JP2015214527A - Imidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel pyrazine derivative that is useful as a therapeutic agent or preventive agent for diseases associated with URAT1, such as gout, hyperuricemia, hypertension, kidney diseases such as interstitial nephritis, diabetes, arteriosclerosis, or Lesch-Nyhan syndrome.SOLUTION: The present invention provides an imidazole derivative that is represented by formula (I), or pharmaceutically acceptable salt or solvate thereof.

Description

  The present invention relates to an imidazole derivative useful as a pharmaceutical product. More specifically, the pyrazine-substituted imidazole derivative has URAT1 inhibitory activity, and includes gout, hyperuricemia, hypertension, interstitial nephritis and other renal diseases, diabetes, arteriosclerosis, Lesch-Nyhan syndrome, etc. The present invention relates to an imidazole derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof useful for the treatment or prevention of a disease involving URAT1.

  Uric acid is the final product produced by purine bodies being degraded in the liver. The main excretion route of uric acid in the living body is kidney, about 2/3 is excreted in urine, and the rest is excreted from feces. Although the blood uric acid level of healthy persons is maintained, hyperuricemia occurs due to excessive uric acid production or decreased uric acid excretion.

  Hyperuricemia, which results in a high blood uric acid level, is a factor that causes gout and urinary calculi, and is also said to be a cause of kidney damage and arteriosclerosis. In recent years, research reports that the higher the blood uric acid level, the higher the incidence of lifestyle-related diseases such as metabolic syndrome and hypertension, and chronic kidney disease, are being recognized as a risk factor for these diseases. Therefore, improvement of hyperuricemia is expected to lead to improvement of various diseases (Non-Patent Document 1).

  Recently, a gene (SLC22A12) encoding a human kidney urate transporter has been identified. The transporter (urate transporter 1, URAT1) encoded by this gene is a 12-transmembrane molecule belonging to the OAT family, which expresses mRNA specifically in the kidney, and further, proximal tubules in human kidney tissue sections. Localization on the luminal side was observed. Experiments using the Xenopus oocyte expression system showed uric acid uptake via URAT1. Furthermore, it has been reported that probenecid or benzbromarone that inhibits URAT1 is useful as a therapeutic or prophylactic agent for hyperuricemia and gout (Non-patent Document 2).

Edited by the Japan Gout and Nucleic Acid Metabolism Society Guidelines Revision Committee Guidelines for Treatment of Hyperuricemia and Gout 2nd Edition, Medical Review (2010) Enomoto A. et al. , Nature 417, 447-452 (2002).

The problem to be solved by the present invention is to provide a novel compound having URAT1 inhibitory activity.
Another object of the present invention is to provide gout, hyperuricemia, hypertension, interstitial nephritis and other renal diseases, diabetes, arteriosclerosis, containing the novel compound having URAT1 inhibitory activity as an active ingredient. Or a therapeutic or prophylactic agent for a disease involving URAT1, such as Lesch-Nyhan syndrome.
Furthermore, another object of the present invention is to provide a URAT1 inhibitor or a pharmaceutical composition having URAT1 inhibitory activity.

  As a result of intensive studies to solve the above problems, the present inventors have reached the following invention. That is, the present invention is an imidazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof. Furthermore, the imidazole derivatives of the present invention and pharmaceutically acceptable salts thereof, and solvates thereof have excellent URAT1 inhibitory activity.

Ｒ^４は、水素原子、又はＣ_１〜Ｃ_６アルキル基を表し、
Ｒ^５、及びＲ^６は、同一又は異なって、水素原子、Ｃ_１〜Ｃ_６アルキル基、ハロゲン原子、Ｃ_１〜Ｃ_６アルコキシ基、トリフルオロメチル基、トリフルオロメトキシ基、シアノ基、ニトロ基、又はＣ_１〜Ｃ_３アルキレンジオキシ基を表し、
ただし、Ｒ^５及びＲ^６のどちらか一方が水素原子である場合、他方は水素原子、又はハロゲン原子ではなく、
Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、及びＲ^１４は、同一又は異なって、水素原子、ハロゲン原子、Ｃ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６アルコキシ基、ジフルオロメチル基、トリフルオロメチル基、シアノ基、又はジ（Ｃ_１〜Ｃ_６アルキル）アミノ基を表し、
ただし、Ｒ^１１及びＲ^１２のどちらか一方が水素原子である場合、他方は水素原子ではなく、
Ｒ^１５及びＲ^１６は、ハロゲン原子を表し、
ｐ及びｑは、０又は１を表し、
Ｗは、硫黄原子、酸素原子、又はＮＲ^ｇを表し、
Ｒ^ｇは、水素原子、Ｃ_１〜Ｃ_６アルキル基、又はベンジル基を表す。］ [Where:
A represents a single bond, a sulfur atom, —S (O) ₂ —, or an oxygen atom,
When A is a single bond,
R ¹ is a C ₂ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group optionally substituted by ¹ to 3 R ^a. , C ₃ -C ₆ cycloalkyl C ₁ -C ₃ alkyl group, or optionally substituted by 1 to 3 R ^b {Phenyl group, naphthalen-2-yl group, pyrazol-2-yl group, pyrazole -4-yl group, pyrazol-5-yl group, pyrrol-2-yl group, furan-2-yl group, furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, thiazole- 5-yl group, benzothiophen-2-yl group, or benzothiophen-3-yl group}
When A is an oxygen atom, a sulfur atom, or —S (═O) ₂ —, R ¹ is a C _{1 to} C ₆ alkyl group optionally substituted with 1 to 3 R ^a , C ₃ to C ₆ cycloalkyl represents a C ₁ -C ₃ alkyl group, or a C ₂ -C ₆ alkynyl group,
R ^a is a hydroxyl group, a cyano group, a halogen atom, a trifluoromethyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₆ alkenyl group, a C ₁ -C ₆ alkynyl group, a C ₂ -C ₇ alkylcarbonyl group, Represents a phenyl group optionally substituted with ₁ to 3 C ₁ -C ₆ alkyl groups, a C ₃ -C ₆ cycloalkyl group, or —CONH— (C ₁ -C ₆ alkyl);
R ^b represents a C _{1 to} C ₆ alkyl group, a C _{1 to} C ₆ alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxyl group, or a C _{2 to} C ₇ alkylcarbonyl group,
R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a halogen atom, a trifluoromethyl group, a phenyl group which may be substituted with 1 to 3 halogen atoms, C ₂ -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 1 -C ₆ alkoxy _group, C 2 -C ₇ alkylcarbonyl _group, C 1 -C ₆ alkylthio group, a difluoromethyl group, a cyano group, a phenoxy group, Or COOR ^c ,
R ^c represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a tetrazolyl group, —COOR ^d , or —CONHSOOR ^e ,
R ^d is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with one phenyl group, a trifluoromethyl group, a phenyl group optionally substituted with 1 to 3 R ^f , or pyridyl. Represents a group,
R ^e is optionally substituted with one phenyl group, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a trifluoromethyl group, and 1 to 3 R ^f. Represents a good phenyl group, pyridyl group,
R ^f represents a C _{1 to} C ₆ alkyl group or a halogen atom,
Z represents any of the groups represented by the following Z1 to Z7,

R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen atom, a C ₁ -C ₆ alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, or a nitro group. , or represents _C 1 -C ₃ alkylenedioxy group,
However, when one of R ⁵ and R ⁶ is a hydrogen atom, the other is not a hydrogen atom or a halogen atom,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are the same or different and are a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or C ₁ -C _6. Represents an alkoxy group, a difluoromethyl group, a trifluoromethyl group, a cyano group, or a di (C ₁ -C ₆ alkyl) amino group;
However, when one of R ¹¹ and R ¹² is a hydrogen atom, the other is not a hydrogen atom,
R ¹⁵ and R ¹⁶ represent a halogen atom;
p and q represent 0 or 1,
W represents a sulfur atom, an oxygen atom, or NR ^g ;
R ^g represents a hydrogen _atom, C 1 -C ₆ alkyl group, or a benzyl group. ]

The present invention also relates to a pharmaceutical composition comprising the imidazole derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
Furthermore, the present invention provides a URAT1 inhibitor containing an imidazole derivative represented by the following formula (IA) or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, and a formula (IA) Gout, hyperuricemia, hypertension, kidney disease, diabetes, arteriosclerosis, and Lesch-Nyhan syndrome, which contain an imidazole derivative or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient And the like, a preventive or therapeutic agent for diseases involving URAT1.

Ｒ^４は、水素原子、又はＣ_１〜Ｃ_６アルキル基を表し、
Ｒ^５’、及びＲ^６’は、同一又は異なって、水素原子、Ｃ_１〜Ｃ_６アルキル基、ハロゲン原子、Ｃ_１〜Ｃ_６アルコキシ基、トリフルオロメチル基、トリフルオロメトキシ基、シアノ基、ニトロ基、Ｃ_１〜Ｃ_３アルキレンジオキシ基、又はフェノキシ基を表し、
Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、及びＲ^１４は、同一又は異なって、水素原子、ハロゲン原子、Ｃ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６アルコキシ基、ジフルオロメチル基、トリフルオロメチル基、シアノ基、又はジ（Ｃ_１〜Ｃ_６アルキル）アミノ基を表し、
Ｒ^１５及びＲ^１６は、ハロゲン原子を表し、
ｐ及びｑは、０又は１を表し、
Ｗは、硫黄原子、酸素原子、又はＮＲ^ｇを表し、
Ｒ^ｇは、水素原子、Ｃ_１〜Ｃ_６アルキル基、又はベンジル基を表す。］ [Where:
A represents a single bond, a sulfur atom, —S (═O) ₂ —, or an oxygen atom,
When A is a single bond,
R ^{1 ′} is a C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl optionally substituted with 1 to 3 R ^a. Group, C ₃ -C ₆ cycloalkyl C ₁ -C ₃ alkyl group, or optionally substituted by 1 to 3 R ^b {phenyl group, naphthalen-2-yl group, pyrazol-2-yl group, Pyrazol-4-yl group, pyrazol-5-yl group, pyrrol-2-yl group, furan-2-yl group, furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, thiazole -5-yl group, benzothiophen-2-yl group, or benzothiophen-3-yl group}
When A is an oxygen atom, a sulfur atom, or —S (═O) ₂ —, R ^{1 ′} is a C _{1 to} C ₆ alkyl group optionally substituted with 1 to 3 R ^{a s} , C ₃ -C ₆ cycloalkyl _C 1 -C ₃ alkyl _group, a C 2 -C ₆ alkynyl group, or 1-3 phenyl group which may be substituted by ^{R b,}
R ^a is a hydroxyl group, a cyano group, a halogen atom, a trifluoromethyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₂ -C ₇ alkylcarbonyl group, Represents a phenyl group optionally substituted with ₁ to 3 C ₁ -C ₆ alkyl groups, a C ₃ -C ₆ cycloalkyl group, or —CONH— (C ₁ -C ₆ alkyl);
R ^b represents a C _{1 to} C ₆ alkyl group, a C _{1 to} C ₆ alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxyl group, or a C _{2 to} C ₇ alkylcarbonyl group,
R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a halogen atom, a trifluoromethyl group, a phenyl group which may be substituted with 1 to 3 halogen atoms, C ₂ -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 1 -C ₆ alkoxy _group, C 2 -C ₇ alkylcarbonyl _group, C 1 -C ₆ alkylthio group, a difluoromethyl group, a cyano group, a phenoxy group, Or COOR ^c ,
R ^c represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a tetrazolyl group, —COOR ^d , or —CONHSOOR ^e ,
R ^d is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with one phenyl group, a trifluoromethyl group, a phenyl group optionally substituted with 1 to 3 R ^f , or pyridyl. Represents a group,
R ^e is optionally substituted with one phenyl group, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a trifluoromethyl group, and 1 to 3 R ^f. Represents a good phenyl group, pyridyl group,
R ^f represents a C _{1 to} C ₆ alkyl group or a halogen atom,
Z represents any of the following groups represented by Z1 ′ or Z2 to Z7,

R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ^{5 ′} and R ^{6 ′} are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen atom, a C ₁ -C ₆ alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro _group, C 1 -C ₃ alkylenedioxy group, or phenoxy group,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are the same or different and are a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or C ₁ -C _6. Represents an alkoxy group, a difluoromethyl group, a trifluoromethyl group, a cyano group, or a di (C ₁ -C ₆ alkyl) amino group;
R ¹⁵ and R ¹⁶ represent a halogen atom;
p and q represent 0 or 1,
W represents a sulfur atom, an oxygen atom, or NR ^g ;
R ^g represents a hydrogen _atom, C 1 -C ₆ alkyl group, or a benzyl group. ]

  According to the present invention, it is useful as a therapeutic or prophylactic agent for diseases involving URAT1, such as gout, hyperuricemia, hypertension, renal diseases such as interstitial nephritis, diabetes, arteriosclerosis, or Lesch-Nyhan syndrome Novel imidazole derivatives or pharmaceutically acceptable salts thereof, or solvates thereof.

  Terms used alone or in combination in the present specification will be described below. Unless otherwise specified, the description of each substituent is common to each site. Also, combinations of substituents and variables are allowed only if such a combination results in a chemically stable compound. If the substituent itself is substituted with more than one group, these multiple groups can be on the same or different carbons as long as a stable structure results.

In the present invention, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present invention, the “C ₁ -C ₆ alkyl group” means a linear or branched aliphatic saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Specific examples include butyl group, isobutyl group, t-butyl group, pentyl group, isopentyl group, and hexyl group.

In the present invention, the “C ₂ -C ₆ alkenyl group” means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms having an unsaturated double bond, such as a vinyl group, 1 -Propenyl group, 2-propenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 2-buten-1-yl group, 2-buten-1-yl group, 3-butene-1 -Yl group, 2-penten-1-yl group, 3-penten-1-yl group, 4-penten-1-yl group, 5-hexen-1-yl group, 4-hexen-1-yl group, 3 -Hexen-1-yl group, 2-hexen-1-yl group, 3-methyl-2-buten-1-yl group, 3-methyl-3-penten-1-yl group, 3-methyl-2-pentene -1-yl group, 4-methyl-3-penten-1-yl group, 4-methyl-2-pente 1-yl group, and 2-methyl-2-penten-1-yl group, and the like.

In the present invention, the “C ₂ -C ₆ alkynyl group” means a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms having an unsaturated triple bond, such as an ethynyl group, 1- Propyn-1-yl group, 2-propyn-1-yl group, 2-butyn-1-yl group, 3-butyn-1-yl group, 2-pentyn-1-yl group, 3-pentyn-1-yl Group, 4-pentyn-1-yl group, 5-hexyn-1-yl group, 4-hexyn-1-yl group, 3-hexyn-1-yl group, 2-hexyn-1-yl group, and the like. It is done.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” means a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. It can be mentioned as a specific group.
In the present invention, “C ₃ -C ₆ cycloalkyl C ₁ -C ₃ alkyl group” means that “C ₁ -C ₃ alkyl group” is substituted with one “C ₃ -C ₆ cycloalkyl group” at any position. For example, cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpentyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclohexylmethyl group, and cyclohexylethyl group. Can be mentioned as a specific group.

In the present invention, the “C ₁ -C ₆ alkoxy group” means a linear or branched aliphatic saturated hydrocarbon oxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, Specific examples include an isopropoxy group, a butoxy group, an isobutoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group.

In the present invention, the “C ₂ -C ₇ alkylcarbonyl group” means a group consisting of a “C ₁ -C ₆ alkyl group” and a carbonyl group. For example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, n -Pentylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group, isopentylcarbonyl group, 2-methylbutylcarbonyl group, 3-methylbutylcarbonyl group, 1-ethylpropylcarbonyl group, 1,1-dimethylpropylcarbonyl group Group, 1,2-dimethylpropylcarbonyl group, neopentylcarbonyl group, 4-methylpentylcarbonyl group, 3-methylpentylcarbonyl group, 2-methylpentylcarbonyl group, 1-methylpentylcarbonyl group, 3,3-dimethylbutyl Carbonyl group, 2,2-dimethylbut Rucarbonyl group, 1,1-dimethylbutylcarbonyl group, 1,2-dimethylbutylcarbonyl group, 1,3-dimethylbutylcarbonyl group, 2,3-dimethylbutylcarbonyl group, 1-ethylbutylcarbonyl group, 2-ethyl Examples thereof include a butylcarbonyl group and an n-hexylcarbonyl group.

In the present invention, the “C ₁ -C ₆ alkylsulfonyl group” means a group consisting of a “C ₁ -C ₆ alkyl group” and a sulfonyl group. For example, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, isopropyl Examples include a sulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, and a hexylsulfonyl group.

In the present invention, “di (C ₁ -C ₆ alkyl) amino group” means an amino group in which two identical or different “C ₁ -C ₆ alkyl groups” are substituted on nitrogen, for example, dimethyl Amino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di (sec-butyl) amino group, di (tert-butyl) amino group, dipentylamino group, dihexylamino group, etc. Is mentioned.

In the present invention, the “C ₁ -C ₆ alkylthio group” means a group consisting of a “C ₁ -C ₆ alkyl group” and a thio group. For example, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, Examples include butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, neopentylthio group, tert-pentylthio group, 2-methylbutylthio group, hexylthio group, and isohexylthio group.

In the present invention, the “C ₁ -C ₃ alkylenedioxy group” means a group consisting of C ₁ -C ₃ alkylene and two oxy groups. For example, methylenedioxy (-OCH ₂ O-), ethylenedioxy _{(-OCH 2} CH ₂ O-), trimethylenedioxy _{(-OCH 2 CH 2 CH 2 O-} ), and propylene dioxy (-OCH ₂ CH _(CH 3) O-) group and the like.

In the present invention, the “C ₁ -C ₃ alkylene group” is formed by losing two hydrogen atoms from two different carbon atoms of a saturated straight chain or branched aliphatic hydrocarbon having 1 to 3 carbon atoms. This means a divalent group, and examples include methylene, ethylene, trimethylene, and tetramethylene groups.

In the above definition, for example, “C” such as “C ₁ ” represents a carbon atom, and the number attached thereafter represents the number of carbon atoms. For example, “C ₁ -C ₆ ” represents a range from 1 to 6 carbon atoms. Of course, in the present invention, if the number of carbon atoms is different, it means that group having that carbon number. For example, “C ₂ -C ₆ alkyl group” means an alkyl group defined by “C ₁ -C ₆ alkyl group” having 2 to 6 carbon atoms. The same applies to the treatment of the number of carbon atoms in other groups.

  The present invention relates to an imidazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof.

  Furthermore, the present invention provides a URAT1 inhibitor containing an imidazole derivative represented by the following formula (IA) or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, and gout, hyperuricemia Further, the present invention relates to a therapeutic or prophylactic agent for one or more diseases selected from hypertension, kidney disease, diabetes, arteriosclerosis, or Lesch-Nyhan syndrome.

Since the imidazole derivative represented by the formula (IA) includes the imidazole derivative represented by the formula (I), the imidazole derivative represented by the formula (I) and the imidazole derivative represented by (IA) Matters common to both are explained together.
In the formulas (I) and (IA), A represents a single bond, a sulfur atom, —S (O) ₂ —, or an oxygen atom. Among them, A is preferably a single bond or a sulfur atom, and particularly preferably a single bond.

In the formula (I), when A is a single bond, R ¹ is a C ₂ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₂ which may be substituted with 1 to 3 R ^a. -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₃ -C ₆ cycloalkyl C ₁ -C ₃ alkyl group, 1 to 3 phenyl groups optionally substituted with R ^b , 1 to 3 R ^b in the optionally substituted naphthalen-2-yl group, 1-3 R ^b in the optionally substituted pyrazol-2-yl group, optionally substituted with 1-3 R ^b which may pyrazol-4-yl group, 1-3 ^{R b} in an optionally substituted pyrazol-5-yl group, 1-3 ^{R b} in the optionally substituted pyrrol-2-yl group , 1-3 ^{R b} may be substituted with furan-2-yl group, substituted with 1-3 ^{R b} Which may be furan-3-yl group, 1-3 R ^b in the optionally substituted thiophen-2-yl group, 1-3 R ^b may be substituted by thiophene -3 - yl group, 1-3 optionally substituted by ^{R b} thiazol-5-yl group, 1-3 ^{R b} in the optionally substituted benzothiophen-2-yl group, or 1 The benzothiophen-3-yl group which may be substituted by 3 ^Rb is represented.

In the formula (IA), when A is a single bond, R ^{1 ′} is a C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₆ optionally substituted with 1 to 3 R ^a , C _{2 to} C ₆ alkenyl groups, C _{2 to} C ₆ alkynyl groups, C _{3 to} C ₆ cycloalkyl C _{1 to} C ₃ alkyl groups, 1 to 3 phenyl groups optionally substituted with R ^b , 1 to 3 number of R ^b in an optionally substituted naphthalen-2-yl group, 1-3 R ^b in the optionally substituted pyrazol-2-yl group, optionally substituted with 1-3 R ^b which may be pyrazol-4-yl group, 1-3 ^{R b} in an optionally substituted pyrazol-5-yl group, 1-3 ^{R b} may be substituted pyrrole-2-yl group, 1-3 ^{R b} may be substituted with furan-2-yl group, with 1-3 ^{R b} Conversion which may be furan-3-yl group, 1-3 R ^b in the optionally substituted thiophen-2-yl group, 1-3 good thiophene optionally substituted by R ^b - 3-yl group, 1-3 optionally substituted by ^{R b} thiazol-5-yl group, 1-3 ^{R b} in the optionally substituted benzothiophen-2-yl group, or 1 Represents a benzothiophen-3-yl group optionally substituted with 3 ^Rb .

In the formula (I), when A is an oxygen atom, a sulfur atom, or —S (═O) ₂ —, R ¹ may be substituted with 1 to 3 R ^a C _{1 to} C ₆ alkyl _group, a C 3 -C ₆ cycloalkyl _C 1 -C ₃ alkyl or _C 2 -C ₆ alkynyl group.
In the formula (IA), when A is an oxygen atom, a sulfur atom, or —S (═O) ₂ —, R ^{1 ′} may be substituted with 1 to 3 R ^a C ₁ to C ₆ alkyl _group, a C 3 -C ₆ cycloalkyl _C 1 -C ₃ alkyl _group, C 2 -C ₆ alkynyl group, or 1-3 phenyl group which may be substituted by ^{R b.}

In the formulas (I) and (IA), R ^a is a hydroxyl group, a cyano group, a halogen atom, a trifluoromethyl group, a C _{1 to} C ₆ alkoxy group, a C _{2 to} C ₆ alkenyl group, or a C _{2 to} C ₆ alkynyl. _group, C 2 -C ₇ alkylcarbonyl group, 1-3 _C 1 -C ₆ alkyl phenyl group optionally substituted with a _group, C 3 -C ₆ cycloalkyl group, or a -CONH- _(C 1 ~ It represents a C ₆ alkyl).

In the formulas (I) and (IA), R ^b is a C _{1 to} C ₆ alkyl group, a C _{1 to} C ₆ alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxyl group, or C _{2 to} C _7. Represents an alkylcarbonyl group.

In the formula (I), R ¹ is substituted with 1 to 3 R ^a in common when A represents a single bond, a sulfur atom, —S (═O) ₂ —, or an oxygen atom. which may be _C 2 -C ₆ alkyl group, or a _C 2 -C ₆ alkynyl group are preferable, among them, an ethyl group, a propyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, cyclohexylmethyl group, phenylethyl group, A 2-butyn-1-yl group or an isopropyl group is preferred.

In the formula (IA), R ^{1 ′} is substituted with 1 to 3 R ^a in common when A represents a single bond, a sulfur atom, —S (═O) ₂ —, or an oxygen atom. C ₁ -C ₆ alkyl group which may be substituted is preferable, and among them, methyl group, ethyl group, propyl group, butyl group, isobutyl group, cyclopropylmethyl group, cyclohexylmethyl group, phenylmethyl group, phenylethyl group, 2 -A butyn-1-yl group or an isopropyl group is more preferable.

In the formulas (I) and (IA), R ² is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a halogen atom, a trifluoromethyl group, or 1 to 3 halogen atoms. in an optionally substituted phenyl _group, C 2 -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 1 -C ₆ alkoxy _group, C 2 -C ₇ alkylcarbonyl _group, C 1 -C ₆ alkylthio group , Difluoromethyl group, cyano group, phenoxy group, or COOR ^c . R ^c represents a hydrogen atom or a C _{1 to} C ₆ alkyl group.

In the formulas (I) and (IA), R ² is substituted with a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a halogen atom, or 1 to 3 halogen atoms. An optionally substituted phenyl group is preferred, and among them, a hydrogen atom, a methyl group, a cyclopropyl group, a butyl group, a chlorine atom, or a phenyl group optionally substituted with 1 to 3 halogen atoms is more preferred. Furthermore, a methyl group or a chlorine atom is preferable.

In the formulas (I) and (IA), R ³ represents a tetrazolyl group, —COOR ^d , or —CONHSOOR ^e . R ^d is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with one phenyl group, a trifluoromethyl group, a phenyl group optionally substituted with 1 to 3 R ^f , or pyridyl. Represents a group. R ^e is optionally substituted with one phenyl group, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a trifluoromethyl group, and 1 to 3 R ^f. It may represent a phenyl group or a pyridyl group. R ^f _is, represents a C 1 -C ₆ alkyl group, or a halogen atom.

In the formulas (I) and (IA), R ³ is preferably a carboxyl group, a tetrazolyl group, —CONHSOOMe, —CONHSOOcPr, a methoxycarbonyl group, or an ethoxycarbonyl group, and among them, a carboxyl group, a methoxycarbonyl group, or an ethoxy group. A carbonyl group is more preferred.

In the formula (I), Z represents any of the groups represented by the following Z1 to Z7, and in the formula (IA), Z represents any of the groups represented by Z1 ′ or Z2 to Z7.

In the formula (I), R ⁴ in Z ₁ represents a hydrogen atom or a C ₁ -C ₆ alkyl group. R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen atom, a C ₁ -C ₆ alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, or a nitro group. , or a _C 1 -C ₃ alkylenedioxy group. R ¹⁵ represents a halogen atom, and p represents 0 or 1.
However, in the formula (I), when either one of R ⁵ and R ^{6 in} Z1 is a hydrogen atom, the other is not a hydrogen atom or a halogen atom.

In the formula (IA), R ⁴ in Z ₁ represents a hydrogen atom or a C ₁ -C ₆ alkyl group. R ^{5 ′} and R ^{6 ′} are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen atom, a C ₁ -C ₆ alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro _group, a C 1 -C ₃ alkylenedioxy group, or a phenoxy group. R ¹⁵ represents a halogen atom, and p represents 0 or 1.

In the formulas (I) and (IA), R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ in Z2 to Z7 are the same or different and are hydrogen atoms. represents a halogen _atom, C 1 -C ₆ alkyl _group, C 1 -C ₆ alkoxy group, a difluoromethyl group, a trifluoromethyl group, a cyano group, or a di _(C 1 -C ₆ alkyl) amino group. W represents a sulfur atom, an oxygen atom, or NR ^g. R ^g represents a hydrogen _atom, C 1 -C ₆ alkyl group, or a benzyl group. R ¹⁶ represents a halogen atom, and q represents 0 or 1.
However, in the formula (I), when one of R ¹¹ and R ^{12 in} Z6 is a hydrogen atom, the other is not a hydrogen atom.

Hereinafter, preferable Z1 to Z7 will be described as common to the formulas (I) and (IA).
In the formulas (I) and (IA), Z is preferably Z1 to Z3.
A more preferred specific example of Z1 is a group represented by the following formula Z1a.

R ⁴ is preferably a hydrogen atom, and R ⁵ and R ⁶ are each preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, a trifluoromethyl group, or a cyano group. Among these, a methyl group, a fluorine atom, a chlorine atom, a bromine atom, or a trifluoromethyl group is preferable.

As Z2, the substitution positions on R ⁷ and the naphthalene ring are preferably the 2-position, 4-position, and 8-position, and R ⁷ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, or trifluoro A methyl group and a cyano group are preferred. Among these, a hydrogen atom, 2-methyl group, 4-methyl group, 4-bromo group, 8-methyl group, or 8-bromo group is preferable. q is preferably 0.

As Z3, W is preferably a sulfur atom. The substitution positions on R ⁸ and the benzo [b] thiophene ring, benzofuran ring, or indole ring are preferably 4-position and 5-position, and R ⁸ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, A methoxy group, a trifluoromethyl group, and a cyano group are preferable. Among them, a hydrogen atom, 4-methyl group, 4-chloro group, 4-bromo group, 4-trifluoromethyl group, 5-methyl group, 5-chloro group, or 5-trifluoromethyl group is preferable.

As Z4, W is preferably a sulfur atom. The substitution position on R ⁹ and its benzothiophene ring, benzofuran ring, or indole ring is preferably a hydrogen atom or a 5-fluoro group.
As Z5, R ¹⁰ is preferably a hydrogen atom.
As Z6, W is preferably a sulfur atom. R ¹¹ and R ¹² each preferably represent a hydrogen atom or a halogen atom, and the substitution positions on R ¹¹ and R ¹² and their thiophene ring, furan ring, or pyrrole ring are 2, 5 -Dichloro substitution is preferred.
As Z7, W is preferably a sulfur atom. The substitution position on R ¹³ and R ¹⁴ and their thiophene ring, furan ring, or pyrrole ring is preferably 2,4-dichloro substitution.

In the formulas (I) and (IA), A, R ¹ and R ^{1 ′} , R ² , R ³ , Z (W, R ⁴ , R ⁵ and R ^{5 ′} , R ⁶ and R ^{6 ′} , R ⁷ , ^{R 8, R 9, R 10} , R 11, R 12, R 13, R 14, R 15, R 16, p, q, R d), R a, R b, R c, R d, R e, The combination of R ^f and R ^g is preferably a combination of the above-described preferred groups, and more preferably a combination of the more preferred groups.

  Specific examples of the imidazole derivative represented by the formula (I) of the present invention include the following compounds.

  Among these, preferred compounds are those shown in the following table.

  Further particularly preferred compounds are A1, A15, A17, A30, A31, A57, A60, A67, A74, A91, A92, A95, A97, A99, A101, A110, A111, A112, A113, A114, A115, A116, A117, A118, A119, A120, A123, A127, A128, A129, A130, A132, A133, A137, A138, A139, A140, A142, A143, A144, A147, A148, A149, A150, A152, A153, A155, A158, A160, A161, A178, A179, A180, A181, A182, A183, A184, A185, A186, A187, A189, A191, A192, A193, A194, A195, A196 A197, A198, A200, A201, A202, A205, A210, A212, A216, A217, A220, A223, A226, A237, A242, A243, A244, A245, A246, A247, A248, A249, A250, A251, A254, These compounds are A256, A269, A270, A273, A274, A276, and A277.

  The present invention also relates to a pharmaceutically acceptable salt of the pyrazine derivative represented by the formula (I). Examples of such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and carbonic acid; formic acid, acetic acid, propionic acid, trifluoroacetic acid, phthalic acid, Acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids Salts: salts with amino acids such as lysine, arginine, ornithine, glutamic acid and aspartic acid; salts with alkali metals such as sodium, potassium and lithium; salts with alkaline earth metals such as calcium and magnesium; aluminum, zinc and iron Salts with metals such as methylamine, ethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine Salts with organic bases such as piperidine, piperazine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N-methylglucamine, N, N′-dibenzylethylenediamine; ammonium salts, etc. It is done.

The various pharmaceutically acceptable salts of the pyrazine derivative represented by the formula (I) can be appropriately produced based on ordinary knowledge in the art.
The compounds of the present invention also include stereoisomers, racemates, and all possible optically active forms of pyrazine derivatives represented by formula (I). In addition, the compounds of the invention may give rise to tautomers depending on the combination of the substituents, and such tautomers are also included in the compounds of the present invention.

  The present invention also relates to a solvate of a pyrazine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof. Such solvents include water, methanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, Examples thereof include t-butylmethyl ether, benzene, toluene, DMF, and DMSO. Particularly preferred are water, methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, acetone, methyl ethyl ketone, and ethyl acetate.

<General synthesis example>
The imidazole derivatives represented by the above formulas (I) and (IA) may be synthesized by any method, but can be synthesized, for example, as shown in the following schemes A to F.

1) Scheme A
A is a single bond, when ^{R 3} is a carboxyl group, or COONHSO ₂ R ^e, can be performed as shown in the following scheme A. That is, a commercially available imidazole derivative (A-1) is N-alkylated by a reaction using a base and a halide compound or a Mitsunobu reaction using an alcohol to obtain a compound (A-2). The compound (A-3) can be obtained by the subsequent oxidation reaction. Furthermore, an acyl sulfonamide body (A-4) can be obtained by performing a condensation reaction with an alkyl sulfonamide as needed.

  N-alkylation of compound (A-1) to (A-2) can obtain compound (A-2) by a reaction using a base and a halide compound or a Mitsunobu reaction using an alcohol. Examples of the base when a base and a halide compound are used include potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, and sodium hydride. Among these, potassium carbonate, cesium carbonate, triethylamine, and diisopropyl are preferable bases. Ethylamine is mentioned. Examples of halide compounds include chlorides, bromides, and iodides, and chlorides and bromides are preferred halide compounds. The reaction temperature in the presence of a base and a halide compound is preferably room temperature to 150 ° C, more preferably 50 ° C to 120 ° C. The solvent in this reaction is not particularly limited, and examples thereof include ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, dimethylformamide, N-methylpyrrolidone and the like. Amides, toluene, xylene, and mixed solvents thereof. Moreover, the alkylation from the compound (A-1) to the compound (A-2) proceeds also by Mitsunobu reaction with alcohol. As conditions for the Mitsunobu reaction, a compound (A-2) is obtained by reacting a phosphine compound, a condensing agent, an alcohol, and a compound (A-1) in an inert solvent. Examples of the phosphine include tributylphosphine, triphenylphosphine, and tricyclohexylphosphine, with triphenylphosphine being preferred. Examples of the condensing agent include diethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate (DIAD). The reaction temperature of this Mitsunobu reaction may be any of 0 ° C. to 100 ° C., but preferable reaction temperatures include room temperature to 80 ° C. The solvent for Mitsunobu reaction is not particularly limited. For example, ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, dimethylformamide, and N-methyl Examples include amides such as pyrrolidone, halogen solvents such as dichloromethane, toluene, xylene, and mixed solvents thereof.

As the oxidation reaction of the compound (A-2), a pinic reaction is widely known, and conditions using sodium chlorite and sodium dihydrogen phosphate in the presence of 2-methyl-2-butene are preferable. As the reaction solvent, it is preferable to use a mixed solvent of alcohols such as tetrahydrofuran (THF), t-butanol, and propanol and water. The reaction temperature is preferably from room temperature to 50 ° C.
The condensation reaction from compound (A-3) to compound (A-4) proceeds by reacting compound (A-3) with alkylsulfonamide in the presence of a base and a condensing agent in an inert solvent. Examples of the solvent include ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogen solvents such as dichloromethane and carbon tetrachloride, acetonitrile, and These mixed solvents are exemplified. Preferred solvents are tetrahydrofuran (THF), dimethylformamide, or dichloromethane. Examples of the base include potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, and sodium hydride. Preferred bases are triethylamine and diisopropylethylamine. For the condensing agent, dicyclohexylcarbodiimide (DCC), diphenylphosphoric acid azide (DPPA), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI or WSC), O- (7-azabenzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′ -Tetramethyluronium tetrafluoroborate (TATU) etc. are mentioned, Preferably it is WSC. The reaction temperature may be 0 ° C. to 100 ° C., but the preferred reaction temperature is room temperature to 50 ° C.

2) Scheme B
Further, for example, when ^{R 3} is COOR ^d, or -CONHSO ₂ R ^e, it can also be carried out as the following scheme B. That is, after obtaining compound (B-3) by imidazole ring formation reaction using compound (B-1) and compound (B-2), reaction using base / halide compound or Mitsunobu reaction using alcohol N-alkylation is performed to obtain compound (B-4). If necessary, the compound (B-5) can be obtained by hydrolyzing the ester group. Furthermore, an acyl sulfonamide body (B-6) can also be obtained by performing condensation reaction with alkyl sulfonamide as needed. Further, after obtaining compound (B-8) by N-alkylation reaction of compound (B-7) that can be easily synthesized as another route, compound (B-9) was obtained by bromination reaction, and palladium was further used. Compound (B-4) can also be obtained by CO insertion reaction in alcohol.

  Here, in the imidazole ring formation reaction using the compound (B-1) and the compound (B-2), for example, in the presence of 2 equivalents or more, preferably 10 equivalents or more of ammonium acetate in acetic acid, the compound ( It is obtained by heating B-1) and compound (B-2). The reaction temperature for this reaction is preferably from room temperature to 150 ° C, more preferably from 50 ° C to 120 ° C. The N-alkylation reaction of compound (B-3) is preferably carried out under the conditions described in Scheme A.

In the hydrolysis reaction from compound (B-4) to compound (B-5), compound (B-4) is reacted with an equal amount or a small excess of base in a mixed solvent of an inert solvent and water. To make progress. Usually, it is carried out by reacting for 1 to 24 hours. Preferred bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide. The solvent is not particularly limited, but it is preferable to react in an organic solvent such as tetrahydrofuran (THF) and alcohols such as methanol and ethanol and a mixed solvent of water.
The condensation reaction from compound (B-5) to compound (B-6) is preferably performed under the conditions described in Scheme A.

The N-alkylation reaction from compound (B-7) to compound (B-8) is preferably carried out under the conditions described in Scheme A.
Bromination from compound (B-8) to compound (B-9) is preferably carried out under the conditions described in the following scheme C.
The CO insertion reaction from compound (B-9) to compound (B-4) proceeds in a CO atmosphere using a palladium catalyst, a base, and compound (B-9) in an alcohol solvent. For the alcohol solvent, methanol or ethanol is preferred. For the palladium catalyst, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ (dppf)), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ) or the like is preferable. . The base is preferably triethylamine or diisopropylethylamine. The reaction temperature of this reaction is preferably room temperature to 150 ° C, more preferably 50 ° C to 90 ° C.

3) Scheme C
R ¹ may be substituted with ¹ to 3 R ^b {phenyl group, naphthalen-2-yl group, pyrazol-2-yl group, pyrazol-4-yl group, pyrazol-5-yl group, pyrrole 2-yl group, furan-2-yl group, furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, thiazol-5-yl group, benzothiophen-2-yl group, or Benzothiophen-3-yl group} and when R ³ is —COOR ^d , —CONHSO ₂ R ^e , they can be synthesized as shown in Scheme C below. That is, after bromination of a commercially available imidazole derivative (C-1) to obtain a compound (C-2), the compound (C-2) was N-alkylated by a reaction using a base / halide compound or a Mitsunobu reaction using an alcohol. C-3) is obtained. The compound (C-4) is obtained by the Suzuki coupling reaction of the compound (C-3) and the boronic acid derivative. A compound (C-5) can be obtained by hydrolyzing an ester group as needed. Furthermore, an acyl sulfonamide body (C-6) can also be obtained by performing condensation reaction with alkyl sulfonamide as needed.

  Preferable reagents for bromination from the compound (C-1) to (C-2) in Scheme C include bromine and N-bromosuccinimide (NBS). Further, the solvent in this reaction is not particularly limited. For example, ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, acetonitrile, dichloromethane, and tetrachloride. Examples thereof include halogen solvents such as carbon, and mixed solvents thereof. This reaction is carried out at 0 ° C. to 100 ° C., preferably at room temperature to 50 ° C.

N-alkylation of compounds (C-2) to (C-3) is preferably performed under the conditions described in Scheme A.
For the coupling reaction from compound (C-3) to compound (C-4), Suzuki coupling, Stille coupling or the like can be used.

Stille coupling reaction from compound (C-3) to compound (C-4) involves heating compound (C-3), a tin derivative, a palladium catalyst, and a base in a solvent inert to the reaction. proceed. This reaction is preferably performed in an inert gas atmosphere. As a tin derivative, a trialkyltin derivative can be mentioned as a preferred example. As the palladium catalyst, [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ (dppf)), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ) or the like is used. It is preferable to use it. Moreover, as a base, potassium carbonate and a cesium carbonate can be mentioned as a preferable base. The solvent used in this reaction is not particularly limited. For example, ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, or 1,2-diethoxyethane, dimethylformamide, or N-methyl It is preferable to use amides such as pyrrolidone, toluene, xylene, or a mixed solvent thereof. This reaction proceeds if the reaction is carried out at 50 ° C. to 150 ° C., but is preferably carried out at 80 ° C. to 120 ° C.

In the Suzuki coupling reaction from compound (C-3) to compound (C-4), compound (C-3), boronic acid derivative, palladium catalyst, and base are heated in a solvent inert to the reaction. It progresses by that. This reaction is preferably performed in an inert gas atmosphere. Preferred examples of the boronic acid derivative include boronic acid and boronic acid pinacol ester. As the palladium catalyst, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ (dppf)), tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ), etc. Is preferably used. Moreover, as a base, potassium carbonate, a cesium carbonate, and potassium phosphate can be mentioned as a preferable base. The solvent used in this reaction is not particularly limited. For example, ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, or 1,2-diethoxyethane, dimethylformamide, or N-methyl It is preferable to use amides such as pyrrolidone, alcohols such as ethanol, 2-propanol, or butanol, toluene, xylene, water, or a mixed solvent thereof. This reaction proceeds at 50 ° C. to 150 ° C., preferably 80 ° C. to 120 ° C.

The hydrolysis reaction from compound (C-4) to compound (C-5) is preferably performed under the conditions described in Scheme B.
The condensation reaction from compound (C-5) to compound (C-6) is preferably carried out under the conditions described in Scheme A.

4) Scheme D
When A is a sulfur atom and R ³ is -COOR ^d , it can be synthesized as shown in Scheme D below. That is, the intermediate (D-1) in Scheme C is reacted with 3-mercaptopropionic acid ester to give compound (D-2), and S-dealkylated to give compound (D-3). Compound (D-4) is obtained by S-alkylating the compound (D-3). If necessary, compound (D-5) can be hydrolyzed to obtain compound (D-5).

The reaction from compound (D-1) to compound (D-2) proceeds by heating 3-mercaptopropionic acid ester, palladium catalyst, and base in a solvent inert to the reaction. This reaction is preferably performed in an inert gas atmosphere. The ester of 3-mercaptopropionic acid ester is not particularly limited, but 2-ethylhexyl ester can be mentioned as a preferred example. In addition, as a palladium catalyst, a combination of tris (dibenzylideneacetone) dipalladium (0) (Pd ₂ (dba) ₃ ) and xanthphos, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ (dppf)) or tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ) or the like is preferably used. As the base, potassium carbonate, cesium carbonate, potassium phosphate, and diisopropylethylamine can be mentioned as preferable bases. The solvent used in this reaction is not particularly limited. For example, ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, or 1,2-diethoxyethane, dimethylformamide, or N-methyl It is preferable to use amides such as pyrrolidone, alcohols such as ethanol, 2-propanol, or butanol, toluene, xylene, water, or a mixed solvent thereof. This reaction proceeds at 50 ° C. to 150 ° C., preferably 80 ° C. to 120 ° C.

  The reaction from compound (D-2) to compound (D-3) proceeds with compound (D-2) and a base in a solvent inert to the reaction. This reaction is preferably performed in an inert gas atmosphere. As the base, an alkali metal alkoxide is preferable, and tert-butoxy potassium can be mentioned as a preferable base. The solvent in this reaction is not particularly limited, but for example, amides such as dimethylformamide or N-methylpyrrolidone are preferably used.

S-alkylation of compound (D-3) to compound (D-4) can obtain compound (D-4) by a reaction using a base and a halide compound. Examples of the base include potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, and sodium hydride. Among them, preferable bases include potassium carbonate, cesium carbonate, triethylamine, and diisopropylethylamine. Examples of halide compounds include chlorides, bromides, and iodides, and chlorides and bromides are preferred halide compounds. The reaction temperature in the presence of a base and a halide compound is preferably from room temperature to 150 ° C., more preferably from 50 ° C. to 120 ° C. Further, the solvent in this reaction is not particularly limited. For example, ethers such as tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, dimethylformamide, and N-methyl Examples include amides such as pyrrolidone, toluene, xylene, and mixed solvents thereof.
The hydrolysis reaction from compound (D-4) to compound (D-5) is preferably performed under the conditions described in Scheme B.

5) Scheme E
When R ³ is a tetrazolyl group or thiomethylpropanoic acid, it can also be carried out as shown in Scheme E below. That is, about a tetrazole body, a cyano group is introduce | transduced using palladium with respect to the same compound (E-1) as the compound (B-9) as described in the said scheme B, and it is set as a compound (E-2), A compound (E-3) can be obtained by reacting a cyano group with sodium azide to convert it to a tetrazolyl group. In the case of thiomethylpropanoic acid, an SH group is introduced into compound (E-1) using palladium to form compound (E-4), and then S-alkylation is performed to obtain compound (E-5). Can be obtained. If necessary, the ester can be hydrolyzed to obtain the compound (E-6).

The cyanation reaction from compound (E-1) to compound (E-2) is carried out by using [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ (dppf)) in DMF, or tetrakis (triphenylphosphine) palladium (Pd _{(PPh 3) 4)} a palladium catalyst and ZnCN ₂ and conditions for heating the like are preferable. This reaction is carried out at 50 to 150 ° C, preferably 80 to 100 ° C. The conversion from the compound (E-2) to the compound (E-3) is preferably performed under the condition of reacting triethylamine hydrochloride and sodium azide in DMF. This reaction is carried out at 100 to 170 ° C, preferably 120 to 150 ° C. Compound (E-2) can also be synthesized from compound (E-7) corresponding to compound (A-2) described in Scheme A. For example, it can be converted into a cyano group by reacting at room temperature in a mixed solvent of ethanol and pyridine with ammonium hydroxide to form an oxime, and then reacting with heating. Although it does not specifically limit as heating temperature which converts an oxime into a cyano group, About 80 to 120 degreeC is preferable. For the introduction of the SH group from the compound (E-1) to the compound (E-4), see Org. Lett. 2004, 6, 4587-4590. Org. Lett. 2007, 9, 3687-3687. The compound (E-1), 2-ethylhexyl 3-mercaptopropionate, Pd ₂ (dba) ₃ , Xantphos, and diisopropylethylamine are heated in 1,4-dioxane with reference to the literature of After introducing the alkylthiol moiety by the above, the compound (D-4) is obtained by conducting a beta elimination reaction under basic conditions. For the beta elimination reaction, conditions using a small excess of KOtBu in DMF at room temperature are preferred. The S-alkylation from the compound (E-4) to the compound (E-5) is preferably carried out under the same conditions as the N-alkylation in Scheme A, more preferably conditions using a base and a halide compound. It is. The hydrolysis is preferably performed under the conditions described in Scheme B.

6) Scheme F
When A is an oxygen atom and R ³ is —COOR ^d , they can be synthesized as shown in Scheme F below. That is, compound (F-2) is obtained by subjecting compound (F-1) obtained in Scheme C above to a substitution reaction using an alcohol and a base, followed by hydrolysis reaction to obtain compound (F-1). -3) can be synthesized.

  The substitution reaction from compound (F-1) to compound (F-2) is performed by reacting compound (F-1) and alcohols in DMF in the presence of a base such as potassium carbonate, cesium carbonate, or tert-butoxide. To make progress. This reaction is carried out at 50 ° C to 150 ° C, preferably 90 ° C to 130 ° C. The hydrolysis from compound (F-2) to compound (F-3) is preferably carried out under the conditions described in Scheme B.

  The pyrazine derivative represented by the formula (IA) of the present invention, and pharmaceutically acceptable salts thereof, and solvates thereof can be used as URAT1 inhibitors. In addition, at least one selected from the group consisting of gout, hyperuricemia, hypertension, interstitial nephritis and other renal diseases, diabetes, arteriosclerosis, and Lesch-Nyhan syndrome, which can be clinically applied as a URAT1 inhibitor. It can be used as a prophylactic or therapeutic agent for two diseases.

  In the present invention, “prevention” means prevention of illness or onset in an individual who has not yet been affected or developed. “Treatment” cures or suppresses symptoms or the like in an already affected or onset of individual. Or to improve.

  The therapeutic or prophylactic agent for gout, hyperuricemia and the like containing the imidazole derivative of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is usually used as a carrier or excipient for formulation. It is prepared using the form and other additives. The carrier or excipient for the preparation may be either solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, etc. Other conventional ones can be mentioned. Administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, liquids, or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories, and transdermal. Good.

  The effective amount of the active ingredient in the URAT1 inhibitor, therapeutic agent or prophylactic agent of the present invention varies depending on the administration route, patient age, sex, and degree of disease, but is usually about 0.1 to 100 mg / day. The frequency is usually 1 to 3 times / day, and 1 to 7 times / week, and it is preferable to prepare the preparation so as to satisfy such conditions. However, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or a dose exceeding the above range may be required.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by this. The abbreviations in the present invention are as follows.
DMF = N, N-dimethylformamide THF = tetrahydrofuran NBS = N-bromosuccinimide NCS = N-chlorosuccinimide DEAD = diethyl azodicarboxylate DIAD = diisopropyl azodicarboxylate PdCl ₂ (dppf) = [1,1-bis (diphenylphos Fino) ferrocene] dichloropalladium (II)
PdCl ₂ (dppf) · CH ₂ Cl ₂ = [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex Pd ₂ (dba) ₃ = tris (dibenzylideneacetone) dipalladium (0)

The structure of the isolated new compound was confirmed by ¹ H NMR and / or mass spectrometry using a single quadrupole instrument equipped with an electron spray source, and other appropriate analytical methods.
For those measured for ¹ H NMR spectrum (400 MHz, DMSO-d ₆ CDCl ₃ , or CD ₃ OD), the chemical shift (δ: ppm) and the coupling constant (J: Hz) are shown. About the result of mass spectrometry, the measured value observed as a value which added proton (H ^<+> ) to M ^< + ^> + H, ie, the compound molecular mass M), is shown. The following abbreviations represent the following:
s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet.

  For compounds synthesized according to the methods of the following examples, a high-performance liquid chromatography (HPLC) analysis and a time-of-flight mass spectrometer (TOF-MS) equipped with an electrospray ion source were further analyzed. Analysis was also performed by the mass spectrometry used.

The retention time (unit: minute) of a compound in HPLC analysis under the following analysis conditions is shown as HPLC retention time.
HPLC measurement condition measuring apparatus: Hewlett-Packard 1100 HPLC
Column: Imtakt Cadenza CD-Cl8 100 mm × 4.6 mm 3 μm
UV: PDA detection (254 nm)
Column temperature: 40 degree Gradient condition:
Solvent: A: H ₂ O / acetonitrile = 95/5
0.05% TFA (trifluoroacetic acid)
B: H ₂ O / acetonitrile = 5/95
0.05% TFA (trifluoroacetic acid)
Flow rate: 1.0 mL / min Gradient: 0 to 1 minute, Solvent B: 2% Solvent A: 98%
1-14 minutes, solvent B: 2% → 100% solvent A: 98% → 0%
14-17 minutes, solvent B: 100% solvent A: 0%
17-19 minutes, solvent B: 100% → 2% solvent A: 0% → 98%

As for the results of mass spectrometry, the value of “M ⁺ + H” (obs. Mass: that is, actual measurement in which proton (H ⁺ ) is added to the molecular mass (M) of the compound, which is observed by the following apparatus and analysis conditions. Value) and the calculated value (pred. Mass) of “M ⁺ + H”, together with the composition formula (Formula) calculated from the actually measured value of “M ⁺ + H”.

TOF-MS measurement condition mass spectrometer: Shimadzu LCMS-IT-TOF
LC: Prominence
Column: Phenomenex Synergy Hydro-RP 4.0 mm × 20 mm 2.5 μm
UV: PDA detection (254 nm)
Flow rate: 0.6 mL / min Column temperature: 40 degrees Detection voltage: 1.63 kV
Gradient conditions:
Solvent: A: H ₂ O / acetonitrile = 95/5
0.1% HCOOH
B: H ₂ O / acetonitrile = 5/95
0.1% HCOOH
Flow rate: 0.5 mL / min Gradient: 0-0.2 min, Solvent B: 2% Solvent A: 98%
0.2-2.5 minutes, solvent B: 2% → 100% solvent A: 98% → 0%
2.5-3.8 minutes, solvent B: 100% solvent A: 0%
3.8-4.0 minutes, solvent B: 100% → 2% solvent A: 0% → 98%
4.0-5.0 minutes, solvent B: 2% solvent A: 98%

[Example 1] Production of 2-butyl-4-chloro-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (Compound A1) (Scheme A)

(1) 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (100 g, 53.6 mmol) was dissolved in DMF (1000 mL), and 1- (chloromethyl) naphthalene (manufactured by Johnson Matthey) ( 121 mL, 803 mmol) and potassium carbonate (111 g, 803 mmol) were added and stirred at 80 ° C. for 4 hours. After the reaction, ethyl acetate was added at room temperature, and the organic phase was washed twice with water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography and then recrystallized (ethyl acetate: hexane = 1: 1) to give 2-butyl-4-chloro-1- (naphthalen-1-ylmethyl) -1H—. Imidazole-5-carbaldehyde (83 g) was obtained.
¹ H-NMR (DMSO) δ: 9.66 (1H, s), 8.14 (1H, d, J = 8.2 Hz), 8.00 (1H, d, J = 7.8 Hz), 7. 86 (1H, d, J = 8.2 Hz), 7.69-7.60 (2H, m), 7.39 (1H, t, J = 7.4 Hz), 6.44 (1H, d, J = 7.1 Hz), 6.08 (2H, s), 2.62 (2H, t, J = 7.4 Hz), 1.58-1.50 (2H, m), 1.27-1.17. (2H, m), 0.74 (3H, t, J = 7.3 Hz).
ESI-MS m / z = 327 (M + H) ⁺

(2) 2-butyl-4-chloro-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carbaldehyde (83 g) and 2-methyl-2-butene (162 mL, 1.52 mol) were tert- Dissolved in butanol (1660 mL), an aqueous solution (830 mL) of sodium chlorite (230 g, 2.54 mol) and sodium dihydrogen phosphate (238 g, 1.52 mol) was added dropwise thereto, and the mixture was stirred at room temperature for 5 hours. . After the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by a conventional method to give 2-butyl-4-chloro-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (compound A1, 51 g) was obtained.
¹ H-NMR (DMSO) δ: 13.09 (1H, s), 8.15 (1H, d, J = 8.2 Hz), 7.99 (1H, d, J = 7.7 Hz), 7. 84 (1H, d, J = 8.2 Hz), 7.67-7.59 (2H, m), 7.40 (1H, t, J = 7.6 Hz), 6.36 (1H, d, J = 7.1 Hz), 6.07 (2H, s), 2.56 (2H, t, J = 7.5 Hz), 1.58-1.50 (2H, m), 1.26-1.17 (2H, m), 0.76 (3H, t).

Example 2 Preparation of 2-butyl-4-chloro-N- (methylsulfonyl) -1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxamide (Compound A97)

(1) 2-Butyl-4-chloro-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (35 mg, 0.102 mmol) obtained in Example 1, methanesulfonamide (14. 3 mg, 0.150 mmol) and DMAP (12 mg, 0.1 mmol) were dissolved in DMF (0.5 mL), WSC (38 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was purified by Lower Summer HPLC to give 2-butyl-4-chloro-N- (methylsulfonyl) -1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxamide (Compound A97). , 20 mg).
1H-NMR (DMSO-D6) δ: 11.80 (1H, brs), 8.12 (1H, d, J = 8.3 Hz), 7.98 (1H, d, J = 7.8 Hz), 7 .85 (1H, d, J = 8.3 Hz), 7.66-7.58 (2H, m), 7.40 (1H, t, J = 7.8 Hz), 6.51 (1H, d, J = 7.3 Hz), 5.91 (2H, s), 2.93 (3H, s), 2.59 (2H, t, J = 8.0 Hz), 1.56-1.48 (2H, m), 1.24-1.18 (2H, m), 0.74 (3H, t, J = 7.3 Hz).

Example 3 Production of 4-methyl-1- (naphthalen-1-ylmethyl) -2- (propylthio) -1H-imidazole-5-carboxylic acid (Compound A172)

(1) Ethyl 5-methyl-1H-imidazole-4-carboxylate (manufactured by Sigma-Aldrich) (7.5 g, 48.7 mmol) was dissolved in acetonitrile (120 mL), and N-bromosuccinimide (10. 4 g, 58.4 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to obtain ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (3.6 g). ¹ H-NMR (CDCl 3) δ: 4.35 (2H, q, J = 7.1 Hz), 2.51 (3H, s), 1.37 (3H, t, J = 7.1 Hz).
ESI-MS m / z = 233 (M ⁺ + H)

(2) Ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (5 g, 21.45 mmol) was dissolved in DMF (40 mL), and potassium carbonate (5.93 g, 42.9 mmol) and 1- (Chloromethyl) naphthalene (manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred at 80 ° C. for 2 hours. After the reaction, water was added and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to obtain ethyl 2-bromo-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylate (3.25 g).
¹ H-NMR (CDCl 3) δ: 8.01 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 7.8 Hz), 7.77 (1H, d, J = 8) .3 Hz), 7.63-7.53 (2 H, m), 7.33 (1 H, t, J = 7.6 Hz), 6.43 (1 H, dd, J = 7.3, 1.0 Hz) 6.07 (2H, s), 4.13 (2H, q, J = 7.1 Hz), 2.58 (3H, s), 1.11 (3H, t, J = 7.1 Hz). ESI-MS m / z = 373 (M ⁺ + H)

  (3) Ethyl 2-bromo-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylate (624 mg, 1.67 mmol), tris (dibenzylideneacetone) dipalladium (5 mol%, 77 mg) and Xantphos (10 mol%, 97 mg) in a suspension of dioxane (6 ml), 3-mercaptopyropionic acid 2-ethylhexyl ester (1.2 eq. 0.46 ml), diisopropylethylamine (2.0 eq. 58 ml) was added and refluxed overnight under a nitrogen atmosphere. After the reaction, water was added and extracted three times with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off and ethyl 2-((3-((2-ethylhexyl) oxy) -3-oxopropyl) thio) -4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxy The rate (724 mg) was obtained. This was dissolved in dimethylformamide (5 ml). Under an ice bath, potassium t-butoxide (1.5 eq., 239 mg) was added, and the mixture was stirred at room temperature for 20 minutes. After the reaction, 3M hydrochloric acid was added and extracted three times with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain ethyl 2-mercapto-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylate (463 mg).

  (4) Ethyl 2-mercapto-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylate (33 mg) was dissolved in dimethylformamide (1 ml) and propyl bromide (0.014 ml ) And triethylamine (0.028 ml) were added, and the mixture was stirred at 80 ° C. for 2 hours. After completion of the reaction, the mixture was extracted 3 times with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain ethyl 4-methyl-1- (naphthalen-1-ylmethyl) -2- (propylthio) -1H-imidazole-5-carboxylate.

(5) Ethyl 4-methyl-1- (naphthalen-1-ylmethyl) -2- (propylthio) -1H-imidazole-5-carboxylate, tetrahydrofuran (1 ml), methanol (0.5 ml) and 4N lithium hydroxide (0.25 ml) was added and stirred at room temperature overnight. After completion of the reaction, 6N hydrochloric acid (0.25 ml) was added, and the mixture was extracted 3 times with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified using column chromatography to obtain 4-methyl-1- (naphthalen-1-ylmethyl) -2- (propylthio) -1H-imidazole-5-carboxylic acid.
Obs. Mass = 341.13 (M ⁺ + H)

Example 4 Production of 2-phenyl-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (Compound A205)

Ethyl 2-bromo-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylate (0.1 mmol, 38 mg), phenylboronic acid (1.7 eq., 21 mg) and tetrakis (tri 2M potassium carbonate (1 eq., 0.051 ml) was added to a suspension of phenylphosphine) palladium (0.05 eq., 6 mg) in toluene (0.35 ml) and refluxed overnight. After completion of the reaction, 2M sodium hydroxide was added, extracted with ethyl acetate, the solvent was distilled off, and ethyl 2-phenyl-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylate was obtained. Obtained. Tetrahydrofuran (1 ml), ethanol (0.5 ml), and 4M lithium hydroxide (0.25 ml) were added, and the mixture was stirred at 60 ° C. overnight. After completion of the reaction, 1M hydrochloric acid (1 ml) was added, extracted with ethyl acetate, and the solvent was distilled off. The residue was purified using column chromatography to obtain 2-phenyl-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid.
Obs. Mass = 343.14 (M ⁺ + H)

Example 5 Production of 4-methyl-1- (naphthalen-1-ylmethyl) -2- (o-tolyloxy) -1H-imidazole-5-carboxylic acid (Compound A278)

Ethyl 2-bromo-4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylate (0.11 mmol, 40 mg) is dissolved in dimethylformamide (0.5 ml) to give 2-methylphenol. (0.16 mmol, 18 mg) and cesium carbonate (3 eq., 105 mg) were added, and the mixture was stirred at 80 ° C. overnight. After completion of the reaction, water was added and extracted with ethyl acetate, and the solvent was distilled off. The residue was dissolved in tetrahydrofuran (0.25 ml) and methanol (0.25 ml), 5M sodium hydroxide (4 eq., 0.086 ml) was added, and the mixture was stirred at 60 ° C. for 1 hr. After completion of the reaction, 6M hydrochloric acid was added, extracted with ethyl acetate, and the solvent was distilled off. Purification was performed using column chromatography to obtain 4-methyl-1- (naphthalen-1-ylmethyl) -2- (o-tolyloxy) -1H-imidazole-5-carboxylic acid.
Obs. Mass = 373.15 (M ⁺ + H)

[Examples 6 to 290]
Compound numbers A2 to A286 were synthesized with reference to the synthesis methods of Schemes A to F described in the above Examples 1 to 5 or the general synthesis method.

[Example 291] A test compound for inhibition of uric acid transport using human URAT1-expressing cells was dissolved in DMSO (manufactured by Sigma) so as to have a concentration of 20 mM, and then adjusted to a target concentration at the time of use.
Human URAT1 (hURAT1) full-length cDNA was subcloned into the expression vector pCMV6-Kan / Neo, and the human URAT1 gene was introduced into human fetal kidney-derived cells (HEK293 cells) by the liposomal method using Lipofectamine 2000 (Invitrogen). HEK293 cells expressing the human URAT1 gene due to geneticin resistance were selected. It was confirmed that the human URAT1 gene expressed its function using as an index the transport of uric acid labeled with ¹⁴ C into cells.
Human URAT1-expressing HEK293 cells were seeded in a 24-well cell culture dish at 3 × 10 ⁵ cells / mL / well and Dulbecco's modified Eagle medium (D-MEM medium) containing 10% fetal bovine serum at 37 ° C. After culturing for 2 days, the following uric acid transport inhibition test was performed.

After removing the medium from each well by suction, the cells were replaced with a solution in which NaCl in Hanks' Balanced Salt Solution (HBSS) was replaced with Na-gluconate (hereinafter referred to as HBSS / Na-gluconate), and pre-treated at 37 ° C. for about 10 minutes. Incubated. After removing HBSS / Na-gluconate by suction, ¹⁴ C-uric acid solution containing Example Compound and radioligand ( ¹⁴ C-labeled uric acid; final concentration 25 μM) pre-warmed to 37 ° C. was added. Incubation reaction was carried out at 37 ° C. for 5 minutes. After the reaction, the ¹⁴ C-uric acid solution was removed by suction and washed 3 times with ice-cooled HBSS. Human URAT1-expressing HEK293 cells were lysed with 0.2 mol / L NaOH aqueous solution (hereinafter referred to as cell sample) and collected from the well, and the cell sample and liquid scintillation cocktail ULTIMA GOLD (manufactured by PerkinElmer) were mixed together, and a liquid scintillation counter Radioactivity was measured with (Beckman Coulter).
The radioactivity indicating URAT1 specific uric acid transport (radioactivity in human URAT1-expressing cells HEK293 cells in the absence of the Example compound (DMSO added)) is defined as 100%, and the uric acid transport rate (% of control) at each concentration of the Example compound. uptake) was calculated, and the concentration of the example compound (IC ₅₀ ) at which the uric acid transport rate was inhibited by 50% was determined. The results are shown in the table. In addition, symbols (*, **, ***) in the table represent the following inhibitory activity values.
IC ₅₀ ≦ 0.2 μM: ***
0.2 μM <IC ₅₀ ≦ 2 μM: **
2 μM <IC ₅₀ ≦ 20 μM: *

[Example 292] Test for efficacy evaluation of capuchin capuchin monkeys Test compounds (3 mg / kg to 100 mg / kg) suspended in 0.5% methylcellulose solution were administered to the capuchin capuchin monkeys from the nasal cavity into the stomach using a disposable catheter and syringe. . Blood before administration, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, 4 hours from immediately after administration, 4 to 8 hours after administration, 8 to 16 hours after administration Urine samples were collected between 16 and 24 hours after administration. The concentrations of uric acid and creatinine in the collected blood and urine samples were measured with an automatic analyzer (JEOL Ltd.). Uric acid was measured using L-type Wako UA · F (Wako Pure Chemical Industries), and creatinine was measured using L-type Wako Creatinine · F (Wako Pure Chemical Industries). The uric acid clearance was calculated from the uric acid concentration in blood and urine, and the creatinine clearance was calculated from the creatinine concentration in the same manner, and the uric acid excretion rate was determined by the following equation.
Uric acid excretion rate (%) = (Uric acid clearance / creatinine clearance) × 100

In this test, the compounds A1, A15, A17, A30, A31, A57, A60, A67, A74, A95, A97, A99, A110, A112, A114, A116, A205, A210, A212, A216, A223, A226 , And A247 promoted uric acid excretion.
From the above results, it was found that the imidazole derivative of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof has an excellent uric acid excretion promoting action.

  The imidazole derivative of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof is used as a pharmaceutical product.

Claims (24)

An imidazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[Where:
A represents a single bond, a sulfur atom, —S (═O) ₂ —, or an oxygen atom,
When A is a single bond,
R ¹ is a C ₂ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group optionally substituted by ¹ to 3 R ^a. , C ₃ -C ₆ cycloalkyl C ₁ -C ₃ alkyl group, or optionally substituted by 1 to 3 R ^b {Phenyl group, naphthalen-2-yl group, pyrazol-2-yl group, pyrazole -4-yl group, pyrazol-5-yl group, pyrrol-2-yl group, furan-2-yl group, furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, thiazole- 5-yl group, benzothiophen-2-yl group, or benzothiophen-3-yl group}
When A is an oxygen atom, a sulfur atom, or —S (═O) ₂ —, R ¹ is a C _{1 to} C ₆ alkyl group optionally substituted with 1 to 3 R ^a , C ₃ to C ₆ cycloalkyl represents a C ₁ -C ₃ alkyl group, or a C ₂ -C ₆ alkynyl group,
R ^a is a hydroxyl group, a cyano group, a halogen atom, a trifluoromethyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₂ -C ₇ alkylcarbonyl group, Represents a phenyl group optionally substituted with ₁ to 3 C ₁ -C ₆ alkyl groups, a C ₃ -C ₆ cycloalkyl group, or —CONH— (C ₁ -C ₆ alkyl);
R ^b represents a C _{1 to} C ₆ alkyl group, a C _{1 to} C ₆ alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxyl group, or a C _{2 to} C ₇ alkylcarbonyl group,
R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a halogen atom, a trifluoromethyl group, a phenyl group which may be substituted with 1 to 3 halogen atoms, C ₂ -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 1 -C ₆ alkoxy _group, C 2 -C ₇ alkylcarbonyl _group, C 1 -C ₆ alkylthio group, a difluoromethyl group, a cyano group, a phenoxy group, Or COOR ^c ,
R ^c represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a tetrazolyl group, —COOR ^d , or —CONHSOOR ^e ,
R ^d is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with one phenyl group, a trifluoromethyl group, a phenyl group optionally substituted with 1 to 3 R ^f , or pyridyl. Represents a group,
R ^e is optionally substituted with one phenyl group, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a trifluoromethyl group, and 1 to 3 R ^f. Represents a good phenyl group, pyridyl group,
R ^f represents a C _{1 to} C ₆ alkyl group or a halogen atom,
Z represents any of the groups represented by the following Z1 to Z7,

R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen atom, a C ₁ -C ₆ alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, or a nitro group. , or represents _C 1 -C ₃ alkylenedioxy group,
However, when one of R ⁵ and R ⁶ is a hydrogen atom, the other is not a hydrogen atom or a halogen atom,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are the same or different and are a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or C ₁ -C _6. Represents an alkoxy group, a difluoromethyl group, a trifluoromethyl group, a cyano group, or a di (C ₁ -C ₆ alkyl) amino group;
However, when one of R ¹¹ and R ¹² is a hydrogen atom, the other is not a hydrogen atom,
R ¹⁵ and R ¹⁶ represent a halogen atom;
p and q represent 0 or 1,
W represents a sulfur atom, an oxygen atom, or NR ^g ;
R ^g represents a hydrogen _atom, C 1 -C ₆ alkyl group, or a benzyl group. ]   The imidazole derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein A represents a single bond.   The imidazole derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein A represents a sulfur atom. R ¹ is represents a 1-3 optionally substituted with ^{R a} _C 2 _{~C 6} alkyl group, or _C 3 -C ₆ cycloalkyl _C 1 -C ₃ alkyl group, of claims 1 to 3 The imidazole derivative according to any one of the above, or a pharmaceutically acceptable salt thereof, or a solvate thereof. R ¹ represents an ethyl group, a propyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, a cyclohexylmethyl group, a phenylethyl group, a 2-butyn-1-yl group, or an isopropyl group. The imidazole derivative according to any one of the above, or a pharmaceutically acceptable salt thereof, or a solvate thereof. R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a halogen atom, or a phenyl group optionally substituted with 1 to 3 halogen atoms. The imidazole derivative in any one of -5, or its pharmaceutically acceptable salt, or those solvates. R ² represents a hydrogen atom, a methyl group, a cyclopropyl group, a butyl group, a chlorine atom, or a phenyl group which may be substituted with 1 to 3 halogen atoms, according to any one of claims 1 to 5. Or an pharmaceutically acceptable salt thereof, or a solvate thereof. The pyridine derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ³ represents a carboxyl group, a tetrazolyl group, -CONHSOOMe, -CONHSSOOcPr, a methoxycarbonyl group, or an ethoxycarbonyl group, or Their solvates. The pyridine derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ³ represents a carboxyl group, a methoxycarbonyl group, or an ethoxycarbonyl group.   The imidazole derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z represents Z1. Z is represented by the following formula Z1a

[Wherein, definitions of R ⁴ , R ⁵ and R ⁶ are the same as described above. ]
The pyridine derivative according to claim 10 or a pharmaceutically acceptable salt thereof, or a solvate thereof, which represents any of the groups represented by: R ⁴ represents a hydrogen atom,
The imidazole derivative according to claim 11, wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or a trifluoromethyl group. Or a pharmaceutically acceptable salt thereof, or a solvate thereof.   The imidazole derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z represents Z2. R ⁷ represents a hydrogen atom, a 2-methyl group, a 4-methyl group, a 4-bromo group, an 8-methyl group, or an 8-bromo group on the naphthalene ring;
The imidazole derivative according to claim 13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein q represents 0.   The imidazole derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z represents Z3 and W represents a sulfur atom. R ⁸ is a hydrogen atom, 4-methyl group, 4-chloro group, 4-bromo group, 4-trifluoromethyl group, 5-methyl group, 5-chloro group, or 5-trifluorofluoro group on the benzothiophene ring. The imidazole derivative according to claim 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a methyl group. An imidazole derivative selected from the following compounds (A1) to (A163), (A285) and (A286), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(A1) 2-butyl-4-chloro-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A4) 2-butyl-4-chloro-1-((4-methylbenzo [b] Thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A5) 2-butyl-4-chloro-1- (2-chlorobenzyl) -1H-imidazole-5-carboxylic acid (A6) 2- Butyl-4-chloro-1- (3-chlorobenzyl) -1H-imidazole-5-carboxylic acid (A9) 2-butyl-4-chloro-1- (2- (trifluoromethyl) benzyl) -1H-imidazole -5-carboxylic acid (A12) 2-butyl-4-chloro-1- (2-methoxybenzyl) -1H-imidazole-5-carboxylic acid (A13) 2-butyl-4-chloro-1- ( -(Trifluoromethoxy) benzyl) -1H-imidazole-5-carboxylic acid (A14) 2-butyl-4-chloro-1- (3- (trifluoromethoxy) benzyl) -1H-imidazole-5-carboxylic acid ( A15) 1- (Benzo [b] thiophen-3-ylmethyl) -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (A16) 2-butyl-4-chloro-1-((5-methylbenzo [B] Thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A17) 2-butyl-4-chloro-1- (2,5-dimethylbenzyl) -1H-imidazole-5-carboxylic acid (A18) 2-Butyl-4-chloro-1- (2,6-dimethylbenzyl) -1H-imidazole-5-carboxylic acid (A19) 2-butyl-4-c B-1- (2-ethylbenzyl) -1H-imidazole-5-carboxylic acid (A20) 2-butyl-4-chloro-1- (2-isopropylbenzyl) -1H-imidazole-5-carboxylic acid (A21) 2-Butyl-4-chloro-1- (2,3-dimethylbenzyl) -1H-imidazole-5-carboxylic acid (A25) 2-butyl-1- (2,5-dimethylbenzyl) -4-methyl-1H -Imidazole-5-carboxylic acid (A26) 2-butyl-4-chloro-1- (2,5-difluorobenzyl) -1H-imidazole-5-carboxylic acid (A30) 1- (2,5-bis (tri Fluoromethyl) benzyl) -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (A31) 2-butyl-4-chloro-1-((2-methylnaphthalen-1-y L) Methyl) -1H-imidazole-5-carboxylic acid (A33) 2-butyl-4-chloro-1- (2-fluoro-3-methylbenzyl) -1H-imidazole-5-carboxylic acid (A35) 2- Butyl-4-chloro-1- (4-fluoro-2- (trifluoromethyl) benzyl) -1H-imidazole-5-carboxylic acid (A36) 1- (2,4-bis (trifluoromethyl) benzyl)- 2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (A41) 2-butyl-4-chloro-1- (2-chloro-4-fluorobenzyl) -1H-imidazole-5-carboxylic acid (A42) ) 2-Butyl-4-chloro-1- (2,3-dichlorobenzyl) -1H-imidazole-5-carboxylic acid (A43) 2-butyl-4-chloro-1- (3,4-di Rolobenzyl) -1H-imidazole-5-carboxylic acid (A47) 2-butyl-4-chloro-1- (2,4-dichlorobenzyl) -1H-imidazole-5-carboxylic acid (A48) 2-butyl-4- Chloro-1- (3,5-dichlorobenzyl) -1H-imidazole-5-carboxylic acid (A49) 2-butyl-4-chloro-1-((5-chlorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A51) 2-butyl-4-chloro-1-((4,6-difluorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A53) 2-Butyl-4-chloro-1-((5-fluorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A54) -Butyl-4-chloro-1-((6-fluorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A55) 2-butyl-4-chloro-1-(( 6-chloro-4-methylbenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A56) 2-butyl-4-chloro-1-((4,6-dichlorobenzo [b ] Thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A57) 1-((4-bromobenzo [b] thiophen-3-yl) methyl) -2-butyl-4-chloro-1H- Imidazole-5-carboxylic acid (A58) 2-butyl-4-chloro-1- (2-chloro-5-fluorobenzyl) -1H-imidazole-5-carboxylic acid (A60) 2-butyl-4-c Loro-1- (2,5-dichlorobenzyl) -1H-imidazole-5-carboxylic acid (A63) 2-butyl-4-chloro-1-((4,5-dimethylbenzo [b] thiophen-3-yl ) Methyl) -1H-imidazole-5-carboxylic acid (A64) 2-butyl-4-chloro-1-((5-methoxybenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic Acid (A65) 2-butyl-4-chloro-1-((4-fluoro-5-methylbenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A67) 2-butyl- 4-Chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A68) 2-butyl-4-chloro-1-((5-cycl Propylbenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A69) 2-butyl-4-chloro-1-((7-chloro-4-methylbenzo [b] thiophene-3 -Yl) methyl) -1H-imidazole-5-carboxylic acid (A71) 2-butyl-4-chloro-1-((5-chloro-4-methylbenzo [b] thiophen-3-yl) methyl) -1H- Imidazole-5-carboxylic acid (A72) 2-butyl-4-chloro-1-((4-chloro-5-fluorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid ( A74) 2-Butyl-4-chloro-1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A 5) 2-Butyl-4-chloro-1-((5- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A76) 2-butyl-4 -Chloro-1-((4,5-dichlorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A78) 1-((5-bromobenzo [b] thiophene-3- Yl) methyl) -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (A79) 1-((7-bromo-4-methylbenzo [b] thiophen-3-yl) methyl) -2-butyl -4-chloro-1H-imidazole-5-carboxylic acid (A80) 4-bromo-2-butyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A84) 2- Butyl-1- (naphthalen-1-ylmethyl) -4-phenyl-1H-imidazole-5-carboxylic acid (A85) 2-butyl-4-chloro-1-((2-methoxynaphthalen-1-ylmethyl) -1H -Imidazole-5-carboxylic acid (A87) 2-butyl-4-chloro-1-((8-fluoronaphthalen-1-yl) methyl) -1H-imidazole-5-carboxylic acid (A88) 2-butyl-4 -Chloro-1-((2-ethoxynaphthalen-1-yl) methyl) -1H-imidazole-5-carboxylic acid (A89) 2-butyl-4-chloro-1-((4- (dimethylamino) naphthalene- 1-yl) methyl) -1H-imidazole-5-carboxylic acid (A90) 2-butyl-4-chloro-1-((2-methylbenzo [b] thiophen-4-yl) Til) -1H-imidazole-5-carboxylic acid (A91) 1-((8-bromonaphthalen-1-yl) methyl) -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (A92) 2 -Butyl-4-chloro-1-((3- (difluoromethyl) benzo [b] thiophen-4-yl) methyl) -1H-imidazole-5-carboxylic acid (A93) 2-butyl-4-chloro-1 -((8-Methylnaphthalen-1-yl) methyl) -1H-imidazole-5-carboxylic acid (A94) 2-butyl-4-chloro-1-((5-methylnaphthalen-1-yl) methyl)- 1H-imidazole-5-carboxylic acid (A95) 2-butyl-4-chloro-1-((4-methylnaphthalen-1-yl) methyl) -1H-imidazole-5-carboxylic acid (A9) ) 2-Butyl-4-chloro-N- (methylsulfonyl) -1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxamide (A98) 2-butyl-4-chloro-N- (ethyl) (Sulfonyl) -1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxamide (A99) 2-butyl-4-chloro-N- (cyclopropylsulfonyl) -1- (naphthalen-1-ylmethyl) -1H -Imidazole-5-carboxamide (A101) 1-((4-bromonaphthalen-1-yl) methyl) -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (A102) 2-butyl-4- Chloro-1-((4-cyanonaphthalen-1-yl) methyl) -1H-imidazole-5-carboxylic acid (A103) 1-((2 -Bromonaphthalen-1-yl) methyl) -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (A104) 2-butyl-4-chloro-1-((4-fluoronaphthalen-1-yl) ) Methyl) -1H-imidazole-5-carboxylic acid (A105) 1- (benzo [b] thiophen-7-ylmethyl) -2-butyl-4-chloro-1H-imidazole-5-carboxylic acid (A106) 1- (Benzo [b] thiophen-7-ylmethyl) -2-butyl-4-chloro-N- (methylsulfonyl) -1H-imidazole-5-carboxamide (A107) 2-butyl-4- (3-fluorophenyl)- 1- (Naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A108) 2-butyl-4- (4-fluorophenyl) -1 (Naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A109) 2-butyl-4- (2-fluorophenyl) -1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A110) 2-Butyl-4-chloro-N- (methylsulfonyl) -1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxamide ( A111) 2-butyl-4-chloro-N- (cyclopropylsulfonyl) -1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxamide ( A112) 2-Butyl-4-chloro-1-((4-methylnaphthalen-1-yl) methyl) -N- (methylsulfonyl) 1H-imidazole-5-carboxamide (A113) 2-butyl-4-chloro-N- (cyclopropylsulfonyl) -1-((4-methylnaphthalen-1-yl) methyl) -1H-imidazole-5-carboxamide ( A114) 2-butyl-4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -N- (methylsulfonyl) -1H-imidazole-5-carboxamide (A115) 2-butyl- 4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -N- (cyclopropylsulfonyl) -1H-imidazole-5-carboxamide (A116) 1-((4-bromobenzo [b ] Thiophen-3-yl) methyl) -2-butyl-4-chloro-N- (methylsulfonyl) -1H-imidazo 5-Carboxamide (A117) 1-((4-Bromobenzo [b] thiophen-3-yl) methyl) -2-butyl-4-chloro-N- (cyclopropylsulfonyl) -1H-imidazole-5 Carboxamide (A118) 2-butyl-4-chloro-N- (ethylsulfonyl) -1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxamide (A119) 2-Butyl-N- (tert-butylsulfonyl) -4-chloro-1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5 Carboxamide (A120) 2-butyl-4-chloro-N- (phenylsulfonyl) -1-((4- (trifluoromethyl) benzo [ ] Thiophen-3-yl) methyl) -1H-imidazole-5-carboxamide (A121) 2-butyl-4-chloro-N-tosyl-1-((4- (trifluoromethyl) benzo [b] thiophene-3 -Yl) methyl) -1H-imidazole-5-carboxamide (A122) 2-butyl-4-chloro-1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -N- ((Trifluoromethyl) sulfonyl) -1H-imidazole-5-carboxamide (A123) N- (benzylsulfonyl) -2-butyl-4-chloro-1-((4- (trifluoromethyl) benzo [b] thiophene -3-yl) methyl) -1H-imidazole-5-carboxamide (A124) 2-butyl-4-chloro-N-((3-fluoro Phenyl) sulfonyl) -1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxamide (A126) N-((3-bromophenyl) sulfonyl) -2-butyl-4-chloro-1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxamide (A127) 2-butyl-4-chloro —N- (ethylsulfonyl) -1-((4-methylnaphthalen-1-yl) methyl) -1H-imidazole-5-carboxamide (A128) 2-butyl-N- (tert-butylsulfonyl) -4-chloro -1-((4-Methylnaphthalen-1-yl) methyl) -1H-imidazole-5-carboxamide (A129) 2-butyl -4-chloro-1-((4-methylnaphthalen-1-yl) methyl) -N-((trifluoromethyl) sulfonyl) -1H-imidazole-5-carboxamide (A130) 2-butyl-4-chloro- 1-((4-Methylnaphthalen-1-yl) methyl) -N- (phenylsulfonyl) -1H-imidazole-5-carboxamide (A131) 2-butyl-4-chloro-1-((4-methylnaphthalene- 1-yl) methyl) -N-tosyl-1H-imidazole-5-carboxamide (A132) N- (benzylsulfonyl) -2-butyl-4-chloro-1-((4-methylnaphthalen-1-yl) methyl ) -1H-imidazole-5-carboxamide (A133) 2-butyl-4-chloro-N-((3-fluorophenyl) sulfonyl) -1 ((4-Methylnaphthalen-1-yl) methyl) -1H-imidazole-5-carboxamide (A134) N-((4-bromophenyl) sulfonyl) -2-butyl-4-chloro-1-((4- Methylnaphthalen-1-yl) methyl) -1H-imidazole-5-carboxamide (A135) N-((3-bromophenyl) sulfonyl) -2-butyl-4-chloro-1-((4-methylnaphthalene-1 -Yl) methyl) -1H-imidazole-5-carboxamide (A136) 1- (benzo [b] thiophen-3-ylmethyl) -2-butyl-4-chloro-N- (methylsulfonyl) -1H-imidazole-5 Carboxamide (A137) 1- (benzo [b] thiophen-3-ylmethyl) -2-butyl-4-chloro-N- (cyclopro Rusulfonyl) -1H-imidazole-5-carboxamide (A138) 2-butyl-4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -N- (ethylsulfonyl) -1H- Imidazole-5-carboxamide (A139) 2-butyl-N- (tert-butylsulfonyl) -4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5 Carboxamide (A140) 2-butyl-4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -N- (phenylsulfonyl) -1H-imidazole-5-carboxamide (A141) 2- Butyl-4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -N-tosyl-1H -Imidazole-5-carboxamide (A142) 2-butyl-4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -N-((trifluoromethyl) sulfonyl) -1H-imidazole -5-carboxamide (A143) N- (benzylsulfonyl) -2-butyl-4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxamide (A144) ) 2-Butyl-4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -N-((3-fluorophenyl) sulfonyl) -1H-imidazole-5-carboxamide (A145) N-((4-bromophenyl) sulfonyl) -2-butyl-4-chloro-1-((4-chlorobenzo [b] thio Phen-3-yl) methyl) -1H-imidazole-5-carboxamide (A146) N-((3-bromophenyl) sulfonyl) -2-butyl-4-chloro-1-((4-chlorobenzo [b] thiophene) -3-yl) methyl) -1H-imidazole-5-carboxamide (A147) 1-((4-bromobenzo [b] thiophen-3-yl) methyl) -2-butyl-4-chloro-N- (ethylsulfonyl) ) -1H-imidazole-5-carboxamide (A148) 1-((4-bromobenzo [b] thiophen-3-yl) methyl) -2-butyl-N- (tert-butylsulfonyl) -4-chloro-1H- Imidazole-5-carboxamide (A149) 1-((4-bromobenzo [b] thiophen-3-yl) methyl) -2-butyl- -Chloro-N-((trifluoromethyl) sulfonyl) -1H-imidazole-5-carboxamide (A150) 1-((4-bromobenzo [b] thiophen-3-yl) methyl) -2-butyl-4-chloro -N- (phenylsulfonyl) -1H-imidazole-5-carboxamide (A151) 1-((4-bromobenzo [b] thiophen-3-yl) methyl) -2-butyl-4-chloro-N-tosyl-1H -Imidazole-5-carboxamide (A152) N- (benzylsulfonyl) -1-((4-bromobenzo [b] thiophen-3-yl) methyl) -2-butyl-4-chloro-1H-imidazole-5-carboxamide (A153) 1-((4-Bromobenzo [b] thiophen-3-yl) methyl) -2-butyl-4-chloro-N -((3-Fluorophenyl) sulfonyl) -1H-imidazole-5-carboxamide (A154) 1-((4-bromobenzo [b] thiophen-3-yl) methyl) -N-((4-bromophenyl) sulfonyl ) -2-Butyl-4-chloro-1H-imidazole-5-carboxamide (A155) 1-((4-bromobenzo [b] thiophen-3-yl) methyl) -N-((3-bromophenyl) sulfonyl) -2-Butyl-4-chloro-1H-imidazole-5-carboxamide (A158) 1- (benzo [b] thiophen-3-ylmethyl) -2-butyl-4-chloro-N- (pyridin-4-ylsulfonyl) ) -1H-imidazole-5-carboxamide (A160) 2-butyl-4-chloro-1- (2,5-dichlorobenzyl)- -(Methylsulfonyl) -1H-imidazole-5-carboxamide (A161) 2-butyl-4-chloro-N- (cyclopropylsulfonyl) -1- (2,5-dichlorobenzyl) -1H-imidazole-5-carboxamide (A162) 2-Benzyl-1- (2,5-dichlorobenzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A163) 2-cyclopropyl-1- (2,5-dichlorobenzyl) -4 -Methyl-1H-imidazole-5-carboxylic acid (A285) 5- (2-butyl-4-chloro-1- (naphthalen-1-ylmethyl) -1H-imidazol-5-yl) -1H-tetrazole (A286) 5- (2-Butyl-4-chloro-1-((4-chlorobenzo [b] thiophen-3-yl) methyl) -1H-imi 5-yl)-1H-tetrazole An imidazole derivative selected from the following compounds (A165) to (A204) or a pharmaceutically acceptable salt thereof, or a solvate thereof:
(A165) 1- (Naphthalen-1-ylmethyl) -2- (propylthio) -1H-imidazole-5-carboxylic acid (A166) 2- (butylthio) -1- (naphthalen-1-ylmethyl) -1H-imidazole 5-carboxylic acid (A168) 2- (isobutylthio) -1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A169) 2-((cyclopropylmethyl) thio) -1- (naphthalene) -1-ylmethyl) -1H-imidazole-5-carboxylic acid (A170) 2- (benzylthio) -1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A171) 2- (ethylthio)- 4-Methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A172) 4- Tyl-1- (naphthalen-1-ylmethyl) -2- (propylthio) -1H-imidazole-5-carboxylic acid (A173) 2- (butylthio) -4-methyl-1- (naphthalen-1-ylmethyl) -1H -Imidazole-5-carboxylic acid (A174) 2- (isopropylthio) -4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A175) 2- (isobutylthio) -4 -Methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A176) 2-((cyclopropylmethyl) thio) -4-methyl-1- (naphthalen-1-ylmethyl) -1H -Imidazole-5-carboxylic acid (A177) 2- (benzylthio) -4-methyl-1- (naphthalen-1-ylmethyl)- H-imidazole-5-carboxylic acid (A178) 1- (2,5-dichlorobenzyl) -2- (ethylthio) -4-methyl-1H-imidazole-5-carboxylic acid (A179) 1- (2,5- (Dichlorobenzyl) -4-methyl-2- (propylthio) -1H-imidazole-5-carboxylic acid (A180) 2- (butylthio) -1- (2,5-dichlorobenzyl) -4-methyl-1H-imidazole 5-carboxylic acid (A181) 1- (2,5-dichlorobenzyl) -2- (isopropylthio) -4-methyl-1H-imidazole-5-carboxylic acid (A182) 1- (2,5-dichlorobenzyl) 2- (Isobutylthio) -4-methyl-1H-imidazole-5-carboxylic acid (A183) 2-((cyclopropylmethyl) thio) -1- (2,5 -Dichlorobenzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A184) 2- (benzylthio) -1- (2,5-dichlorobenzyl) -4-methyl-1H-imidazole-5-carboxylic acid ( A185) 1- (2,5-Dichlorobenzyl) -4-methyl-2- (methylthio) -1H-imidazole-5-carboxylic acid (A186) 1- (2,5-dichlorobenzyl) -4-methyl-2 -(Phenethylthio) -1H-imidazole-5-carboxylic acid (A187) 1- (2,5-dichlorobenzyl) -4-methyl-2-((3-phenylpropyl) thio) -1H-imidazole-5 Carboxylic acid (A188) 1- (2,5-dichlorobenzyl) -2-((2-methoxyethyl) thio) -4-methyl-1H-imidazole-5-carbon (A189) 1- (2,5-dichlorobenzyl) -2-((2-hydroxypropyl) thio) -4-methyl-1H-imidazole-5-carboxylic acid (A190) 1- (2,5-dichlorobenzyl ) -2-((3-Hydroxypropyl) thio) -4-methyl-1H-imidazole-5-carboxylic acid (A191) 1- (2,5-dichlorobenzyl) -4-methyl-2- (propylsulfonyl) -1H-imidazole-5-carboxylic acid (A192) 1- (2,5-dichlorobenzyl) -4-methyl-2- (pentylthio) -1H-imidazole-5-carboxylic acid (A193) 1- (2,5 -Dichlorobenzyl) -2- (hexylthio) -4-methyl-1H-imidazole-5-carboxylic acid (A194) 1- (2,5-dichlorobenzyl) -2- ( Sopentylthio) -4-methyl-1H-imidazole-5-carboxylic acid (A195) 2-((cyclohexylmethyl) thio) -1- (2,5-dichlorobenzyl-4-methyl-1H-imidazole-5-carboxylic acid (A196) 1- (2,5-dichlorobenzyl) -4-methyl-2-((2-methylbenzyl) thio) -1H-imidazole-5-carboxylic acid (A197) 1- (2,5-dichlorobenzyl ) -4-Methyl-2-((3-methylbenzyl) thio) -1H-imidazole-5-carboxylic acid (A198) 1- (2,5-dichlorobenzyl) -4-methyl-2-((4- Methylbenzyl) thio) -1H-imidazole-5-carboxylic acid (A199) 1- (2,5-dichlorobenzyl) -4-methyl-2-((2-oxo-2- (propioxy) Ruamino) ethyl) thio) -1H-imidazole-5-carboxylic acid (A200) 1- (2,5-dichlorobenzyl) -4-methyl-2-((4,4,4-trifluorobutyl) thio)- 1H-imidazole-5-carboxylic acid (A201) 1- (2,5-dichlorobenzyl) -2-((4-fluorobutyl) thio) -4-methyl-1H-imidazole-5-carboxylic acid (A202) 2 -(2-butyn-1-ylthio) -1- (2,5-dichlorobenzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A203) 2-((cyanomethyl) thio) -1- (2 , 5-dichlorobenzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A204) 2-((3-cyanopropyl) thio) -1- (2,5-dichlorobenzyl) -4-methyl -1H- imidazole-5-carboxylic acid An imidazole derivative selected from the following compounds (A205) to (A284) or a pharmaceutically acceptable salt thereof, or a solvate thereof:
(A205) 4-Methyl-1- (naphthalen-1-ylmethyl) -2-phenyl-1H-imidazole-5-carboxylic acid (A207) 4-methyl-1- (naphthalen-1-ylmethyl) -2- (3 -(Trifluoromethyl) phenyl) -1H-imidazole-5-carboxylic acid (A209) 4-methyl-1- (naphthalen-1-ylmethyl) -2- (m-tolyl) -1H-imidazole-5-carboxylic acid (A210) 2- (3-Fluorophenyl) -4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A211) 2- (3-chlorophenyl) -4-methyl-1 -(Naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A212) 1- (2,5-dimethylbenzyl) -4-methyl-2 Phenyl-1H-imidazole-5-carboxylic acid (A213) 1- (2,5-dimethylbenzyl) -2- (4-fluorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A214) 1- (2,5-Dimethylbenzyl) -2- (3-fluorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A216) 2- (3,5-difluorophenyl) -1- (2,5 -Dimethylbenzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A217) 1- (2,5-dimethylbenzyl) -4-methyl-2- (3- (trifluoromethyl) phenyl) -1H- Imidazole-5-carboxylic acid (A218) 2- (3,5-bis (trifluoromethyl) phenyl) -1- (2,5-dimethylbenzyl) -4-methyl-1 -Imidazole-5-carboxylic acid (A219) 1- (2,5-dimethylbenzyl) -2- (3-hydroxyphenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A220) 1- (2, 5-bis (trifluoromethyl) benzyl) -4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid (A221) 4-chloro-1- (2,5-dimethylbenzyl) -2-phenyl-1H -Imidazole-5-carboxylic acid (A222) 4-chloro-1- (naphthalen-1-ylmethyl) -2-phenyl-1H-imidazole-5-carboxylic acid (A223) 2- (3,5-difluorophenyl)- 4-Methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A224) 1- (2-chloro-5-fluorobenzene) Benzyl) -4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid (A226) 1- (2,5-dichlorobenzyl) -4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid ( A228) 4-Methyl-1- (3-phenoxybenzyl) -2-phenyl-1H-imidazole-5-carboxylic acid (A231) 4-methyl-1-((2-methylnaphthalen-1-yl) methyl)- 2- (3- (trifluoromethyl) phenyl) -1H-imidazole-5-carboxylic acid (A232) 2- (3-fluorophenyl) -4-methyl-1-((2-methylnaphthalen-1-yl) Methyl) -1H-imidazole-5-carboxylic acid (A233) 1- (3,5-di-tert-butylbenzyl) -4-methyl-2-phenyl-1H-imida 5-Carboxylic acid (A234) 2- (3-Fluorophenyl) -4-methyl-1-((4-methylbenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A235) 2- (3,5-Difluorophenyl) -4-methyl-1-((4-methylbenzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A236) 2- (3-Fluorophenyl) -4-methyl-1-((4- (trifluoromethyl) benzo [b] thiophen-3-yl) methyl) -1H-imidazole-5-carboxylic acid (A237) 1-(( 4-chlorobenzo [b] thiophen-3-yl) methyl) -2- (3-fluorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A238) 1-((4 Chlorobenzo [b] thiophen-3-yl) methyl) -2- (3,5-difluorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A239) 4-cyclopropyl-1- (naphthalene-1) -Ylmethyl) -2-phenyl-1H-imidazole-5-carboxylic acid (A240) 4-butyl-1- (naphthalen-1-ylmethyl) -2-phenyl-1H-imidazole-5-carboxylic acid (A241) 1- (Benzo [b] thiophen-3-ylmethyl) -2- (3-fluorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A242) 1- (2,5-dichlorobenzyl) -2- ( 3-Fluorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A243) 1- (2,5-dichlorobenzyl) -2- ( 3-Fluorophenyl) -4- (trifluoromethyl) -1H-imidazole-5-carboxylic acid (A244) 2- (3-chlorophenyl) -1- (2,5-dichlorobenzyl) -4-methyl-1H- Imidazole-5-carboxylic acid (A245) 1- (2,5-dichlorobenzyl) -4-methyl-2- (3- (trifluoromethyl) phenyl) -1H-imidazole-5-carboxylic acid (A246) 1- (2,5-dichlorobenzyl) -2- (3-methoxyphenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A247) 2- (3-cyanophenyl) -1- (2,5-dichloro Benzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A248) 1- (2,5-dichlorobenzyl) -4-methyl-2- (m-tolyl) -1H Imidazole-5-carboxylic acid (A249) 1- (2,5-dichlorobenzyl) -4-methyl-2- (naphthalen-2-yl) -1H-imidazole-5-carboxylic acid (A250) 4-chloro-1 -(2,5-dichlorobenzyl) -2-phenyl-1H-imidazole-5-carboxylic acid (A251) 4-bromo-1- (2,5-dichlorobenzyl) -2-phenyl-1H-imidazole-5 Carboxylic acid (A252) 2- (4-chlorophenyl) -1- (2,5-dichlorobenzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A253) 1- (2,5-dichlorobenzyl)- 2- (3,4-Dichlorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A254) 1- (2,5-dichlorobenzyl) -2- (3 -Dichlorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A255) 2- (2-chlorophenyl) -1- (2,5-dichlorobenzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A256) 1- (2,5-Dichlorobenzyl) -2- (3,5-difluorophenyl) -4-methyl-1H-imidazole-5-carboxylic acid (A268) 2- (1-isobutyl-1H-pyrazole -4-yl) -4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A269) 1- (2,5-dichlorobenzyl) -2- (furan-3-yl) ) -4-Methyl-1H-imidazole-5-carboxylic acid (A270) 1- (2,5-dichlorobenzyl) -4-methyl-2- (thiophen-3-yl) -1H-imidazole-5-carboxylic acid (A271) 1- (2,5-dichlorobenzyl) -4-methyl-2- (4-methylthiophen-3-yl) -1H-imidazole-5-carboxylic acid (A272) ) 2- (2-Chlorothiophen-3-yl) -1- (2,5-dichlorobenzyl) -4-methyl-1H-imidazole-5-carboxylic acid (A273) 1- (2,5-dichlorobenzyl) -4-methyl-2- (thiazol-5-yl) -1H-imidazole-5-carboxylic acid (A274) 1- (2,5-dichlorobenzyl) -4-methyl-2- (2-methylthiazole-5) -Yl) -1H-imidazole-5-carboxylic acid (A275) 1-((2,5-dichlorothiophen-3-yl) methyl) -4-methyl-2- (2-methylthiazole-5- ) -1H-imidazole-5-carboxylic acid (A276) 1- (2,5-dichlorobenzyl) -2- (2-ethylthiazol-5-yl) -4-methyl-1H-imidazole-5-carboxylic acid (A277) 1-((2,5-dichlorothiophen-3-yl) methyl) -2- (2-ethylthiazol-5-yl) -4-methyl-1H-imidazole-5-carboxylic acid (A281) 2 -(2-Cyanophenoxy) -4-methyl-1- (naphthalen-1-ylmethyl) -1H-imidazole-5-carboxylic acid (A284) 4-methyl-1- (naphthalen-1-ylmethyl) -2- ( 2- (Trifluoromethyl) phenoxy) -1H-imidazole-5-carboxylic acid   A pharmaceutical composition comprising the imidazole derivative according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. A URAT1 inhibitor comprising an imidazole derivative represented by the following formula (IA) or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[Where:
A represents a single bond, a sulfur atom, —S (═O) ₂ —, or an oxygen atom,
When A is a single bond,
R ^{1 ′} is a C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl optionally substituted with 1 to 3 R ^a. Group, C ₃ -C ₆ cycloalkyl C ₁ -C ₃ alkyl group, or optionally substituted by 1 to 3 R ^b {phenyl group, naphthalen-2-yl group, pyrazol-2-yl group, Pyrazol-4-yl group, pyrazol-5-yl group, pyrrol-2-yl group, furan-2-yl group, furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, thiazole -5-yl group, benzothiophen-2-yl group, or benzothiophen-3-yl group}
When A is an oxygen atom, a sulfur atom, or —S (═O) ₂ —, R ^{1 ′} is a C _{1 to} C ₆ alkyl group optionally substituted with 1 to 3 R ^{a s} , C ₃ -C ₆ cycloalkyl _C 1 -C ₃ alkyl _group, a C 2 -C ₆ alkynyl group, or 1-3 phenyl group which may be substituted by ^{R b,}
R ^a is a hydroxyl group, a cyano group, a halogen atom, a trifluoromethyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₂ -C ₇ alkylcarbonyl group, Represents a phenyl group optionally substituted with ₁ to 3 C ₁ -C ₆ alkyl groups, a C ₃ -C ₆ cycloalkyl group, or —CONH— (C ₁ -C ₆ alkyl);
R ^b represents a C _{1 to} C ₆ alkyl group, a C _{1 to} C ₆ alkoxy group, a halogen atom, a trifluoromethyl group, a cyano group, a hydroxyl group, or a C _{2 to} C ₇ alkylcarbonyl group,
R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a halogen atom, a trifluoromethyl group, a phenyl group which may be substituted with 1 to 3 halogen atoms, C ₂ -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 1 -C ₆ alkoxy _group, C 2 -C ₇ alkylcarbonyl _group, C 1 -C ₆ alkylthio group, a difluoromethyl group, a cyano group, a phenoxy group, Or COOR ^c ,
R ^c represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ³ represents a tetrazolyl group, —COOR ^d , or —CONHSOOR ^e ,
R ^d is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with one phenyl group, a trifluoromethyl group, a phenyl group optionally substituted with 1 to 3 R ^f , or pyridyl. Represents a group,
R ^e is optionally substituted with one phenyl group, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group, a trifluoromethyl group, and 1 to 3 R ^f. Represents a good phenyl group, pyridyl group,
R ^f represents a C _{1 to} C ₆ alkyl group or a halogen atom,
Z represents any of the following groups represented by Z1 ′ or Z2 to Z7,

R ⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ^{5 ′} and R ^{6 ′} are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen atom, a C ₁ -C ₆ alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro _group, C 1 -C ₃ alkylenedioxy group, or phenoxy group,
R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are the same or different and are a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or C ₁ -C _6. Represents an alkoxy group, a difluoromethyl group, a trifluoromethyl group, a cyano group, or a di (C ₁ -C ₆ alkyl) amino group;
R ¹⁵ and R ¹⁶ represent a halogen atom;
p and q represent 0 or 1,
W represents a sulfur atom, an oxygen atom, or NR ^g ;
R ^g represents a hydrogen _atom, C 1 -C ₆ alkyl group, or a benzyl group. ]   A URAT1 inhibitor comprising the imidazole derivative represented by the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.   Gout, hyperuricemia, hypertension, renal disease, containing as an active ingredient the imidazole derivative represented by formula (IA) according to claim 21 or a pharmaceutically acceptable salt thereof, or a solvate thereof, A therapeutic or prophylactic agent for one or more diseases selected from diabetes, arteriosclerosis, or Lesch-Nyhan syndrome.   Gout, hyperuricemia, hypertension, kidney disease, containing as an active ingredient the imidazole derivative represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, A therapeutic or prophylactic agent for one or more diseases selected from diabetes, arteriosclerosis, or Lesch-Nyhan syndrome.