阅读说明：本技术 2-[5-（咪唑-1-基甲基）吡啶-3-基]苯并咪唑衍生物化合物及包含其的药物 (2- [5- (imidazol-1-ylmethyl) pyridin-3-yl ] benzimidazole derivative compound and medicine comprising the same ) 是由 井泽彰宏 奥村侑纪 福井友理惠 市川浩章 真矢启史 池永美穗 奥平宏之 土井祥宽 成 于 2018-12-20 设计创作，主要内容包括：本发明提供下式(1)表示的化合物或其盐、及包含其的药物。式(1)中,X<Sub>1</Sub>表示氢原子或卤素原子,X<Sub>2</Sub>表示氟原子或腈基,X<Sub>3</Sub>表示放射性卤素原子。<Image he="312" wi="700" file="DDA0002553131500000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides a compound represented by the following formula (1) or a salt thereof, and a pharmaceutical composition containing the sameA medicine is provided. In the formula (1), X 1 Represents a hydrogen atom or a halogen atom, X 2 Represents a fluorine atom or a nitrile group, X 3 Represents a radioactive halogen atom.)

1. A compound represented by the following formula (1) or a salt thereof,

in the formula (1), X₁Represents a hydrogen atom or a halogen atom, X₂Represents a fluorine atom or a nitrile group, X₃Represents a radioactive halogen atom.

2. The compound or a salt thereof according to claim 1, wherein in the formula (1), X is₁Is a hydrogen atom.

3. The compound or a salt thereof as claimed in claim 2, wherein, in the formula (1), X₂Is a fluorine atom.

4. The compound or a salt thereof according to claim 1, wherein in the formula (1), X is₁Is a halogen atom.

5. The compound or a salt thereof according to any one of claims 1 to 4, wherein in the formula (1), X is₃Is a radioactive fluorine atom.

6. A medicament comprising a compound according to any one of claims 1 to 5 or a salt thereof.

7. The medicament according to claim 6, which is an image diagnostic agent for adrenal disorders.

8. The medicament of claim 6, which is an image diagnostic agent for positron emission tomography.

9. A compound represented by the following formula (2) or a salt thereof,

in the formula (2), X₁Represents a hydrogen atom or a halogen atom, X₂Represents a fluorine atom or a nitrile group, R₁Represents a halogen atom, a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group.

10. A method for producing a radioactive compound represented by the following formula (1) or a salt thereof, wherein the radioactive compound represented by the following formula (1) or a salt thereof is produced from the compound or a salt thereof according to claim 9 by a radioactive halogenation reaction,

in the formula (1), X₁Represents a hydrogen atom or a halogen atom, X₂Represents a fluorine atom or a nitrile group, X₃Represents a radioactive halogen atom.

Technical Field

The present invention relates to 2- [5- (imidazol-1-ylmethyl) pyridin-3-yl ] benzimidazole derivative compounds, and medicaments comprising the same.

Background

As a disease caused by adrenal cortical abnormality, Primary Aldosteronism (PA) is known. Primary aldosteronism is the following disease: the overexpression of aldosterone synthase (CYP11B2) is caused by the proliferation of adrenal adenoma or adrenal gland (non-patent document 1), and the autonomous production of aldosterone from the adrenal gland is promoted, resulting in hypertension and hypokalemia. In the case of unilateral adrenal lesions, surgical removal may be used for treatment, while in the case of bilateral lesions, medication-based treatments may be used.

As a pharmacotherapy for primary aldosteronism, aldosterone receptor antagonists are mainly used at present. CYP11B2, an aldosterone synthase, is being studied as a target molecule for other drug therapies (non-patent document 2).

Etomidate is used as an intravenous anesthetic abroad, but it is known that etomidate inhibits synthesis of adrenocortical steroids mainly by binding to 11 β hydroxylase (CYP11B1) which is essential for biosynthesis of cortisol, corticosterone, and aldosterone (non-patent document 3). Therefore, etomidate has been reported to have a side effect of causing a decrease in aldosterone concentration and cortisol concentration in plasma (non-patent document 4).

In recent years, attempts have been made in humans to visualize adrenal lesions by single photon emission tomography (SPECT) and Positron Emission Tomography (PET) in order to perform non-invasive focal diagnosis of adrenal lesions, such as aldosterone-producing adenomas. Patent documents 1 and 2 and non-patent documents 5 to 8 report various radiolabeled compounds targeting adrenal steroid biosynthetic enzymes. For example, non-patent documents 5 and 8 report the use thereof¹¹As a result of clinical studies on medetomidine (methadate) labeled with C, non-patent document 6 reports the use thereof¹⁸Results of clinical studies on F-labeled etomidate, and reports on the use thereof in non-patent documents 7 and 9¹²³Results of a clinical study with the label iodomedetomidate. These radiolabeled compounds are reported to be useful for imaging adrenal lesions.

The inventors of the present application have found that a 2- (3-pyridyl) -1H-benzimidazole derivative compound specifically accumulates in an aldosterone-producing tumor, and have proposed to use the compound as an image diagnostic agent for adrenal disorders, a therapeutic agent for aldosterone-producing tumors, and the like (patent document 4).

Disclosure of Invention

Patent document 3 discloses a compound having high CYP11B2 selectivity, but does not describe specific accumulation in aldosterone-producing tumors in normal regions of the adrenal gland.

Patent document 4 discloses a certain specific binding property of a 2- (3-pyridyl) -1H-benzimidazole derivative compound to a human aldosterone-producing tumor, but a compound having a higher binding property to a human aldosterone-producing tumor is required.

The present invention has been made in view of the above circumstances, and an object thereof is to provide a compound having specific and higher binding properties to an aldosterone-producing tumor, and a drug containing the same.

That is, one embodiment of the present invention provides a compound represented by the following formula (1) or a salt thereof.

[ chemical formula 1]

In the above formula (1), X₁Represents a hydrogen atom or a halogen atom, X₂Represents a fluorine atom or a nitrile group, X₃Represents a radioactive halogen atom. X₁When it is a hydrogen atom, X₂Preferably a fluorine atom. X₁When it is a halogen atom, X₂May be any of a fluorine atom and a nitrile group.

Another embodiment of the present invention provides a compound represented by the following formula (2) or a salt thereof.

[ chemical formula 2]

In the above formula (2), X₁Represents a hydrogen atom or a halogen atom, X₂Represents a fluorine atom or a nitrile group, R₁Represents a halogen atom, a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group.

In another embodiment of the present invention, there is provided a method for producing a radioactive compound represented by the above formula (1) or a salt thereof from a compound represented by the above formula (2) or a salt thereof by a radioactive halogenation reaction.

The present invention provides a compound having a high binding property to a human aldosterone-producing tumor, and a pharmaceutical agent comprising the same.

Drawings

[ FIG. 1] A]To use compounds separatelyArticle [ 2]¹⁸F]100 (control), (ii)¹⁸F]101、[¹⁸F]102 and [ 2]¹⁸F]103 in the autoradiogram obtained in evaluation 1 of the example, samples 1 to 6 each represent a different region of interest, Compound [ 2], in the lesion region¹⁸F]The left column of 100 (control) shows the results of immunohistochemical staining of the same samples. The autoradiogram in the figure is an autoradiogram in which accumulation of radioactivity in each region (lesion region, normal region) is represented on the same scale with reference to a standard radiation source. In addition, the arrows in the column "immunohistochemical staining" in the figure indicate the lesion areas of the human aldosterone-producing tumors.

[ FIG. 2A)]To show the compound obtained in example¹⁸F]101 in vivo distribution in the liver, kidney and spleen over time.

[ FIG. 2B]To show the compound obtained in example¹⁸F]102 in vivo distribution in the liver, kidney and spleen over time.

[ FIG. 2C ]]To show the compound obtained in example¹⁸F]103 in vivo distribution in the liver, kidney and spleen, and "＊" in the figure indicates that the number of experiments was 1.

Detailed Description

In the present invention, the "halogen atom" is at least one selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and an astatine atom.

In the present invention, the term "salt" may be a pharmaceutically acceptable salt. For example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosyl acid (glucuronic acid, galacturonic acid, and the like), α -hydroxy acids (citric acid, tartaric acid, and the like), amino acids (aspartic acid, glutamic acid, and the like), aromatic acids (benzoic acid, cinnamic acid, and the like), sulfonic acids (p-toluenesulfonic acid, ethanesulfonic acid, and the like) can be formed.

In the present invention, the "radioactive halogen atom" isAt least one selected from radioactive isotopes of fluorine, chlorine, bromine and iodine, preferably used¹⁸F、^34mCl、⁷⁶Br、¹²³I、¹²⁴I or¹²⁵I. Here, in the present invention, the "radioactive iodine atom" means¹²³I、¹²⁴I or¹²⁵Any of I.

In the formula (1), X is represented by the formula₁When it is a hydrogen atom, X₂Preferably a fluorine atom. From the same viewpoint, X in the above formula (1)₁When it is a halogen atom, X₂Preferably a fluorine atom or a nitrile group. From the same viewpoint, X in the above formula (1)₁When it is a fluorine atom, X₂Preferably a fluorine atom or a nitrile group.

In the above formula (1), a radioactive halogen atom is used as X₃And can be applied to the use of an image diagnostic agent for nuclear medicine examination.

Preferred embodiments of the compound according to the present invention include 3 compounds represented by the following chemical formula.

[ chemical formula 3]

[ chemical formula 4]

[ chemical formula 5]

In the present invention, the substituted or unsubstituted alkylsulfonyloxy group is preferably an alkylsulfonyloxy group having 1 to 12 carbon atoms. For substituted alkylsulfonyloxy groups, the hydrogen atoms of the alkyl chain may be substituted by halogen atoms. In the present invention, the substituted or unsubstituted arylsulfonyloxy group is preferably a substituted or unsubstituted phenylsulfonyloxy group, and more preferably a substituted phenylsulfonyloxy group. The substituted arylsulfonyloxy group is preferably a group in which a hydrogen atom of an aryl ring is substituted with an alkyl group having 1 to 12 carbon atoms or a nitro group. Preferred examples of the substituted or unsubstituted alkylsulfonyloxy group and the substituted or unsubstituted arylsulfonyloxy group include a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group and a trifluoromethanesulfonyloxy group.

An example of a method for producing a radioactive compound represented by the above formula (1) will be described below with reference to the following scheme 1. X in the compound represented by the formula (1)₃A compound which is a hydroxyl group as a starting material, wherein R in the above formula (2) is introduced into the hydroxyl group₁The group shown (halogen atom, substituted or unsubstituted alkylsulfonyloxy group, or substituted or unsubstituted arylsulfonyloxy group) as a labeling precursor gives a compound represented by the above formula (2) (scheme 1, step a). Next, targeting R using radioactive halide ions₁Nucleophilic substitution reaction of the group shown above gives a radioactive compound represented by the above formula (1) (scheme 1, step b).

[ chemical formula 6]

Here, the "radioactive halide ion" may include a radioactive fluoride ion (for example, ")¹⁸F]Fluoride ion), radioactive chloride ion (e.g., etc^34mCl]Chloride ion), radioactive bromide ion (e.g., etc⁷⁶Br]Bromide ion), radioactive iodide ion (e.g., etc¹²³I]Iodide ion, [ 2]¹²⁴I]Iodide ion, [ 2]¹²⁵I]Iodide ion). When a radioactive fluoride ion is used, R in the compound represented by the above formula (2) is used as a labeling precursor₁Is preferably a chlorine atom, a bromine atom, an iodine atom, a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group. In addition, when radioactive chloride ions are used,as the labeling precursor, in the compound represented by the above formula (2), R₁Is preferably a bromine atom, an iodine atom, a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group. When a radioactive bromide ion is used, R in the compound represented by the above formula (2) is used as a labeling precursor₁Is preferably an iodine atom, a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group. When a radioactive iodide ion is used, R in the compound represented by the above formula (2) is used as a labeling precursor₁Is preferably a substituted or unsubstituted alkylsulfonyloxy group, or a substituted or unsubstituted arylsulfonyloxy group. The nucleophilic substitution reaction using such a radioactive halide ion is preferably carried out in the presence of a base such as an alkali metal carbonate (for example, sodium carbonate or potassium carbonate).

For example, X in the radioactive compound represented by the above formula (1) can be obtained by performing a radiofluorination reaction using a radiofluoride ion₃Is a radioactive compound of radioactive fluorine atom. The radiofluorination reaction is preferably carried out in the presence of a base, and may also be carried out in the presence of 4,7,13,16,21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ]]In the presence of various phase transfer catalysts such as hexacosane (trade name: Kryptofix 222).

When the radioactive compound represented by the above formula (1) or a salt thereof is used as a pharmaceutical, it is preferable that after the radioactive halogenation reaction, unreacted radioactive halogen and insoluble impurities are removed by a membrane filter, a column packed with various fillers, HPLC, or the like and purified.

In the present invention, a drug can also be produced from the compound produced in the above-described manner or a salt thereof. In this specification, "drug" may be defined as: a formulation comprising a compound represented by the above formula (1) or a salt thereof in a form suitable for administration into a living body. The medicament may be administered orally or parenterally (e.g., intravenously, subcutaneously, intramuscularly, intramedullary, topically, rectally, transdermally, nasally or pulmonarily). Examples of administration forms for oral administration include tablets, capsules, pills, granules, fine granules, powders, liquid preparations, syrups, suspensions, and the like. Examples of administration forms for parenteral administration include aqueous preparations for injection, oily preparations for injection, suppositories, nasal preparations, percutaneous absorbents (lotions, emulsions, ointments, creams, mucilages, gels, patches (tape preparations, transdermal patch preparations (patch preparations), wet cloths, etc.), powders for external use, and the like).

The medicaments to which the present invention relates may be prepared using known techniques and may further contain non-toxic and inactive carriers commonly used in the art of formulation. The carrier that can be contained in the drug of the present invention is not particularly limited as long as it is a substance that is commonly used in the field of pharmaceutical preparations and does not react with the compound represented by the above formula (1) or a salt thereof, and examples thereof include excipients, binders, lubricants, stabilizers, disintegrants, buffers, solubilizing agents, isotonic agents, solubilizing agents, pH adjusters, surfactants, emulsifiers, suspending agents, dispersants, anti-settling agents, thickeners, viscosity adjusters, gelling agents, analgesics, preservatives, plasticizers, percutaneous absorption enhancers, anti-aging agents, moisturizers, preservatives, perfumes, and the like. These carriers may be used in combination of two or more kinds as appropriate.

In addition, the drug of the present invention can be highly accumulated specifically in an aldosterone-producing tumor when introduced into a living body. Thus, by using a radioactive halogen atom as X in the above formula (1)₃The halogen atom (b) can be used to detect radiation noninvasively from outside the living body by using a radioactive detector, a single photon emission tomography scanner, a positron emission tomography scanner, scintigraphy, or the like, and can image aldosterone-producing tumors and adrenal gland diseases. Therefore, the drug of the present invention is useful as an image diagnostic agent for nuclear medicine examination, specifically, an image diagnostic agent for Positron Emission Tomography (PET) and an image diagnostic agent for single photon emission tomography (SPECT). For example, use¹⁸F、⁷⁶Br、¹²⁴When a positron-emitting nuclide such as I is a radioactive halogen atom, it can be used as an image for positron emission tomographyUse of a diagnostic agent, use¹²³When I is a radioactive halogen atom, it can be used as a diagnostic imaging agent for single photon emission tomography. In addition, the compound can also be used in the above formula (1)¹⁹F is an element suitable for nuclear magnetic signal measurement as X₃And a halogen atom of (a) to image an aldosterone-producing tumor using a magnetic resonance imaging device (MRI).