.5.3]hexadec-7-yloxy was obtained (1.025 g, 55% yield).

Mass spectrometry of the obtained compound confirmed a peak at m/z=402 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by formula (20). The purity of the compound represented by formula (20) confirmed by high performance liquid chromatography (HPLC) was 96.7%.

"Example 11"
(Synthesis of compound 21)
Pipette of the compound represented by formula (14) was carried out in the same manner as in Example 1, except that 4,4,4-trifluoro-2-butanone was used instead of 4-(trifluoromethyl)cyclohexanone. An intermediate compound was synthesized in which a hydrogen atom was attached to the nitrogen atom of the lysine ring.
Then, instead of 3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecan-15-one (2-1), using the above intermediate compound, methyl iodide The target compound represented by formula (21) was synthesized in the same manner as in Example 10, except that 1-bromobutane was used instead.

Mass spectrometry of the obtained compound confirmed a peak at m/z=364 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by the formula (21). The purity of the compound represented by formula (21) confirmed by high performance liquid chromatography (HPLC) was 96.0%.

"Example 12"
(Synthesis of compound 22)
In the same manner as in Example 1, except that 1,1,1,7,7,7-hexafluoro-4-heptanone was used instead of 4-(trifluoromethyl)cyclohexanone, An intermediate compound was synthesized in which a hydrogen atom was attached to the nitrogen atom of the piperidine ring of the indicated compound.
And, instead of 3,11-bis(trifluoromethyl)-7-azadispiro[5.1.5.3]hexadecan-15-one (2-1), except for using the above intermediate compound, In the same manner as in Example 10, the target compound represented by formula (22) was synthesized.

Mass spectrometry of the obtained compound confirmed a peak at m/z=514 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by the formula (22). The purity of the compound represented by formula (22) confirmed by high performance liquid chromatography (HPLC) was 95.5%.

"Example 13"
(Synthesis of compound 23)
<Synthesis of 2,2,6-trimethyl-6-(2,2,2-trifluoromethyl)piperidin-4-one (2-6)>
Under an argon stream, 1.695 g (10.0 mmol) of 1,2,2,6,6-pentamethyl-4-piperidone (1-7) obtained by the above reaction, 4,4,4-trifluorobutane- 1.891 g (15.0 mmol) of 2-one was dissolved in 10 ml of dimethylsulfoxide (DMSO), and 1.605 g (30.0 mmol) of ammonium chloride was added over 20 minutes to react.

The reaction mixture was stirred at 60°C for 5 hours, cooled to room temperature, water was added, and neutralized with 1N-hydrochloric acid. After extraction with diethyl ether, the water bath was adjusted to pH 9 with a 10% potassium carbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product, 2,2,6-trimethyl-6-(2) represented by formula (2-6). ,2,2-trifluoromethyl)piperidin-4-one was obtained (0.290 g, 13% yield).

<Synthesis of 2,2,6-trimethyl-4-oxo-6-(2,2,2-trifluoromethyl)piperidine-1-oxyl (23)>
0.290 g (1.30 mmol) of 2,2,6-trimethyl-6-(2,2,2-trifluoromethyl)piperidin-4-one (2-6) obtained by the above reaction, sodium tungstate 0.066 g (0.200 mmol) of dihydrate and 5 ml of ethanol (EtOH) were mixed and cooled in an ice bath. 2 ml (19 mmol) of 30% hydrogen peroxide water was slowly added, and the mixture was stirred at room temperature for 24 hours to react.

Potassium carbonate was added to the reaction solution, extracted with chloroform, and dried over magnesium sulfate. After concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the desired product, 2,2,6-trimethyl- 4-oxo-6-(2,2,2-trifluoromethyl)piperidine-1-oxyl was obtained (0.219 g, 71% yield).

Mass spectrometry of the resulting compound confirmed a peak at m/z=238 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by the formula (23). The purity of the compound represented by formula (23) confirmed by high performance liquid chromatography (HPLC) was 95.9%.

"Example 14"
(Synthesis of compound 24)
In the same manner as in Example 13, except that 1,1,1,7,7,7-hexafluoro-4-heptanone was used instead of 4,4,4-trifluorobutan-2-one. 2,2-Dimethyl-4-oxo-6,6-bis(3,3,3-trifluoropropyl)piperidine-1-oxyl represented by the formula (24), which is the desired product, was synthesized.

Mass spectrometry of the obtained compound confirmed a peak at m/z=334 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by the formula (24). The purity of the compound represented by formula (24) confirmed by high performance liquid chromatography (HPLC) was 96.6%.

"Example 15"
(Synthesis of compound 25)
<Synthesis of 2,2-dimethyl-4-hydroxy-6,6-bis(3,3,3-trifluoropropyl)piperidine-1-oxyl (25)>
Under an argon stream, 0.334 g of 2,2-dimethyl-4-oxo-6,6-bis(3,3,3-trifluoropropyl)piperidine-1-oxyl (24) (1. 00 mmol) was dissolved in 5 ml of ethanol (EtOH) and cooled in an ice bath. 0.019 g (0.50 mmol) of sodium borohydride was slowly added and stirred at room temperature for 6 hours to react.

Saturated saline was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the desired product, 2,2-dimethyl-4-hydroxy-6,6-bis represented by formula (25). (3,3,3-Trifluoropropyl)piperidine-1-oxyl was obtained (0.269 g, 80% yield).

Mass spectrometry of the obtained compound confirmed a peak at m/z=336 (M ⁺ ). From this, it was confirmed that the synthesized compound was the compound represented by the formula (25). The purity of the compound represented by formula (25) confirmed by high performance liquid chromatography (HPLC) was 95.2%.

"Comparative Example 1"
A trifluoromethylbenzene represented by the following formula (A1) was prepared.
"Comparative Example 2"
(Synthesis of compound A2)
Trifluoromethylbenzene represented by formula (A1) and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPOL) represented by formula (A2) below (manufactured by Tokyo Chemical Co., Ltd. ) were mixed at a molar ratio ((A1):(A2)) of 1:1 to obtain a compound of Comparative Example 2.

The ¹⁹ F spin-lattice relaxation time (T1) of the compounds of Examples 1 to 15 and Comparative Examples 1 and 2 thus obtained was measured by the method described below. Table 1 shows the results.

(Measurement of ¹⁹ F spin-lattice relaxation time (T1))
The compound was dissolved in a deuterated chloroform solution at a concentration of 50 mM, and the longitudinal relaxation time (T1) of the ¹⁹ F nucleus was measured by the repeated rotation method using a 500 MHz NMR device under the conditions shown below.
(Measurement condition)
NMR equipment: JNM-ECA500 (manufactured by JOEL)
Measurement temperature: 36°C
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]
Accumulated times: 16 times

In addition, for the compounds of Examples 1 to 15 and the compound of Comparative Example 3 represented by the above formula (A3), the energy level of the half-occupied orbital (SOMO) was calculated by the method shown below. Table 1 shows the results.

(Calculation of SOMO energy level)
Molecular orbital calculations of compounds were performed using Gaussian09 manufactured by Gaussian, USA. The energy level of the half-occupied orbital (SOMO) was calculated by structure optimization calculation by the density functional theory (DFT) using B3LYP as the functional and 6-31+G(d, p) as the basis function.

As shown in Table 1, the compounds of Examples 1 to 15 had shorter ¹⁹ F spin-lattice relaxation times (T1) than the compounds of Comparative Examples 1 and 2.
In addition, the compounds of Examples 1 to 15 had higher energy levels of semi-occupied molecular orbitals (SOMO) than the compound of Comparative Example 3.

This is because Comparative Example 3 (Compound A3) has only one carbon atom between the carbon atoms at positions 2 and 5 of the pyrrolidine ring and the fluorine atom, and the compounds of Examples 1 to 15 This is because the distance between the nitroxide radical and the fluorine atom is short compared to . As a result, the nitroxide radical contained in Comparative Example 3 (Compound A3) is easily affected electronically by the fluorine atom, and the effect of the fluorine atom as an electron-withdrawing group is thought to have reduced the SOMO energy level. Presumed.

Further, for the compounds of Example 1 and Comparative Example 1, a 5 mM deuterated chloroform solution and a 10 mM deuterated chloroform solution were prepared, 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: RARE VTR
Repeat time: TR=1500ms
Echo time: TE=12ms
Accumulation times: 36 times Total imaging time: 16 minutes 33 seconds

FIG. 1 is a ¹⁹ F spin-lattice relaxation time (T1) weighted image of ¹⁹ F-MRI of Example 1 (compound 11). FIG. 2 is a ¹⁹ F spin-lattice relaxation time (T1) weighted image of ¹⁹ F-MRI of Comparative Example 1 (compound A1).
The image of Example 1 (Compound 11) shown in FIG. 1 is the same as that of Comparative Example 1 (Compound A1) shown in FIG. It was brighter than the image of
Further, from FIG. 1, it can be confirmed that by using Example 1 (compound 11) as a contrast agent for MRI diagnosis using fluorine as a detection nucleus, high-sensitivity images that are sufficiently clinically applicable can be obtained. rice field.

It is possible to provide a highly stable contrast agent in vivo. Also, a highly sensitive magnetic resonance image can be obtained.

Claims (9)

1. A fluorine-containing compound represented by the following general formula (1) or (2).
   

   

   
   (In general formula (1), R ¹ , R ² , R ³ and R ⁴ are any one of the following (1-1) to (1-4), and R ¹ , R ² , R ³ and R ⁴ are (1-3) below, or one or both of R ¹ and R ² , R ³ and R ⁴ are (1-4).)
   (In general formula (2), R ¹ , R ² , R ³ and R ⁴ are any one of the following (1-1) to (1-4), and R ¹ , R ² , R ³ and R ⁴ is (1-3) below, or one or both of R ¹ and R ² , R ³ and R ⁴ are (1-4), X is a hydrogen atom or a fluorine atom It is either a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms with a substituent that does not contain
   (1-1) an alkyl group having 1 to 10 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom;
   (1-2) a cyclic alkyl group having 5 to 7 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; It is the basis of
   (1-3) an alkyl group having 1 to 10 carbon atoms and having one or more trifluoromethyl groups;
   (1-4) a cyclic alkyl group having 5 to 7 carbon atoms and having one or more trifluoromethyl groups, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; is.
2. The fluorine-containing compound according to claim 1, wherein (1-1) is a chain alkyl group having 1 to 5 carbon atoms substituted or unsubstituted with a fluorine atom-free substituent.
3. (1-2) is a cyclohexyl group substituted or unsubstituted with a substituent containing no fluorine atom, wherein R ¹ and R ² or R ³ and R ⁴ are bonded to each other; 3. The fluorine-containing compound according to claim 1 or claim 2.
4. The fluorine-containing compound according to any one of claims 1 to 3, wherein (1-3) is a chain alkyl group having 1 to 5 carbon atoms and having one or more trifluoromethyl groups.
5. wherein (1-4) is a cyclohexyl group having one or more trifluoromethyl groups, and R ¹ and R ² or R ³ and R ⁴ are a group formed by bonding together; The fluorine-containing compound according to any one of claims 1 to 4.
6. Any one of claims 1 to 5, wherein R ¹ and R ³ in the general formula (1) or the general formula (2) are the same, and R ² and R ⁴ are the same. The fluorine-containing compound according to .
7. 2. The formula according to claim 1, wherein X in the general formula (2) is either a hydrogen atom or a chain alkyl group having 1 to 5 carbon atoms substituted or unsubstituted with a substituent containing no fluorine atom. Fluorine-containing compound.
8. The fluorine-containing compound according to any one of claims 1 to 7, which is used as a contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus.
9. A contrast agent for magnetic resonance imaging diagnosis using fluorine as a detection nucleus,
   A contrast agent containing the fluorine-containing compound according to any one of claims 1 to 8.

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