JPH09165378A - N1-(8f)fluorobenzyl heterocyclic compound and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having an angiotensin II receptor- antagonizing action, having a [<18> F] fluoro group introduced thereinto, and useful for labeling reagents for positive electron radiation tomography. SOLUTION: This compound is expressed by the formula I [the ring A is a (substituted) (condensed) imidazole ring; X is a substituent; Ph is (substituted) phenyl; (m) is 0, 1; (n) is 0-3; (p) is 1, 2], for example, 1-(4-butoxy-3-[<18> F]fluorobenzyl)-2-butyl-4-chloro-imidazole-5-acetic acid. The compound of formula I is obtained by reacting a compound of formula II with a [<18> F] electrophilic fluorinating agent such as [<18> F] acetylhypofluorite e.g. in a reaction solvent such as a chlorofluorocarbon compound or (trifluoro)acetic acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a heterocyclic compound having an N ^1- (substituted) benzyl group, wherein the benzyl group is fluorine-containing.
A novel N ^1- [ ¹⁸ F] fluoro (substituted) benzyl heterocyclic compound having 18 introduced therein and a method for producing the same are described in more detail, in particular, non-peptidic angiotensin II.
(N ¹ -substituted benzyl) heterocyclic compounds, which are often found in receptor antagonists (hereinafter referred to as AII), are further introduced with a [ ¹⁸ F] fluoro group in the N ¹ -substituted benzyl group, and are themselves AII receptor antagonists. A novel drug having physiological activity as a drug (N ¹
The present invention relates to a-[ ¹⁸ F] fluoro (substituted) benzyl) heterocyclic compound, a process for producing the same, and use of the thus obtained compound as a reagent for positron emission tomography (PET).

[0002]

BACKGROUND OF THE INVENTION The renin-angiotensin system is an important hormonal system that is deeply involved in blood pressure and water / electrolyte metabolism in the body, and plays an important role in regulating homeostasis such as blood pressure. Then, the active substance of this system, AII
Angiotensin II converting enzyme (hereinafter A
Inhibitors of CE) are commonly used to treat hypertension. However, these drugs have side effects such as coughing,
There is a problem that the production of AII by enzymes other than ACE cannot be suppressed, and studies on non-peptidic AII receptor antagonists are being conducted all over the world as drugs that do not have these drawbacks. Examples of these compounds having an AII receptor antagonistic action include (N ¹ -substituted benzyl) benzimidazole-7-carboxylic acid compounds represented by CV-11974 (Takeda Pharmaceutical Co., Ltd.) and TCV-194. In addition to the (N ¹ -substituted benzyl) imidazole-5-acetic acid compound described above, compounds such as DuP-753 (DuPont-Merck) and L-159,884 (Merck) have been announced, and peripheral compounds thereof have also been reported. Although many have been synthesized, most of them have the general formula III

Embedded image The N ¹ -benzyl heterocyclic structure represented by is included in the molecule.

On the other hand, fluorine has almost the same van der Waals radius as a hydrogen atom, shows a mimetic effect with a hydrogen atom, and also shows a hydrogen bondability with a hydrogen atom similar to a hydroxy group. Much research has been done on its application in the field, and many fluorine-containing drugs and biomaterials have been developed (“Fluorine Chemistry”).
Tomoya Kitazume Kodansha; "Study of Fluorine" Shinnosuke Matsuura Todai Press; "Compound of Fluorine" Nobuo Ishikawa Kodansha;
"Fluorine pharmacy" written by Yoshiro Kobayashi Hirokawa Shoten).

In recent years, positron emission tomography (PET), which uses a compound labeled with a positron-emitting radionuclide as one of the non-invasive tomography diagnostic techniques, is rapidly becoming widespread ("Radiation Medical System"). 6 (Special Volume) Positron CT Nakayama Shoten; “Brain Function and Positron CT” by Keiichi Matsuura, Shujunsha). According to PET, it is possible to non-invasively obtain images showing the distribution and activity of physiological functions in a living body by using a labeled body of various physiologically active substances with positron-emitting nuclides, brain, circulatory organ, It is possible to test the function of each organ such as the digestive organs, determine the lesion site, and diagnose the condition, but in addition to the development of new drugs such as the distribution of the drug in the body, the mechanism of action, the prediction of side effects, and vice versa. If it is used as a probe (searcher), useful knowledge can be obtained in the search for physiological functions related thereto. As a method for synthesizing a labeled substance with a positron radionuclide for PET, a labeling method with an ¹¹ C nuclide has already been well established and is relatively popular (“Positron CT”, written by Tateno, Yukio Medical School). However, since the ¹¹ C nuclide has a very short half-life (20 minutes), labeling with fluorine-18 having a relatively long half-life (110 minutes) is more preferable. However, although fluorine-18 is one of the positron-emitting radionuclides with the longest half-life, it is sufficiently efficient to produce a labeled product within the short half-life and to perform a PET test. You need good manufacturing methods.

[0005]

However, in the research and development of the above-mentioned non-peptidic AII receptor antagonists, a large number of compounds (mainly compounds belonging to the category of (N ^1- (substituted) benzyl) heterocyclic compounds) were synthesized. Despite being
The compound in which fluorine is introduced into the N ¹ -benzyl group is 2 or 3
Except for Known compounds include 4-chloro-1- (2-fluorobenzyl) -2- described in Furukawa Sumiyasu et al., Takeda Research Institute, 50, 56-74.
Phenylimidazole-5-acetic acid, 4-chloro-1-
There is only (2-chloro-6-fluorobenzyl) -2-phenylimidazole-5-acetic acid, and its production method uses a benzyl halogenide in which fluorine-19 is introduced from the beginning, and the imidazole ring is Although it is a method of substitution (benzylation) and has a relatively long half-life, it is not applicable at all to the production of the compound into which fluorine-18 introduced according to the present invention is intended. Also, with respect to AII receptor antagonists, ¹¹ C-labeled compounds have been synthesized and are being studied by PET (R. F. Dannars et al.,
Journal of Nuclear Medicine (J.
Nuclear Medicine, 35 (5), Proceedings, 41st Annual Meeting of Society of Nucleaire Medicine, Orlando, Florida, No. 12 (1994) and Zee Servo et al. Proceedings No. 497, etc.) alone, no labeling with fluorine-18 was known.

[0006]

Means and Embodiments for Solving the Problems In the course of further investigation regarding the non-peptide AII receptor antagonist, the present inventors have made it possible to visualize the AII receptor in vivo by PET, and As a result of studies aimed at providing the [ ¹⁸ F] fluorine-labeled AII receptor antagonist and a method for producing the same, which are useful for studying the biodistribution, site of action, and behavior of the and its antagonists, this system compounds often found N ¹ - (substituted) benzyl heterocyclic moiety of N ¹ - (substituted) that benzyl group can be selectively fluorinated by electrophilic fluorinating agent, the resulting N ¹ - fluoro (substituted ) benzyl body found to have similar strong physiological activity and a non-fluoro substituents, and further, as the electrophile fluorinating agent ^[18 F] PET labeling agent by using a fluoro electrophilic fluorinating agent To confirm that useful novel ^[18 F] fluorine-labeled AII receptor antagonists is obtained, further extensive studies based on these findings, and completed the present invention.

That is, the present invention has the general formula I

Embedded image As a novel fluorine-18 labeled AII receptor antagonist
^{The present invention} relates to a 1- [ ¹⁸ F] fluoro (substituted) benzyl compound, a process for producing the same, and use of these compounds as a drug for PET. In the present invention, N ^1- (substitution) of the starting material
Benzyl heterocyclic compounds have the general formula II

Embedded image (In the formula, ring A represents an optionally substituted imidazole or fused imidazole ring group, N represents a nitrogen atom at the 1-position in those rings, X represents a substituent group, and Ph represents a substituent group. Represents a phenyl group which may have n.
-3, and m represents 0 or 1. ) Is an N ¹ -benzyl heterocyclic compound.

In the general formula II, the substituent represented by X may be any group as long as the object of the present invention is satisfied, and it may be an alkyl group, a cycloalkyl group, an alkoxy group, a halogeno (fluoro, chloro, bromo or iodo). )
Group, halogenomethyl group, halogenoalkoxy group, carboxyl group, alkoxycarbonyl group, acyl group, (N-
(Substituted) carbamoyl group, nitro group, amino group, substituted amino group, acylamino group, alkyl- and arylsulfonylamino group, cyano group, 5-tetrazolyl group and the like. Ph represents a phenyl group which may have a substituent, and examples of the substituent include the same groups as those represented by X.

The alkyl group represented by X is an alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, hexyl groups, etc.). The cycloalkyl group represented by X has 3 carbon atoms.
-6 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl groups, etc.) can be mentioned. Examples of the alkoxy group represented by X include an alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy groups, etc.). The halogeno group represented by X includes fluoro, chloro, bromo and iodo groups, and the halogenomethyl group also includes monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, monobromomethyl groups and the like. 2-fluoroethoxy as a halogenoalkoxy group, 2,
2,2-trifluoroethoxy group and the like can be mentioned. X
The alkoxycarbonyl group represented by has 2 carbon atoms.
An alkoxycarbonyl group of -7 (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,
Examples include butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like. Examples of the (substituted) carbamoyl group represented by X are N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl, N-hexylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, Examples thereof include piperidinocarbonyl, morpholinocarbonyl, and (4′-methylpiperazino) carbonyl group. The acyl group represented by X is an acyl group having 2 to 11 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl,
Benzoyl, toluoyl, naphthylcarbonyl, adamantylcarbonyl group and the like). The substituted amino group represented by X is N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N-
Hexylamino, N, N-dimethylamino, N, N-diethylamino, piperidino, morpholino, 4-methylpiperazino group and the like can be mentioned. Examples of the acylamino group represented by X include an amino group having an acyl group having 2 to 11 carbon atoms as a substituent (eg, acetylamino group, etc.). The alkylsulfonylamino group represented by X is a methanesulfonylamino group, an ethanesulfonylamino group, a trifluoromethanesulfonylamino group, or the like, and the arylsulfonylamino group is a benzenesulfonylamino group, a toluenesulfonylamino group, or an acetylaminobenzenesulfonylamino group. Group, a trifluoromethylbenzenesulfonylamino group, and the like.

Thus, the imidazole N in the general formula I
Specific examples of the benzyl residue on one nitrogen atom include the followings. Benzyl, 2-, 3- and 4-methylbenzyl, 4-chlorobenzyl, 2-,
3- and 4-nitrobenzyl, 2-fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 3,4
-And 2,6-dichlorobenzyl, 2- and 4-methoxybenzyl, 2-, 3- and 4-ethoxybenzyl, 2-chloro-6-fluorobenzyl, 4-butoxybenzyl, 3-methyl-4-methoxybenzyl , 3-methyl-4-ethoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 4-carboxybenzyl, 2-chloro-4-carboxybenzyl, 4
-(1H-tetrazolyl-5-yl) benzyl, 4- (2
-Carboxybenzoylamino) benzyl, 4- (phenylsulfonylaminocarbonyl) benzyl, 4- (N-
(2-carboxy-3-methylphenyl) carbamoyl)
Benzyl, 4- (N- (2- (1H-tetrazole-5-
(Yl) phenyl) carbamoyl) benzyl, 4- (2-carboxy-6-methylbenzoylamino) benzyl, (2 ′
-Cyanobiphenyl-4-yl) methyl, (2'-carboxybiphenyl-4-yl) methyl, (2'-benzoylaminosulfonylbiphenyl-4-yl) methyl,
(2 '-(1H-tetrazol-5-yl) biphenyl-
4-yl) methyl, (2 '-(1H-tetrazole-5-
Yl) -3-methylbiphenyl-4-yl) methyl,
(2 '-(1H-tetrazol-5-yl) -5'-chlorobiphenyl-4-yl) methyl.

The imidazole or condensed imidazole ring group represented by ring A which may have a substituent is:
Optionally substituted imidazole, benzimidazole, tetrahydrobenzimidazole, imidazo
Examples include [5,4-b] pyridine ring, and imidazole and benzimidazole rings are preferable. When the ring A has a substituent, examples of the substituent include the same groups as those described above for X and Ph, but in addition to them, cyanomethyl, hydroxymethyl, formyl, carboxymethyl and these groups can also be used. Of these, the latter three are respectively protected groups thereof, for example, in the case of a hydroxymethyl group, a formyl group such as methoxymethyl, methoxyethoxymethyl, acetoxymethyl, pivaloyloxymethyl, trifluoroacetoxymethyl group. In the case of 1,3-dioxolan-2-yl group, etc., and in the case of a carboxymethyl group, in addition to the above-mentioned alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl group, etc.), (1-ethoxy) ethoxycarbonyl, (1 −
Examples thereof include groups such as pivaloyloxy) ethoxycarbonyl and (1-cyclohexyloxycarbonyloxy) ethoxycarbonyl.

Specific examples of the ring A group having a substituent include:
For example, 2-phenyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-p-tolyl-4-chloro-5-carboxymethylimidazol-1-yl, 2
-P-Bromophenyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-p-chlorophenyl-4-chloro-5-carboxymethylimidazol-1
-Yl, 2-o-fluorophenyl-4-chloro-5-
Carboxymethyl imidazol-1-yl, 2-o-,
-M- and -p-methoxyphenyl-4-chloro-5-
Carboxymethylimidazol-1-yl, 2-p-butoxyphenyl-4-chloro-5-carboxymethylimidazol-1-yl, 2- (3,5-dichloro-4-methoxyphenyl) -4-chloro-5- Carboxymethylimidazol-1-yl, 2- (3-methyl-4-methoxyphenyl) -4-chloro-5-carboxymethylimidazol-1-yl, 2-p-dimethylaminophenyl-4-chloro-5-carboxy Methylimidazole-
1-yl, 2-p-nitrophenyl-4-chloro-5-
Carboxymethylimidazol-1-yl, 2-methyl-4-chloro-5-carboxymethylimidazol-1
-Yl, 2-ethyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-propyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-
Isopropyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-butyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-tert-butyl-4-chloro-5-carboxymethylimidazole- 1-yl, 2-pentyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-cyclopentyl-4-chloro-5-carboxymethylimidazol-1
-Yl, 2-hexyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-cyclohexyl-4
-Chloro-5-carboxymethylimidazol-1-yl, 2-butyl-4-chloro-5-methoxycarbonylmethylimidazol-1-yl, 2-butyl-4-chloro-5-hydroxymethylimidazol-1-yl, Two
-Butyl-4-chloro-5-acetoxymethylimidazol-1-yl, 2-butyl-4-chloro-5-methoxymethylimidazol-1-yl, 2-butyl-4-chloro-5- (5-tetrazoli Lumethyl) imidazole-1
-Yl, 2-methoxy-7-carboxybenzimidazol-1-yl, 2-ethoxy-7-carboxybenzimidazol-1-yl, 2-propoxy-7-carboxybenzimidazol-1-yl, 2-butoxy-7
-Carboxybenzimidazol-1-yl, 2- (2
-Fluoroethoxy) -7-carboxybenzimidazol-1-yl, 2- (2,2,2-trifluoroethoxy) -7-carboxybenzimidazol-1-yl,
2-Methyl-7-carboxybenzimidazole-1-
2-ethyl-7-carboxybenzimidazol-1-yl, 2-propyl-7-carboxybenzimidazol-1-yl, 2-isopropyl-7-carboxybenzimidazol-1-yl, 2-cyclopropyl-7 -Carboxybenzimidazol-1-yl, 2-
Butyl-7-carboxybenzimidazol-1-yl, 2-methoxymethyl-7-carboxybenzimidazol-1-yl, 2-ethoxymethyl-7-carboxybenzimidazol-1-yl, 2-propyl-4-yl
Methylbenzimidazol-1-yl, 2-butyl-4
-Methyl-7-azabenzimidazol-1-yl, 2
-Propyl-4-methyl-7-azabenzimidazol-1-yl, 2-cyclopropyl-4-methyl-7-azabenzimidazol-1-yl, 2-butyl-7-azabenzimidazol-1-yl, 2-ethyl-4,6
-Dimethyl-7-azabenzimidazol-1-yl,
2-phenylbenzimidazol-1-yl, 2-butyl-5-pentanoylamino-6-methyl-7-azabenzimidazol-1-yl and the like can be mentioned. Among them, 2-phenyl-4-chloro-5-carboxymethylimidazol-1-yl, 2-butyl-4-chloro-5-
Carboxymethylimidazol-1-yl, 2-butyl-7-carboxybenzimidazol-1-yl, 2-
Ethoxy-7-carboxybenzimidazol-1-yl and the like are preferable.

The [ ¹⁸ F] electrophilic fluorinating agent can be obtained by a method known per se. For example, for fluorine-18, a small accelerator is used by a method known per se. For example, a neon gas added with a small amount of fluorine-19 as a carrier is irradiated with a deuterium beam to produce a nuclear reaction of ²⁰ Ne (d, α) ¹⁸ F. Can be manufactured by Further, fluorine-18 having a higher specific activity was irradiated with oxygen-18-enriched water by a proton beam to generate ¹⁸ O (p,
n) ¹⁸ obtained by nuclear reaction F ^[18 F] by various methods from fluoride ^[18 F] fluorine gas can also be produced. The [ ¹⁸ F] fluorine gas thus obtained can be used, but acetyl hypofluorite (CH ₃ COO ¹⁸ F) is more preferable, and its production is performed by using, for example, crystalline sodium acetate.
As ^[18 F] solid is contacted with fluorine gas phase / gas phase reaction by gas thereof, or acetic acid solution of ammonium acetate ^[18
F] It can be obtained as a solution by liquid phase / gas phase reaction in which fluorine gas is blown.

Since the present invention relates to N ^1- [ ¹⁸ F] fluorobenzyl heterocyclic compound, the [ ¹⁸ F] electrophilic fluorinating agent used for the production thereof has been described. Fluorine-19 on the N ¹ -benzyl group
Only two known compounds have been introduced, and therefore N ¹ corresponding to the compounds of the invention are
Most of the fluorobenzyl heterocyclic compounds (so-called cold compounds) are novel compounds. In order to obtain such a novel compound, an ordinary fluorinating agent is used instead of the above [ ¹⁸ F] electrophilic fluorinating agent, and the method of the present invention described in detail below is applied. However, it is clear that the purpose can be achieved. As such a fluorinating agent, fluorine (F ₂ ) itself can be used. Fluorine gas is produced by a method known per se such as electrolysis of hydrofluoric acid, and is usually an inert gas such as nitrogen or neon. It is commercially available in a diluted form and is easily available. Furthermore, acetyl hypofluorite (CH ₃ COOF) is more preferable as the fluorinating agent, and this can be produced in the same manner as in the case of CH ₃ COO ¹⁸ F described above.

The fluorination of the compound of general formula II with the [ ¹⁸ F] electrophilic fluorinating agent can be carried out by bringing the compound of general formula II (compound II) into contact with the fluorinating agent by a method known per se. . At this time, it is preferable to efficiently dissipate a large heat of reaction, and therefore the reaction is usually performed by
It may be carried out by passing a gaseous fluorinating agent diluted with an inert gas in the solution of II, or by mixing a solution of the compound II with a fluorinating agent which has been prepared in advance. The preferred concentration of the gaseous fluorinating agent varies depending on the reactivity and stability of the substrate, but is usually about 0.01-5%, preferably 0.1-3%. The amount of [ ¹⁸ F] fluorine that can be produced by a small accelerator is usually nanomolar to picomolar, and by using this to label compound II, PE
It is possible to obtain a practical amount of the labeled substance in the T test.

Examples of the reaction solvent include fluorohalogenoalkanes (freons) (eg, fluorotrichloromethane (freon-11), 1,1,1-fluorodichloroethane (freon 141-B)), lower carboxylic acids (eg, acetic acid). , Trifluoroacetic acid and the like), hydrofluoric acid and a mixed solvent thereof and the like, but freons, acetic acid, trifluoroacetic acid and a mixed solvent thereof are preferable.

The concentration of the compound II as a substrate in these solvents is not particularly limited, but is usually 1 mM-200 mM, more preferably 2 mM-50 mM. The reaction temperature is appropriately selected depending on the reactivity and solubility of the substrate, but is usually -8.
It is selected from the range of 0 ° C to 40 ° C. Preferably -2
It is about 0 ° C to room temperature (about 20-30 ° C), more preferably about -10 ° C to 0 ° C.

After the completion of the reaction, the reaction solution can be treated by a means known per se such as solvent distillation, neutralization, extraction, chromatography, distillation and recrystallization to obtain the desired product. These target compounds may be isolated as they are (free form), or, if necessary, their solvates (eg hydrates).
Alternatively, it may be isolated in the form of a salt (including an acid addition salt).
The salt (acid addition salt) is not particularly limited, and may itself be one used as a medicine or derived from a physiologically acceptable acid or base, such as hydrochloric acid or bromic acid. , Salts with inorganic acids such as iodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, succinic acid, citric acid, ascorbic acid, lactic acid, p-toluenesulfonic acid,
Salts with organic acids such as methanesulfonic acid, fumaric acid, tartaric acid, maleic acid, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, trialkylamines (eg: Trimethylamine, triethylamine, tributylamine, etc.), dibenzylamine, ethanolamine, triethanolamine, salts with organic bases such as N-methylmorpholine, and the like. Especially in the production of [ ¹⁸ F] fluorine-labeled drugs, the production amount is extremely small,
Since it is necessary to use it in a PET test within a short half-life,
After HPLC purification, if necessary, solvents other than water are removed, and operations such as concentration adjustment of the residual liquid, pH adjustment, isotonicity, and sterile filtration with a Millipore filter are carried out to prepare an injectable preparation. Although the dose varies depending on the application form, the active ingredient is contained at 0.1-100 mCi, preferably 0.5-20 mCi, more preferably 1-10 mCi, and used at about 0.1-10 mCi / dose. The injectable preparation may contain diluents such as ethanol and physiological saline, additives such as Triton X, potassium iodide, phosphoric acid, hydrochloric acid, citric acid, sodium hydroxide, sodium hydrogen carbonate and polysorbate 80.
The present invention will be further described below with reference to examples, but the present invention is not limited to these.

[0019]

【Example】

Example 1 2-Butyl-4-chloro-1- (3- [ ¹⁸ F] fluoro-
4-butoxy-benzyl) imidazol-5-acetate and 2-butyl-4-chloro-1- (3,5-di ^[18 F] fluoro-4-butoxy-benzyl) producing small accelerator-5-acetic acid (Saipurisu HM -18 type (Sumitomo Heavy Industries
(Manufactured by Co., Ltd.), and the nickel target container (3
0φ × 242 mm) filled with a small amount (0.14%) of [ ¹⁹ F] F ₂ added as a carrier (4.1 kgf / cm ² ).
Then, it was irradiated with a deuterium beam (10 MeV, 20 μA). After the irradiation was completed, the gas in the target was passed through a column (4φ x 100 mm) packed with crystalline sodium acetate [ ¹⁸
F] Acetyl hypofluorite and then 2-butyl-
4-chloro-1- (4-butoxybenzyl) imidazole-5-acetic acid (30 mg, 79.2 μmol) was dissolved in trifluoroacetic acid (7 ml) at a flow rate of about 100 ml / min.
Keep the temperature of the reaction solution at about -10 to 0 ° C and continue [ ¹⁸
F] Fluorination, and then the reaction solvent was distilled off under reduced pressure, and the residue was dissolved in dimethyl sulfoxide (DMSO) and preparative high performance liquid chromatography (hereinafter referred to as HPLC).
(Column: YMC-pack ODS-AQ, 20φ × 30
0 mm (manufactured by YMC Co., Ltd.); solvent: methanol-
10 mM aqueous phosphoric acid solution (80:20 (v / v)); flow rate: 1
0 ml / min; Detection: UV absorption (hereinafter referred to as UV), 25
0 nm). The eluate was monitored by UV (250 nm) and crystalline sodium iodide radioactivity detector, and radioactive fractions were collected and collected by 2-butyl-4-chloro-
1- (3- [ ¹⁸ F] fluoro-4-butoxybenzyl) imidazole-5-acetic acid and 2-butyl-4-chloro-1
- (3,5-di ^[18 F] fluoro-4-butoxy-benzyl)
A solution of imidazole-5-acetic acid was obtained. Each of these products was analyzed by analytical HPLC (column: YMC-
Puck, ODS-AQ, 4.6φ × 250 mm; solvent was the same as in preparative chromatography), and its purity was also confirmed by giving a peak with radioactivity at the same retention time as the cold body. For the PET test, the organic solvent was further distilled off, and the remaining portion was added with a 5% sodium hydrogen carbonate solution to adjust the pH, and the solution was filtered with a Millipore filter to prepare an injection solution.

Example 2 2-Ethoxy-1- (2- [ ¹⁸ F] fluoro-2 '-(1H
-Tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid, 2-
Ethoxy-1- (3- [ ¹⁸ F] fluoro-2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-
1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1- (2,5-di [ ¹⁸ F] fluoro-2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-
1H-benzimidazole-7-carboxylic acid and 2-
Ethoxy-1- (2,6-di [ ¹⁸ F] fluoro-2 ′-(1H
- except using tetrazol-5-yl) biphenyl-4-yl) added with neon ₂ 0.35% ^[19 F] F for producing a target gas in methyl -1H- benzimidazole-7-carboxylic acid as a carrier, In the same manner as in Example 1, 2-ethoxy-1-(-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-
Benzimidazole-7-carboxylic acid (40 mg, 90.
8 μmol) in trifluoroacetic acid (7 ml) at −10 ° C.
Fluorinated with [ ¹⁸ F] and the reaction solution was treated with HPL according to Example 1.
C, the eluate was monitored by UV (250 nm) and crystalline sodium iodide radioactivity detector, and the radioactive fraction was collected to give the title monofluoro compound in a total radiochemical yield of 4.3%. And the difluoro form was obtained with a total radiochemical yield of 1.4%. Each of these products was confirmed by analytical HPLC (under the same conditions as in Example 1) by giving a peak with radioactivity at the same retention time as the cold form while at the same time their purity (both 9
5%) was also confirmed. For the PET test, the organic solvent was further distilled off, and the rest was added with 5% sodium hydrogen carbonate solution.
The pH was adjusted and filtered with a Millipore filter to prepare an injectable solution.

Example 3 2-Butyl-1- (2- [ ¹⁸ F] fluoro-2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid and 2
- butyl -1- (3- ^[18 F] fluoro -2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl -
Preparation of 1H-benzimidazole-7-carboxylic acid In the same manner as in Example 2, 2-butyl-1- (2 ′-(1H
-Tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid 20 mg
(44.2 μmol) was fluorinated [ ¹⁸ F] in 5 ml of trifluoroacetic acid, the reaction mixture was subjected to HPLC according to Example 1, and the eluate was monitored by UV (250 nm) and sodium iodide radioactivity detector. Then, the radioactive fractions were collected to obtain the title compound in a radiochemical yield of 2% each. The purities were both 95%.

Reference Example 1 2-Butyl-4-chloro-1- (3-fluoro-4-butoxybenzyl) imidazole-5-acetic acid and 2-butyl-4-chloro-1- (3,5-difluoro-4) - butoxybenzyl) imidazole-5 0.2% fluorine / neon gas mixture of about 1L at room temperature the crystalline sodium acetate production Nippon Sanso made 5% fluorine / neon gas mixture obtained by diluting with neon acetic acid (CH ₃ COONa 3H ₂ O) column (diameter approx. 4 mm, length approx. 10 cm), then 2-butyl-4-chloro-1- (4-butoxybenzyl) imidazole-5-acetic acid 20 mg in 5 ml trifluoroacetic acid. The dissolved solution was passed through the solution at room temperature at a flow rate of 50 ml / min, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
% Aqueous sodium thiosulfate solution, then washed with water and dried. After distilling off the solvent under reduced pressure, the residue was subjected to HPLC according to Example 1.
2-butyl-4-chloro-1- (3-fluoro-4-butoxybenzyl) imidazole-5-acetic acid (yield 16%) ¹ H-NMR (CD ₃ OD) δ: 0.88 ( 3H, t, J =
7.4 Hz), 1.00 (3 H, t, J = 7.4 Hz), 1.34
(2H, m), 1.43-1.60 (4H, m), 1.88 (2
H, m), 2.62 (2H, t, J = 7.9Hz), 3.55 (2
H, s), 4.04 (2H, t, J = 6.4Hz), 5.15 (2
H, s), 6.75 (1H, m), 6.84 (1H, dd, J = 1)
1.9, 2.2 Hz), 7.06 (1 H, t, J = 8.5 Hz).
¹⁹ F-NMR (CD ₃ OD) δ: −133.36. And 2-butyl-4-chloro-1- (3,5-difluoro-4-butoxybenzyl) imidazole-5-acetic acid (yield 5%) ¹ H-NMR (CD ₃ OD) δ: 0.96 (3H , T, J =
7.3 Hz), 1.05 (3 H, t, J = 7.3 Hz), 1.41
(2H, m), 1.55-1.66 (4H, m), 1.80 (2
H, m), 2.68 (2H, t, J = 7.9Hz), 3.65 (2
H, s), 4.19 (2H, t, J = 6.3Hz), 5.26 (2
H, s), 6.76 (2H, d, J = 9.0Hz). ¹⁹ F-NM
R (CD ₃ OD) δ: −136.42 was obtained.

Reference Example 2 2-Ethoxy-1- (2-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1
H-benzimidazole-7-carboxylic acid, 2-ethoxy-1- (3-fluoro-2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid, 2-ethoxy-1-
(2,5-difluoro-2 '-(1H-tetrazole-5-
Il) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid and 2-ethoxy-1-
(2,6-difluoro-2 '-(1H-tetrazole-5-
Production of (yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid In the same manner as in Reference Example 1, a column packed with crystalline sodium acetate was filled with about 1 L of a 0.3% fluorine / neon mixed gas. The same as in Reference Example 1) and then 2-ethoxy-1- (2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-
A solution obtained by dissolving 20 mg of 7-carboxylic acid in 5 ml of trifluoroacetic acid was passed at a flow rate of 50 ml / min to obtain a crude product in the same manner as in Example 1, which was then subjected to preparative HPLC.
(Column: YMC-pack ODS-AQ, 20φ × 30
0 mm (manufactured by YMC Co., Ltd.); solvent: methanol-
Acetonitrile-10 mM phosphoric acid aqueous solution (30:20:
50 (v / v)); Flow rate: 10 ml / min; Detection: UV absorption
(Hereinafter referred to as UV), 250 nm), 2-ethoxy-
1- (2-fluoro-2 '-(1H-tetrazole-5-
Iyl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid (yield 10%), ¹ H-NMR (CD ₃ OD) δ: 1.48 (3H, t, J =
7.1Hz), 4.62 (2H, q, J = 7.1Hz), 5.71
(2H, s), 6.75 (H, dd, J = 10.9, 1.7H
z), 6.85 (1H, dd, J = 8.0, 1.7Hz), 7.1
7 (1H, t, J = 8.0Hz), 7.23 (1H, t, J =
7.9 Hz), 7.48-7.75 (6 Hz, m). ¹⁹ F-NMR
(CD ₃ OD) δ: −115.61. 2-Ethoxy-1- (3-fluoro-2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1
H-benzimidazole-7-carboxylic acid (yield 6
%), ¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (3 H, t, J
= 7.1Hz), 4.55 (2H, q, J = 7.1Hz), 5.6
8 (2H, s), 6.68 (1H, t, J = 8.0Hz), 6.8
0 (1H, dd, J = 8.0, 1.7Hz), 6.92 (1H, d
d, J = 11.2, 1.4Hz), 7.19 (1H, t, J =
8.0 Hz), 7.47-7.71 (6 Hz, m). ¹⁹ F-NMR
_{(DMSO-d 6) δ:} -117.36. 2-Ethoxy-1- (2,5-difluoro-2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid (yield 2
%), ¹ H-NMR (CD ₃ OD) δ: 1.48 (3 H, t, J =
7.0Hz), 4.62 (2H, q, J = 7.0Hz), 5.74
(2H, s), 6.53 (1H, dd, J = 10.1, 6.2H
z), 7.02 (1 H, dd, J = 10.1, 6.0 Hz), 7.
22 (1H, t, J = 8.0Hz), 7.49-7.75 (6
H, m). ¹⁹ F-NMR (CD ₃ OD) δ: -121.1
3, -122.81. 2-Ethoxy-1- (2,6-difluoro-2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid (yield 3
%), ¹ H-NMR (CD ₃ OD) δ: 1.46 (3 H, t, J =
7.0Hz), 4.62 (2H, q, J = 7.0Hz), 5.78
(2H, s), 7.16 (1H, m), 7.23 (1H, t, J =
8.0 Hz), 7.43 (1 H, m), 7.52 (2 H, m), 7.
61-7.75 (4H, m). ¹⁹ F-NMR (CD ₃ OD)
δ: -118.05 was obtained.

Reference Example 3 2-butyl-1- (2-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H
-Benzimidazole-7-carboxylic acid and 2-butyl-1- (3-fluoro-2 '-(1H-tetrazole-
Production of 5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid In the same manner as in Reference Example 2, about 1 L of a 0.3% fluorine / neon mixed gas was added to 2-butyl-1- ( 2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid (20 mg) was dissolved in 5 ml of trifluoroacetic acid at a flow rate of 50 ml / min.
Thereafter, a crude product was obtained in the same manner as in Reference Example 2, which was subjected to preparative HPLC (column: YMC-pack ODS-).
AQ, 20φ x 300 mm (manufactured by YMC Corporation);
Solvent: Methanol-10 mM phosphoric acid aqueous solution (50:50
(v / v)); Flow rate: 10 ml / min; Detection: UV absorption (hereinafter referred to as UV), 250 nm), 2-butyl-1- (2
- fluoro -2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl -1H- benzimidazole-7-carboxylic acid (10% ^{yield), 1 H-NMR (CD} 3 OD) δ: 0.94 (3H, t, J =
7.4 Hz), 1.46 (2H, m), 1.80 (2H, m), 2.
12 (2H, t, J = 7.9Hz), 5.96 (2H, s), 6.
66 (1H, dd, J = 11.0, 1.2Hz), 6.73 (1
H, dd, J = 8.0, 1.2 Hz), 7.20 (1 H, t, J
= 8.0 Hz), 7.35-7.88 (7 Hz, m). ¹⁹ F-NM
_{R (CD 3 OD) δ:} -115.12. And 2-butyl-1- (3-fluoro-2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid (yield 6
%), ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (3 H, t, J
= 7.4 Hz), 1.40 (2H, m), 1.76 (2H, m),
2.94 (2H, t, J = 7.7Hz), 5.93 (2H, s),
6.36 (1H, t, J = 8.0Hz), 6.62 (1H, dd,
J = 8.0, 1.5 Hz), 6.69 (1 H, dd, J = 11.
2, 1.5 Hz), 7.20 (1 H, t, J = 8.0 Hz), 7.
44-7.86 (6H, m). ¹⁹ F-NMR (DMSO-
d ₆₎ δ: -117.38 was obtained.

Reference Example 4 1- (Cyclohexyloxycarbonyloxy) ethyl
2-Ethoxy-1- (2-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1
H-benzimidazole-7-carboxylate, 1-
(Cyclohexyloxycarbonyloxy) ethyl 2-
Ethoxy-1- (3-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-
Benzimidazole-7-carboxylate, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- (2,5-difluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl- 1H
-Benzimidazole-7-carboxylate and 1
-(Cyclohexyloxycarbonyloxy) ethyl 2-
Ethoxy-1- (2,6-difluoro-2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1
Production of H-benzimidazole-7-carboxylate 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- (2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-as a starting compound
The reaction was performed in the same manner as in Reference Example 2 except that 1H-benzimidazole-7-carboxylate was used, and the product was separated and purified by preparative HPLC in the same manner as in Reference Example 2 to give 1-.
(Cyclohexyloxycarbonyloxy) ethyl 2-
Ethoxy-1- (2-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-
Benzimidazole-7-carboxylate, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- (3-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H- Benzimidazole-7-carboxylate, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1- (2,5-difluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl- 1H-
Benzimidazole-7-carboxylate and 1-
(Cyclohexyloxycarbonyloxy) ethyl 2-
Ethoxy-1- (2,6-difluoro-2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1
H-benzimidazole-7-carboxylate was obtained.

Reference Example 5 2- (2-Fluoroethoxy) -1- (2-fluoro-2 '
-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid, 2- (2-fluoroethoxy) -1- (3-fluoro-2 '-(1H- Tetrazol-5-yl) biphenyl-
4-yl) methyl-1H-benzimidazole-7-carboxylic acid, 2- (2-fluoroethoxy) -1- (2,5-
Difluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid and 2- (2-fluoroethoxy)
Production of -1- (2,6-difluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid 2- (2-fluoro) as a starting compound Ethoxy) -1-
(2 '-(1H-tetrazol-5-yl) biphenyl-4
-Yl) methyl-1H-benzimidazole-7-carboxylic acid was used, the reaction was carried out in the same manner as in Reference Example 2, and the product was separated and purified by preparative HPLC in the same manner as in Reference Example 2 to give 2- (fluoro). Ethoxy) -1- (2-fluoro-2 '
-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid, 2- (fluoroethoxy) -1- (3-fluoro-2 '
-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid, 2- (fluoroethoxy) -1- (2,5-difluoro-2 '-(1H- Tetrazol-5-yl) biphenyl-
4-yl) methyl-1H-benzimidazole-7-carboxylic acid and 2- (2-fluoroethoxy) -1- (2,
6-Difluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid was obtained.

Reference Example 6 2- (2,2,2-trifluoroethoxy) -1- (2-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benz Imidazole
7-carboxylic acid, 2- (2,2,2-trifluoroethoxy) -1- (3-fluoro-2 ′-(1H-tetrazole-
5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid, 2- (2,2,2-trifluoroethoxy) -1- (2,5-difluoro-2′-
(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid and 2- (2,2,2-trifluoroethoxy) -1-
(2,6-difluoro-2 '-(1H-tetrazole-5-
Production of 2- (2,2,2-trifluoroethoxy) -1- (2 ′-(1H-tetrazole-5) as a raw material compound: production of (yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid -Yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid was used, the reaction was carried out in the same manner as in Reference Example 2, and the product was separated and purified by preparative HPLC in the same manner as in Reference Example 2. And then 2- (2,2,2-fluoroethoxy) -1
-(2-Fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid, 2- (2,2,2-trifluoroethoxy)- 1- (3-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H
-Benzimidazole-7-carboxylic acid, 2- (2,2,
2-trifluoroethoxy) -1- (2,5-difluoro-2 ′-(1H-tetrazol-5-yl) biphenyl-
4-yl) methyl-1H-benzimidazole-7-carboxylic acid and 2- (2,2,2-trifluoroethoxy)
-1- (2,6-Difluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylic acid was obtained.

Reference Example 7 1- (Cyclohexyloxycarbonyloxy) ethyl
2- (2-fluoroethoxy) -1- (2-fluoro-2 '
-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylate, 1- (cyclohexyloxycarbonyloxy) ethyl 2- (2-fluoroethoxy) -1- (3 -Fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-
7-carboxylate, 1- (cyclohexyloxycarbonyloxy) ethyl 2- (2-fluoroethoxy)
-1- (2,5-Difluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylate and 1- (cyclohexyloxycarbonyloxy) ethyl 2 -(2
-Fluoroethoxy) -1- (2,6-difluoro-2'-
Preparation of (1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazol-7-carboxylate. 1- (Cyclohexyloxycarbonyloxy) ethyl 2- (2-fluoroethoxy) -1-
(2 '-(1H-tetrazol-5-yl) biphenyl-4
-Yl) methyl-1H-benzimidazole-7-carboxylate was used, the reaction was performed in the same manner as in Reference Example 2, and the product was separated and purified by preparative HPLC in the same manner as in Reference Example 2 to give 1- (cyclohexyloxy). Carbonyloxy) ethyl 2- (2-fluoroethoxy) -1- (2-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-
7-carboxylate, 1- (cyclohexyloxycarbonyloxy) ethyl 2- (2-fluoroethoxy)
-1- (3-fluoro-2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylate, 1- (cyclohexyloxycarbonyloxy) ethyl 2- (2-fluoroethoxy) -1- (2,5-difluoro-2 ' -(1H-
Tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylate and 1- (cyclohexyloxycarbonyloxy) ethyl 2- (2-fluoroethoxy) -1- (2,6-difluoro -2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7
-The carboxylate was obtained.

Reference Example 8 The following compound was obtained in the same manner. 1- (Cyclohexyloxycarbonyloxy) ethyl 2- (2,2,2-trifluoroethoxy) -1- (2-fluoro-2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazol-7-carboxylate,
1- (cyclohexyloxycarbonyloxy) ethyl
2- (2,2,2-trifluoroethoxy) -1- (3-fluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-
7-carboxylate, 1- (cyclohexyloxycarbonyloxy) ethyl 2- (2,2,2-trifluoroethoxy) -1- (2,5-difluoro-2 '-(1H-tetrazol-5-yl) biphenyl -4-yl) methyl-
1H-Benzimidazole-7-carboxylate and 1- (cyclohexyloxycarbonyloxy) ethyl 2- (2,2,2-trifluoroethoxy) -1- (2,6-
Difluoro-2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl-1H-benzimidazole-7-carboxylate.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 403/10 235 A61K 49/02 C

Claims (5)

[Claims] 1. A compound of the general formula I (In the formula, ¹⁸ F represents positron-disintegrating fluorine-18, ring A represents an imidazole ring which may have a substituent or a condensed imidazole ring, and N represents a 1-position nitrogen atom in the imidazole ring. X represents a substituent, Ph represents a phenyl group which may have a substituent, n represents an integer of 0-3, m represents 0 or 1, and p represents 1 or 2. N ¹ - ^[18 F] fluoro-benzyl heterocyclic compound. 2. The compound is 1- (4-butoxy-3- [ ¹⁸
F] fluorobenzyl) -2-butyl-4-chloro-imidazole-5-acetic acid, 1- (4-butoxy- [G-3,5]
[ ¹⁸ F] Difluorobenzyl) -2-butyl-4-chloro-imidazole-5-acetic acid, 1- (2- [ ¹⁸ F] fluoro-4- (2 ′-(tetrazolyl-5) phenyl)) benzyl-2 -Ethoxybenzimidazole-7-carboxylic acid,
1- (3- ^[18 F] fluoro-4- (2 '- (tetrazolyl -5) phenyl)) benzyl-2-ethoxy-benzimidazole-7-carboxylic acid, 1 - ([G-2,5 ] [18 F] difluoro-4- (2 ′-(tetrazolyl-5) phenyl)) benzyl-2-ethoxybenzimidazole-7-carboxylic acid and 1-([G-2,6] [ ¹⁸ F] difluoro-4-
(2 '-(Tetrazolyl-5) phenyl)) benzyl-2-
The compound of claim 1 selected from the group consisting of ethoxybenzimidazole-7-carboxylic acid. 3. The general formula II: (In the formula, ring A represents an imidazole ring which may have a substituent or a condensed imidazole ring, N represents a 1-position nitrogen atom in the imidazole ring, X represents a substituent group, Ph
Represents a phenyl group which may have a substituent, n represents an integer of 0-3, and m represents 0 or 1), and the N ¹ -benzyl heterocyclic compound is represented by [ ¹⁸ F] electrophilic fluorine. A process for producing an N ^1- [ ¹⁸ F] fluorobenzyl heterocyclic compound represented by the general formula I according to claim 1, which comprises fluorinating [ ¹⁸ F] with an agent. 4. A positron emission tomography method comprising the N ^1- [ ¹⁸ F] fluorobenzyl heterocyclic compound of claim 1 as an active ingredient (P
ET) diagnostic agent. 5. The compound is 1- (4-butoxy-3- [ ¹⁸
F] fluorobenzyl) -2-butyl-4-chloro-imidazole-5-acetic acid, 1- (4-butoxy- [G-3,5]
[ ¹⁸ F] Difluorobenzyl) -2-butyl-4-chloro-imidazole-5-acetic acid, 1- (2- [ ¹⁸ F] fluoro-4- (2 ′-(tetrazolyl-5) phenyl)) benzyl-2 -Ethoxybenzimidazole-7-carboxylic acid,
1- (3- ^[18 F] fluoro-4- (2 '- (tetrazolyl -5) phenyl)) benzyl-2-ethoxy-benzimidazole-7-carboxylic acid, 1 - ([G-2,5 ] [18 F] difluoro-4- (2 ′-(tetrazolyl-5) phenyl)) benzyl-2-ethoxybenzimidazole-7-carboxylic acid and 1-([G-2,6] [ ¹⁸ F] difluoro-4-
(2 '-(Tetrazolyl-5) phenyl)) benzyl-2-
The diagnostic agent for PET according to claim 4, which is selected from the group consisting of ethoxybenzimidazole-7-carboxylic acid.