JP2007254409A - Imidazolidinone derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having sufficient therapeutic effect by 11β-HSD1 inhibiting action and satisfiable as a medicine. <P>SOLUTION: The medicine contains an imidazolidinone derivative expressed by formula (1), or its pharmacologically allowable salt, hydrate or solvate as an active component. In the formula, A is a basic ring of an aromatic hydrocarbon, a basic ring of a compound comprising an aromatic hydrocarbon compound condensed with a saturated ring compound, a basic ring of an aromatic heterocyclic compound or a basic ring of a compound comprising an aromatic heterocyclic compound condensed with a saturated ring compound. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an imidazolidinone derivative useful as an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

11β-HSD1 is an enzyme that converts cortisone to cortisol, and is expressed in the liver, visceral fat and the like, and is thought to function as a factor that amplifies intracellular cortisol concentration at the level of each organ. In addition, 11β-HSD1 is responsible for local action and is responsible for gluconeogenesis in the liver and is associated with visceral fat accumulation. Antihyperglycemic effect by suppressing gluconeogenesis, and the effect of suppressing fat accumulation in visceral fat are expected.
As inhibitors of 11β-HSD1, various compounds such as thiazole derivatives, triazole derivatives, pyrrolidinone derivatives have been reported (Patent Documents 1 to 11). On the other hand, imidazolidinone derivatives related to the compounds of the present invention are disclosed in general papers, but it is not known that the compounds have 11β-HSD1 inhibitory activity (Non-patent Document 1). In addition, the activity of these known 11β-HSD1 inhibitors is not sufficient, and there is a demand for the development of compounds that have therapeutic effects due to 11β-HSD1 inhibitory action and are satisfactory as pharmaceuticals.

International Publication No. WO01 / 90090 Pamphlet International Publication No. WO01 / 90091 Pamphlet International Publication No. WO01 / 90092 Pamphlet International Publication No. WO01 / 90093 Pamphlet International Publication No. WO01 / 90094 Pamphlet International Publication No. WO03 / 065983 Pamphlet International Publication No. WO03 / 104207 Pamphlet International Publication No. WO05 / 108360 Pamphlet International Publication No. WO05 / 108361 Pamphlet International Publication No. WO99 / 31099 Pamphlet International Publication No. WO01 / 17975 Pamphlet Journal of Physical Organic Chemistry (2005), 18 (8), 792-799

  An object of the present invention is to provide an imidazolidinone derivative having excellent 11β-HSD1 inhibitory activity.

  As a result of intensive studies to achieve the above object, the present inventors have found that the imidazolidinone derivative represented by the formula (1) has excellent 11β-HSD1 inhibitory activity, and completed the present invention. It came to do.

  That is, the present invention refers to the following formula (1)

［式中、
芳香族炭化水素化合物の基本環；芳香族炭化水素化合物と飽和環化合物が縮合した化合物の基本環；芳香族複素環化合物の基本環；又は芳香族複素環化合物と飽和環化合物が縮合した化合物の基本環を示し、
Ｒ¹及びＲ²は、同一又は異なって、水素原子；ハロゲン原子；又はＣ_1-6アルキル基を示し、
Ｒ³は、水素原子；ハロゲン原子；水酸基；シアノ基；カルボキシル基；ニトロ基；Ｃ_1-6アルキル基；ハロゲン原子及び水酸基から選ばれる１〜３個の基で置換されたＣ_1-6アルキル基；ハロゲン原子及び水酸基から選ばれる１〜３個の基で置換されたＣ_1-6アルコキシ基；ヘテロアリール基；フェニル基で置換されたヘテロアリール基；又は式（２）
−Ｘ²¹−Ｙ²¹−Ｒ²¹ （２）
（式中、Ｘ²¹は酸素原子；式−ＮＲ²²−；式−ＮＲ²³ＣＯ−；又は式−ＮＲ²⁴ＳＯ₂−（式中、Ｒ²²、Ｒ²³及びＲ²⁴は、同一又は異なって、水素原子；又はＣ_1-6アルキル基を示す。）を示し、Ｙ²¹は単結合；又はＣ_1-6アルキレン基を示し、Ｒ²¹は水素原子；カルバモイル基；アリール基；又はヘテロアリール基を示す。）で表される基を示し、
Ｒ⁴は、ハロゲン原子；Ｃ_1-6アルキル基；又はハロゲン原子及び水酸基から選ばれる１〜３個の基で置換されたＣ_1-6アルキル基を示し、
Ｒ⁵及びＲ⁶は、同一又は異なって、水素原子；Ｃ_1-6アルキル基；ハロゲン原子及び水酸基から選ばれる１〜３個の基で置換されたＣ_1-6アルキル基；又はベンジル基を示し、
Ｒ⁷は、Ｃ_1-6アルキル基；ハロゲン原子、水酸基、シアノ基及びジフェニルメチル基から選ばれる１〜３個の基で置換されたＣ_1-6アルキル基；Ｃ_2-10アルケニル基；Ｃ_3-10シクロアルキル基；Ｃ_3-10シクロアルキルＣ_1-3アルキル基；シンナミル基；フェノキシエチル基；ベンジルオキシカルボニルメチル基；式（３）
−Ｘ³¹−Ｙ³¹−Ｒ³¹ （３）
（式中、Ｘ³¹はＣ_1-6アルキレン基を示し、Ｙ³¹は単結合；酸素原子；式−ＣＯ−；式−ＣＯ_２−；又は式−ＯＣＯ−を表し、Ｒ³¹はＣ_3-10シクロアルキル基；又は飽和複素環基を示す。）で表される基；又は式（４）

[Where:
A basic ring of an aromatic hydrocarbon compound; a basic ring of a compound obtained by condensing an aromatic hydrocarbon compound and a saturated ring compound; a basic ring of an aromatic heterocyclic compound; or a compound obtained by condensing an aromatic heterocyclic compound and a saturated ring compound Show the basic ring,
R ¹ and R ² are the same or different and each represents a hydrogen atom; a halogen atom; or a C _1-6 alkyl group;
R ³ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, a nitro group, a C _1-6 alkyl group; a halogen atom and C _1-6 alkyl substituted with 1 to 3 groups selected from a hydroxyl group A C _1-6 alkoxy group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group; a heteroaryl group; a heteroaryl group substituted with a phenyl group; or formula (2)
-X ²¹ -Y ²¹ -R ²¹ (2)
(Wherein X ²¹ is an oxygen atom; formula —NR ²² —; formula —NR ²³ CO—; or formula —NR ²⁴ SO ₂ — (wherein R ²² , R ²³ and R ²⁴ are the same or different, hydrogen atom;. showing a or C _1-6 alkyl group) indicates, Y ²¹ is a single bond; indicates or C _1-6 alkylene group, R ²¹ is a hydrogen atom; or heteroaryl group; a carbamoyl group; an aryl group A group represented by:
R ⁴ represents a halogen atom; a C _1-6 alkyl group; or a C _1-6 alkyl group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group;
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom; a C _1-6 alkyl group; a C _1-6 alkyl group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group; or a benzyl group Show
R ⁷ is, C _1-6 alkyl group; a halogen atom, a hydroxyl group, C _1-6 alkyl group substituted with 1 to 3 groups selected from cyano group and diphenylmethyl group; C _2-10 alkenyl group; C _3-10 cycloalkyl group; C _3-10 cycloalkyl C _1-3 alkyl group; cinnamyl group; phenoxyethyl group; benzyloxycarbonylmethyl group; formula (3)
-X ³¹ -Y ³¹ -R ³¹ (3)
(Wherein X ³¹ represents a C _1-6 alkylene group, Y ³¹ represents a single bond; an oxygen atom; a formula —CO—; a formula —CO ₂ —; or a formula —OCO—, and R ³¹ represents C _{3 − A} cycloalkyl group; or a saturated heterocyclic group); or a group represented by formula (4)

（式中、Ｘ⁴¹、Ｘ⁴²及びＸ⁴³は、同一又は異なって、単結合；又はＣ_1-4アルキレン基を示し、Ｒ⁴¹は、水素原子；ハロゲン原子；水酸基；シアノ基；ヘテロアリール基；アミノ基；ジＣ_1-3アルキルアミノ基；Ｃ_1-3アルコキシ基；カルバモイルメトキシ基；又はシアノメトキシ基を示し、ｎは０又は１を示し、Ｂは芳香族炭化水素化合物の基本環；又は芳香族複素環化合物の基本環を示し、
Ｒ⁴²及びＲ⁴³は、同一又は異なって、水素原子；ハロゲン原子；Ｃ_1-6アルキル基；又はＣ_1-6アルコキシ基を示し、
Ｒ⁴⁴は、水素原子；ハロゲン原子；水酸基；シアノ基；ニトロ基；アミノ基；カルボキシル基；Ｃ_1-6アルキルオキシカルボニル基；Ｃ_1-6アルキル基；ハロゲン原子及び水酸基から選ばれる１〜３個の基で置換されたＣ_1-6アルキル基；Ｃ_1-6アルコキシ基；ハロゲン原子及び水酸基から選ばれる１〜３個の基で置換されたＣ_1-6アルコキシ基；ヘテロアリール基；フェニル基；１から３個のハロゲン原子で置換されたフェノキシ基；スチリル基；フェニルスルホニルメチル基；又は式（５）
−Ｘ⁵¹−Ｙ⁵¹−Ｒ⁵¹ （５）
（式中、Ｘ⁵¹は酸素原子；Ｃ_1-6アルキレン基；式−ＣＯ−；式−ＮＲ⁵²−；式−ＮＲ⁵³ＣＯ−；式−ＣＯＮＲ⁵⁴−；式−ＮＲ⁵⁵ＳＯ₂−；式−Ｎ（ＳＯ₂Ｒ⁵⁶）ＳＯ₂−；又は式−ＣＨ₂ＳＯ₂−（式中、Ｒ⁵²、Ｒ⁵³、Ｒ⁵⁴、Ｒ⁵⁵及びＲ⁵⁶は、同一又は異なって、水素原子；又はＣ_1-6アルキル基を示す。）を表し、Ｙ⁵¹は単結合；又はＣ_1-6アルキレン基を示し、Ｒ⁵¹は水素原子；カルバモイル基；アリール基；又はヘテロアリール基を示す。）で表される基を示す。）で表される基を示す。］で表されるイミダゾリジノン誘導体若しくはその薬学的に許容される塩又はそれらの水和物又はそれらの溶媒和物（ただし、式（１）中、Ａがベンゼン環、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁵及びＲ⁶が水素原子、Ｒ^４がメチル基、Ｒ⁷が無置換の１−フェネチル基である場合を除く。）を提供する。

(Wherein X ⁴¹ , X ⁴² and X ⁴³ are the same or different and represent a single bond; or a C _1-4 alkylene group, and R ⁴¹ represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a heteroaryl group. An amino group; a diC _1-3 alkylamino group; a C _1-3 alkoxy group; a carbamoylmethoxy group; or a cyanomethoxy group, n represents 0 or 1, and B represents a basic ring of an aromatic hydrocarbon compound; Or a basic ring of an aromatic heterocyclic compound,
R ⁴² and R ⁴³ are the same or different and each represents a hydrogen atom; a halogen atom; a C _1-6 alkyl group; or a C _1-6 alkoxy group,
R ⁴⁴ is selected from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, a carboxyl group, a C _1-6 alkyloxycarbonyl group, a C _1-6 alkyl group, a halogen atom and a hydroxyl group. pieces of C is substituted with a group _1-6 alkyl group; C _1-6 alkoxy groups; C _1-6 alkoxy group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group; a heteroaryl group; phenyl A phenoxy group substituted with 1 to 3 halogen atoms; a styryl group; a phenylsulfonylmethyl group; or the formula (5)
-X ⁵¹ -Y ⁵¹ -R ⁵¹ (5)
(Wherein X ⁵¹ is an oxygen atom; C _1-6 alkylene group; formula —CO—; formula —NR ⁵² —; formula —NR ⁵³ CO—; formula —CONR ⁵⁴ —; formula —NR ⁵⁵ SO ₂ —; formula —N (SO ₂ R ⁵⁶ ) SO ₂ —; or —CH ₂ SO ₂ — (wherein R ⁵² , R ⁵³ , R ⁵⁴ , R ⁵⁵ and R ⁵⁶ are the same or different and represent a hydrogen atom; or C . _{of 1-6} represents an alkyl group) represents, Y ⁵¹ is a single bond; Table in showing a or a heteroaryl group); indicates or C _1-6 alkylene group, R ⁵¹ is a hydrogen atom; a carbamoyl group; an aryl group. Represents a group. ) Is represented. Or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof (wherein, in the formula (1), A represents a benzene ring, R ¹ , R ² , R ³ , R ⁵ and R ⁶ are hydrogen atoms, R ⁴ is a methyl group, and R ⁷ is an unsubstituted 1-phenethyl group.

  According to another aspect of the present invention, the present invention provides any imidazolidinone derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. Provided is a medicament containing as an active ingredient.

  According to another aspect of the present invention, the present invention provides the aforementioned medicament for preventing or treating a disease or condition that can be ameliorated by inhibiting 11β-HSD1.

  According to another aspect of the present invention, the present invention provides the aforementioned medicament, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is diabetes.

  According to another aspect of the present invention, the present invention provides the medicament, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is metabolic syndrome.

  According to another aspect of the present invention, the present invention provides the aforementioned medicament, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is obesity.

  According to another aspect of the present invention, the present invention provides the medicament, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is hypertension.

  According to another aspect of the present invention, the present invention provides the medicament, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is arteriosclerosis.

  According to another aspect of the present invention, the present invention provides the medicament, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is hyperlipidemia.

  According to the present invention, to provide an imidazolidinone derivative or a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof having an unprecedented new skeleton and exhibiting an excellent 11β-HSD1 inhibitory activity. I was able to.

  Hereinafter, the imidazolidinone derivative of the present invention will be described in more detail, but it is not particularly limited to those exemplified.

  The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The C _1-6 alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, sec -Butyl group, tert-butyl group, pentyl group, isopentyl group, 1-ethylpropyl group, hexyl group.

The C _1-6 alkyl group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group is from 1 carbon atom in which the hydrogen atom in the alkyl group is substituted with 1 to 3 halogen atoms or hydroxyl groups. A linear or branched alkyl group having 6 groups is exemplified, and examples thereof include a trifluoromethyl group, a hydroxymethyl group, a 2,2,2-trifluoroethyl group, and a 2-hydroxyethyl group.

A C _1-6 alkyl group substituted with 1 to 3 groups selected from a halogen atom, a hydroxyl group, a cyano group, and a diphenylmethyl group is a halogen atom, hydroxyl group, cyano having 1 to 3 hydrogen atoms in the alkyl group. A linear or branched alkyl group having 1 to 6 carbon atoms substituted with a group or a phenyl group, for example, a trifluoromethyl group, a hydroxymethyl group, a 2,2,2-trifluoroethyl group 2-hydroxyethyl group, cyanomethyl group, cyanobutyl group, 3,3-diphenylpropyl group.

The C _2-10 alkenyl group refers to a linear or branched alkenyl group having 2 to 10 carbon atoms, such as vinyl, allyl, 1-propenyl, 2-propenyl, and isopropenyl. Group, 2-butenyl group, 3-butenyl group, isobutenyl group, 4-pentenyl group, 5-hexenyl group and geranyl group.

The C _3-10 cycloalkyl group represents a cyclic alkyl group having 3 to 10 carbon atoms, and the cyclic alkyl group herein represents a monocyclic hydrocarbon group or a polycyclic hydrocarbon group, The polycyclic hydrocarbon group represents a condensed polycyclic hydrocarbon group, a bridged ring hydrocarbon group or a spiro hydrocarbon group, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, Examples include a cyclopentenyl group, a cyclohexenyl group, a bicyclo [3,3,0] octyl group, and an adamantyl group.

The C _3-10 cycloalkyl C _1-3 alkyl group is a group consisting of a cyclic alkyl group having 3 to 10 carbon atoms and an alkylene group having 1 to 3 carbon atoms, such as a cyclopropylmethyl group, Cyclopropylethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylpropyl group, cycloheptylmethyl group, cyclooctylmethyl group, cyclopentenylmethyl group, cyclohexenylmethyl group, bicyclo [3, 3,0] octylmethyl and adamantylmethyl groups.

The aryl group represents a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 15 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and an anthryl group.
The basic ring of the aromatic hydrocarbon compound is a skeleton ring excluding a substituent in a monocyclic or condensed polycyclic aromatic hydrocarbon compound having 6 to 15 carbon atoms, such as a benzene ring, naphthalene ring, anthracene A ring is mentioned.
The basic ring of a compound obtained by condensing an aromatic hydrocarbon compound and a saturated ring compound is a skeleton ring of a compound obtained by condensing an aromatic hydrocarbon compound and a saturated alicyclic hydrocarbon compound, or an aromatic hydrocarbon compound and a saturated heterocyclic compound. For example, indane ring, 1,2,3,4-tetrahydronaphthalene ring, 1,3-benzodioxole ring, 1,4-benzodioxan ring, 2,3-dihydro-1-benzothiophene ring, 2 , 3-Dihydro-4H-1-benzothiopyran ring, indoline ring, isoindoline ring, 1,2,3,4-tetrahydroquinoline ring, 1,2,3,4-tetrahydroisoquinoline ring, 1,2,3,4 -Tetrahydroquinoxaline ring, 3,4-dihydro-2H-1,4-benzoxazine ring, 3,4-dihydro-2H-1,4-benzothiazine ring.

  The heteroaryl group refers to a monocyclic or condensed aromatic heterocyclic group containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. For example, a pyrrolyl group, a furyl group, a thienyl group , Oxazolyl group, isoxazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,4-thiadiazolyl Group, pyridyl group, pyrazinyl group, pyridazinyl group, 1,2,4-triazinyl group, 1,2,3-triazinyl group, 1,3,5-triazinyl group, benzoxazolyl group, benzisoxazolyl group , Benzothiazolyl group, benzisothiazolyl group, benzimidazolyl group, benzotriazolyl group, benzothiadiazolyl group, benzofurazanyl group, benzopyrani Group, thianaphthenyl group, isothianaphthenyl group, benzofuranyl group, isobenzofuranyl group, benzothienyl group, isoindolyl group, indolyl group, indazolyl group, isoquinolyl group, quinolyl group, phthalazinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, 2,1,3-Benzoxadiazolyl, benzoxazinyl, coumaryl, naphthyridinyl, phthalazinyl, purinyl, pteridinyl, thienofuranyl, imidazothiazolyl, imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl Group and pyridopyrimidinyl group.

The basic ring of the aromatic heterocyclic compound is a skeleton excluding a substituent in a monocyclic or condensed aromatic heterocyclic compound containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom For example, pyrrole ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, imidazole ring, thiazole ring, isothiazole ring, pyrazole ring, triazole ring, tetrazole ring, 1,3,4-oxadiazole Ring, 1,2,4-oxadiazole ring, 1,2,4-thiadiazole ring, pyridine ring, pyrazine ring, pyridazine ring, 1,2,4-triazine ring, 1,2,3-triazine ring, 1 , 3,5-triazine ring, benzoxazole ring, benzisoxazole ring, benzothiazole ring, benzisothiazole ring, benzimidazole ring, benzotriazole ring, benzothiadiazole , Benzofurazan ring, benzopyran ring, thiaphthalene ring, isothiaphthalene ring, isothiaphthalene ring, benzofuran ring, isobenzofuran ring, benzothiophene ring, isoindole ring, indole ring, indazole ring, isoquinoline ring, quinoline ring, phthalazine ring, quinoxaline ring, quinazoline Ring, cinnoline ring, 2,1,3-benzoxadiazole ring, benzoxazine ring, coumarin ring, naphthyridine ring, phthalazine ring, purine ring, pteridine ring, thienofuran ring, imidazothiazole ring, imidazopyridine ring, pyrrolopyridine ring, Examples include a pyrrolopyrimidine ring and a pyridopyrimidine ring.
The basic ring of a compound obtained by condensing an aromatic heterocyclic compound and a saturated ring compound is a skeleton ring of a compound obtained by condensing an aromatic heterocyclic compound and a saturated alicyclic hydrocarbon compound or an aromatic heterocyclic compound and a saturated heterocyclic compound. For example, 2,3-cyclopentenopyridine ring, 3,4-cyclopentenopyridine ring, 5,6,7,8-tetrahydroquinoline ring, 5,6,7,8-tetrahydroisoquinoline ring .

  The heteroaryl group substituted with a phenyl group refers to a heteroaryl group in which a hydrogen atom in the heteroaryl group is substituted with one phenyl group, and examples thereof include a phenylimidazolyl group and a phenylpyrazolyl group.

  The saturated heterocyclic group refers to a monocyclic or condensed saturated heterocyclic group containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and a saturated heterocyclic carbon atom or heteroatom For example, azetidinyl group, pyrrolidinyl group, piperidinyl group, tetrahydrofuranyl group, dihydrofuranyl group, tetrahydropyranyl group, dihydropyranyl group, tetrahydrothiophenyl group, tetrahydrothiopyranyl group, dihydro Thiopyranyl group, tetrahydropyridinyl group, dihydropyridinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, thiazolidinyl group, dioxanyl group, imidazolinyl group, thiazolinyl group, isothiazolidinyl group, thiadinanyl group, diazepanyl group, A dioxolanyl group is mentioned.

The C _1-6 alkoxy group represents a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, Examples include sec-butoxy group, tert-butoxy group, pentoxy group, isopentoxy group, 1-ethylpropoxy group, and hexyloxy group.

_{Examples of the} C _1-3 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group.

The 1-3 C _1-6 alkoxy group substituted by a group selected from a halogen atom and a hydroxyl group, a hydrogen atom definitive alkoxy group is substituted with 1 to 3 halogen atoms or a hydroxyl C _1-6 An alkoxy group is shown, and examples thereof include a trifluoromethoxy group, a difluoromethoxy group, a 2-hydroxyethoxy group, and a 2,2,2-trifluoroethoxy group.

The C _1-6 alkylene group refers to a linear or branched alkylene group having 1 to 6 carbon atoms, such as a methylene group, 1,1-ethylene group, 1,2-ethylene group, 1,2 -(1,1-dimethyl) ethylene group, 1,1-propylene group, 2,2-propylene group, 1,1-cyclopropylene group, 1,3-propylene group, tetramethylene group, pentamethylene group, hexamethylene Group.

The C _1-4 alkylene group represents a linear or branched alkylene group having 1 to 4 carbon atoms, such as a methylene group, 1,1-ethylene group, 1,2-ethylene group, 1,2 -(1,1-dimethyl) ethylene group, 1,1-propylene group, 2,2-propylene group, 1,1-cyclopropylene group, 1,3-propylene group, tetramethylene group are exemplified.
The di-C _1-3 alkylamino group refers to an amino group substituted with 2 linear or branched alkyl groups having 1 to 3 carbon atoms, such as a dimethylamino group, a diethylamino group, di-n-propyl. An amino group is mentioned.

  The phenoxy group substituted with 1 to 3 halogen atoms means a phenoxy group substituted with 1 to 3 halogen atoms in the phenoxy group, for example, 2,4-dichlorophenoxy group, 2-fluoro A phenoxy group is mentioned.

The C _1-6 alkyloxycarbonyl group represents a straight or branched alkyloxycarbonyl group having 1 to 6 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group. , Butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentoxycarbonyl group, isopentoxycarbonyl group, 1-ethylpropoxycarbonyl group, hexyloxycarbonyl group.

  The imidazolidinone derivative of the present invention may be a pharmaceutically acceptable salt, hydrate or solvate thereof. Hereinafter, the imidazolidinone derivatives of the present invention, pharmaceutically acceptable salts, hydrates and solvates thereof are also referred to as “compounds of the present invention”.

In the present invention, the pharmaceutically acceptable salt is, for example, a mineral salt such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonate Sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, Acid addition salts such as organic acid salts such as mandelate, ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate Amino acid salts, or inorganic or ammonium salts such as lithium, sodium, potassium, calcium, magnesium, triethylamine, diisopropylamine, A salt with an organic base such as a rohexylamine salt, preferably a hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, oxalate, Tartrate, citrate, acetate, lactate, glutamate, aspartate, sodium salt, potassium salt, ammonium salt or triethylamine salt are preferable, sodium salt, hydrochloride or sulfate is more preferable. Is the hydrochloride salt. In the present specification, the compound of the present invention includes a compound that is metabolized in vivo and converted into the compound of the present invention, that is, a so-called prodrug.
The hydrate or solvate in the present invention is a pharmaceutically acceptable hydrate or solvate of the compound of the present invention or a salt thereof. The compound of the present invention and its salt may absorb moisture or solvent and be adsorbed with water or adsorbed solvent, or may be hydrated or solvated by exposure to air or recrystallization. The hydrate or solvate in the present invention includes such a hydrate or solvate.

  The compounds of the present invention may have asymmetric centers, in which case there are various optical isomers or configurations. Thus, the compounds of the invention can exist as separate optically active forms of (+) and (−) and as racemates or (±) mixtures. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention include all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can. In addition, the compound of the present invention may have isomers such as cis isomer and trans isomer. The compound of the present invention includes those isomers and those containing these isomers in an arbitrary ratio.

  The compound of the present invention has 11β-HSD1 activity inhibitory activity and can be effectively used for diseases involving 11β-HSD1, such as diabetes, metabolic syndrome, obesity, hypertension, arteriosclerosis, and hyperlipidemia. . That is, the compound of the present invention can be used as an inhibitor of 11β-HSD1, for example, as a therapeutic or prophylactic agent for diabetes, metabolic syndrome, obesity, hypertension, arteriosclerosis, and hyperlipidemia. The compounds of the present invention can be administered alone or with a pharmaceutically or pharmaceutically acceptable carrier or diluent. When the compound of the present invention is used as an 11β-HSD1 inhibitor or the like, the compound of the present invention may be orally or parenterally administered as it is. Moreover, you may administer orally or parenterally as an agent which contains the compound of this invention as an active ingredient. Parenteral administration includes intravenous administration by injection.

When the above agents are administered orally, mix diluents, excipients, disintegrants, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, colorants, flavoring agents, etc. Then, it may be administered as a preparation such as granules, capsules, tablets, medicinal drops, troches, hard candy, powders, and sprays containing the compound of the present invention as an active ingredient. Moreover, you may perform sweetening or flavoring suitably. When the above agent is administered parenterally, an injection, instillation, eye drop, cream, salve, suppository, jelly, gel, containing the compound of the present invention as an active ingredient
It may be administered as a formulation such as a paste, lotion, ointment or aqueous suspension. In formulating, a normal formulation method can be used.

  The compound of the present invention can be administered orally or parenterally, for example, 1 mg to 1000 mg, preferably 10 mg to 200 mg can be administered, for example, 1 to 3 times per day. The dosage of the compound of the present invention can be appropriately adjusted depending on the age, weight and symptoms of the patient.

The inhibition of 11β-HSD1 activity of the compound of the present invention can be evaluated according to a known method such as the method described in Examples.

Although the manufacturing method of the compound concerning this compound is demonstrated in detail, it does not specifically limit to what was illustrated. Moreover, the solvent used for the reaction is not particularly limited as long as it does not inhibit each reaction.
[Scheme 1]

（式中、Ａ、R¹、R²、R³、R⁴、R⁵、R⁶及びR⁷ はそれぞれ前記と同意義である。）
スキーム１は、アミド誘導体（１１）、（１２）又は（１３）を還元してジアミン誘導体（１４）を得て、更にイミダゾリジノン誘導体（１）へ変換する工程を示す。

^{(Wherein, A, R 1, R 2} , R 3, R 4, R 5, R 6 and R ⁷ are as defined above, respectively.)
Scheme 1 shows a process of reducing the amide derivative (11), (12) or (13) to obtain the diamine derivative (14), and further converting it to the imidazolidinone derivative (1).

  For example, in the step of reducing the amide derivative (11), (12) or (13) to convert it to the diamine derivative (14), conversion can be performed using various reducing agents. Examples of the reducing agent used include lithium aluminum hydride, diborane, borane methyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. Examples of the solvent used in this reaction include ethanol, methanol, tetrahydrofuran, dioxane, toluene, xylene and the like. These reactions can be performed at 0 to 150 ° C.

  Further, for example, in the step of converting the diamine derivative (14) to the imidazolidinone derivative (1), conversion can be performed using phosgene, triphosgene {bis (trichloromethyl) carbonate}, phenyl chloroformate, or the like. In this case, the reaction can be carried out using a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium hydrogen carbonate. Examples of the solvent used in this reaction include chloroform, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, toluene, xylene and the like. These reactions can be performed at -20 to 50 ° C.

  Further, this step of converting the diamine derivative (14) to the imidazolidinone derivative (1) can be performed using carbonyldiimidazole or urea. Examples of the solvent used in this reaction include chloroform, ethyl acetate, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, methanol, ethanol, N, N-dimethylformamide, water and the like. These reactions are carried out at 20 to 200 ° C. It can be carried out.

  [Scheme 2]

（式中、Ａ、R¹、R²、R³、R⁴、R⁵、R⁶及びR⁷ はそれぞれ前記と同意義である。PGはアミノ基の保護基を示す。）
スキーム２は、アミン誘導体（２１）からイミダゾリジノン誘導体（２６）へ変換する工程を示す。

(In the formula, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as described above. PG represents an amino-protecting group.)
Scheme 2 shows a process of converting an amine derivative (21) to an imidazolidinone derivative (26).

  For example, the conversion from the amine derivative (21) to the amide derivative (22) by amidation is carried out by a method using a dehydration condensing agent, an activated carboxylic acid such as acid chloride, acid bromide, carboxylic acid active ester, mixed acid anhydride, etc. Or a method using an ester amide exchange reaction using an ester.

  For example, in a method using a dehydrating condensing agent, examples of the dehydrating condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, dicyclohexylcarbodiimide, diphenylphosphoryl azide, and carbonyldiimidazole. Activators such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used. At this time, the reaction can be carried out using a suitable base, which includes amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, or potassium carbonate. Inorganic bases such as Examples of the solvent used in this reaction include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. It can carry out at 50-50 degreeC.

  Further, for example, amidation can be performed using a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate. At this time, the reaction can be carried out using a suitable base, which includes amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, or potassium carbonate. And inorganic bases such as Examples of the solvent used in these reactions include solvents that do not participate in the reaction such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, and ethyl acetate. These reactions are performed at -50 to 50 ° C. It can be carried out.

  Further, for example, in the amidation reaction, the corresponding carboxylic acid or ester can be converted to an acyl halide such as acyl chloride or acyl bromide and then condensed with an amine, and the corresponding carboxylic acid or ester can be converted to an acyl halide. For the conversion, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and the like can be used. Examples of the solvent used in these reactions include solvents that do not participate in the reaction, such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, and ethyl acetate. These reactions are performed at −50 to 100 ° C. be able to. The condensation reaction between the amine and the acyl halide can be carried out using a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, and organic compounds such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate. Inorganic bases such as acid salts or potassium carbonate can be mentioned. Examples of the solvent used in these reactions include solvents that do not participate in the reaction, such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, and ethyl acetate. These reactions are performed at −50 to 100 ° C. be able to.

  As another example of the amidation reaction, for example, an active ester such as 1-benzotriazolyl ester or succinimidyl ester can be used. Examples of the solvent used in these reactions include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate, and the like. The reaction is performed at -50 to 50 ° C. be able to.

  Moreover, as a method using the ester amide exchange reaction using a corresponding ester body, the method of heating amine derivative (21) and ester in the solvent which is not concerned in reaction is mentioned. Examples of the solvent used in this reaction include chloroform, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, methanol, ethanol, N, N-dimethylformamide and the like, and this reaction can be carried out at 50 to 200 ° C.

  In addition, for example, in the step of deprotecting from the amide derivative (22) to obtain (23), different methods can be used depending on the kind of the protecting group. For this deprotection, the method described by PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THEODORA W. GREENE and PETER G. M WUTS can be used. For example, when PG is a group that is deprotected with an acid such as tert-butoxycarbonyl group, trityl group, o-nitrobenzenesulfenyl group, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. It can be deprotected using an acid. These reactions can be carried out by diluting or dissolving the substrate compound with an organic solvent or water. Examples of the organic solvent include ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1, 2-dichloroethane is mentioned. This reaction can be performed at -50-50 degreeC. Further, for example, when PG is a group that is deprotected by a hydrogenolysis reaction such as a benzyloxycarbonyl group, it can be deprotected by a hydrogenolysis reaction using a metal catalyst such as palladium. Examples of the solvent used in this reaction include solvents that do not participate in the reaction, such as ethanol, methanol, tetrahydrofuran, and ethyl acetate. These reactions can be performed at 0 to 100 ° C. In this reaction, hydrogen gas can be used, and a combination of reagents used in a hydrogenolysis reaction using formic acid-ammonium formate as an example can be applied. Further, for example, when PG is a protecting group such as a fluorenyloxycarbonyl group deprotected with a base, it can be deprotected using a base such as diethylamine, piperidine, ammonia, sodium hydroxide or potassium carbonate. These bases can be used alone or diluted or suspended in a solvent. Examples of the solvent used in this reaction include water, ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, and the like. The reaction can be performed at 0 to 100 ° C. . Further, for example, when PG is a group that is deprotected by a metal catalyst such as an allyloxycarbonyl group, it can be deprotected by using tetrakis (triphenylphosphine) palladium or the like as a catalyst or reagent. Examples of the solvent used in this reaction include solvents that do not participate in the reaction, such as dichloromethane, chloroform, and tetrahydrofuran, and this reaction can be performed at 0 to 100 ° C.

  Further, for example, the step of converting the amide derivative (23) into the diamine derivative (24) can be performed by the same method as the method for obtaining the diamine derivative (14) shown in Scheme 1.

  For example, the step of converting the diamine derivative (24) to the imidazolidinone derivative (25) is performed in the same manner as the method for obtaining the imidazolidinone derivative (1) from the diamine derivative (14) shown in Scheme 1. Can do.

For example, in the step of obtaining the imidazolidinone derivative (26) having an N-substituent introduced from the imidazolidinone derivative (25), R ⁷ -Cl, R ⁷ -Br, R ⁷ -I, R ⁷ -OMs, The reaction can be carried out in the presence of a base using R ⁷ -OTs (wherein R ⁷ is as defined above, Ms represents a methanesulfonyl group, and Ts represents a p-tosyl group). . Examples of the base to be used include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as sodium hydride, potassium hydride, n-butyllithium, sodium hydroxide, potassium hydroxide, potassium carbonate and sodium bicarbonate. Examples of the solvent used in this reaction include chloroform, diethyl ether, tetrahydrofuran, dioxane, toluene, xylene, acetonitrile, methanol, ethanol, N, N-dimethylformamide, water, and the like. These reactions are performed at -50 to 150 ° C. It can be carried out.

  [Scheme 3]

（式中、Ａ、R¹、R²、R³、R⁴、R⁵、R⁶及びR⁷ はそれぞれ前記と同意義である。X^aは、塩素原子、臭素原子、メタンスルホニルオキシ基、ｐ−トシルオキシ基等の脱離基を示す。）
スキーム３は、アミド誘導体（３１）又は（３５）からイミダゾリジノン誘導体（２６）又は（３８）へ変換する工程を示す。

(In the formula, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above. X ^a represents a chlorine atom, a bromine atom, a methanesulfonyloxy group, A leaving group such as a p-tosyloxy group is shown.)
Scheme 3 shows a step of converting an amide derivative (31) or (35) to an imidazolidinone derivative (26) or (38).

  For example, the reduction reaction from the amide derivative (31) or (35) to the diamine derivative (32) or (36) can be performed by a method similar to the method for obtaining the diamine derivative (14) shown in Scheme 1.

  For example, the step of converting the diamine derivative (32) or (36) to the imidazolidinone derivative (33) or (37) is the same as the method for obtaining the imidazolidinone derivative (1) shown in Scheme 1. It can be carried out.

For example, the step of converting an imidazolidinone derivative (33) or (37) into an N, N′-disubstituted imidazolidinone derivative (26) or (38) using the compound (34) is shown in Scheme 2. The imidazolidinone derivative (25) shown can be converted into the imidazolidinone derivative (26) in the same manner as described above.

The present invention will be specifically described below with reference examples, examples and test examples, but is not particularly limited to those exemplified.

Reference Example 1 Synthesis of ethyl oxo {[(1S) -1-phenylethyl] amino} acetate
Triethylamine (19.1 ml) was added to a solution of (S)-(−)-phenylethylamine (11.07 g) in chloroform (100 ml), and then chloroglyoxylic acid ethyl ester (12.4 g) in chloroform was cooled with ice. The solution (40 ml) was added and stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform and washed successively with 1M aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 5: 1) to obtain the title compound (19.51 g) as a colorless oily substance.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.38 (t, J = 7.2 Hz, 3 H), 1.57 (d, J = 6.8 Hz, 3 H), 4.34 (q, J = 7.2 Hz, 2 H), 5.05-5.23 (m, 2 H), 7.18-7.46 (m, 5 H).
Reference Example 2 Synthesis of ethyl (benzylamino) (oxo) acetate In the same manner as in Reference Example 1, benzylamine (6.74 g) was used to give the title compound (13.87 g) as a colorless oil.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.39 (t, J = 7.2 Hz, 3 H), 4.36 (q, J = 7.2 Hz, 2 H), 4.53 (d, J = 6.1 Hz, 2 H), 7.10-7.48 (m, 5 H).
Reference Example 3 Synthesis of 3- (4-methoxyphenyl) propyl methanesulfonate
Triethylamine (2.09 ml) was added to a chloroform (50 ml) solution of 3- (4-methoxyphenyl) -1-propanol (1.66 g), and then methanesulfonyl chloride (0.93 ml) was added dropwise under ice cooling. Stir overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The title compound (2.49 g) was obtained as a brown solid.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.98-2.11 (m, 2 H), 2.64-2.74 (m, 2 H), 2.99 (s, 3 H), 3.79 (s, 3 H), 4.22 (t , J = 6.4 Hz, 2 H), 6.81-6.88 (m, 2 H), 7.07-7.14 (m, 2 H).
Reference Example 4 Synthesis of 1- (chloromethyl) -2- (2-phenylethyl) benzene
Triethylamine (479 μl) was added to a solution of 2-phenethylbenzyl alcohol (609 mg) in chloroform (20 ml), methanesulfonyl chloride (0.27 ml) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform and washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The title compound (730 mg) was obtained as a yellow oil.
1H NMR (300 MHz, CHLOROFORM-D) σ 2.83-3.16 (m, 4 H), 4.55 (s, 2 H), 7.12-7.44 (m, 9 H).
Reference Example 5 Synthesis of (1S) -1- (2-chlorophenyl) ethylamine
To a solution of (S)-(−)-phenylethylamine (3.00 g) in diethyl ether (27.5 ml) was added dropwise n-butyllithium (2.6 M n-hexane solution, 9.6 ml) under ice cooling for 15 minutes. Stir. Subsequently, trimethylsilyl chloride (3.14 ml) was added dropwise and stirred for 30 minutes. Further, n-butyllithium (2.6M n-hexane solution, 28.6 ml) was added dropwise and stirred for 1 hour, then the temperature was raised to room temperature and the mixture was stirred overnight. Next, the reaction solution was cooled to −78 ° C., a solution of hexachloroethane (11.72 g) in diethyl ether (29.9 ml) was added dropwise, and the mixture was heated to −45 ° C. and stirred for 1 hour. Next, 3M aqueous hydrochloric acid (90 ml) was added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The organic layer was separated and washed with 3M aqueous hydrochloric acid. Potassium hydroxide was added to the aqueous layer to adjust the pH to 12, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: methanol = 1: 0 to 4: 1) to obtain the title compound (1.005 g) as a pale yellow oily substance.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.40 (d, J = 6.6 Hz, 3 H), 1.57 (s, 2 H), 4.55 (q, J = 6.6 Hz, 1 H), 7.12-7.20 (m , 1 H), 7.23-7.36 (m, 2 H), 7.53 (d, J = 7.8 Hz, 1 H).
Reference Example 6 Synthesis of 1-phenylcyclopropylamine To a solution of benzonitrile (4.040 g) in diethyl ether (130 ml) was added titanium tetraisopropoxide (12.6 ml), and then ethylmagnesium bromide (39 % Diethyl ether solution, 28.5 ml) was added dropwise and stirred for 10 minutes. After raising the temperature to room temperature, boron trifluoride diethyl ether complex (9.8 ml) was added dropwise and stirred for 1 hour. A 1M aqueous hydrochloric acid solution and diethyl ether were added to the reaction solution, and the mixture was partitioned. A 10% aqueous sodium hydroxide solution was added dropwise to the aqueous layer, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 20: 1-7: 1) to obtain the title compound (3.563 g) as a pale yellow oily substance.
1H NMR (300 MHz, CHLOROFORM-D) σ 0.95-1.02 (m, 2 H), 1.04-1.10 (m, 2 H), 1.89 (s, 2 H), 7.15-7.34 (m, 5 H).
Example 1 Synthesis of Compounds (1-1) to (1-73) (1) Synthesis of N-[(1S) -1-phenylethyl] ethanediamide (1A-1) Ethyl oxo { 28% aqueous ammonia (21.9 g) was added to an ethanol solution (60 ml) of [(1S) -1-phenylethyl] amino} acetate (8.00 g), and the mixture was heated to reflux at 90 ° C. for 2.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The title compound (6.61 g) was obtained as a colorless powder by drying under reduced pressure at room temperature for 1.5 days. The structure and NMR data of the obtained compound are shown in Table 1.
(2) Synthesis of N-[(1S) -1-phenylethyl] ethane-1,2-diamine (1B-1) To a tetrahydrofuran suspension (172 ml) of lithium aluminum hydride (10.4 g), Example 1 N-[(1S) -1-phenylethyl] ethanediamide (6.61 g) obtained in (1) was added and heated to reflux for 10 hours. After returning the reaction solution to room temperature, water was added dropwise under ice cooling. Sodium hydroxide (8.5 g, pellets) was added, stirred for 30 minutes, and decanted. Diethyl ether was added and stirred for 1 hour, followed by decantation. Diethyl ether was further added and decantation was performed. The solution collected by decantation was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The title compound (7.92 g) was obtained as a colorless oil. The structure and NMR data of the obtained compound are shown in Table 1.
(3) Synthesis of 1-[(1S) -1-phenylethyl] imidazolidin-2-one (1C-1) N-[(1S) -1-phenylethyl] obtained in Example 1 (2) Triphosgene (3.37 g) was added to a chloroform solution (172 ml) of ethane-1,2-diamine (7.92 g) under ice cooling, and then triethylamine (10.5 ml) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with chloroform and washed successively with 0.1 M aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 3 to 0: 1) to obtain the title compound (3.90 g) as a colorless oily substance. The structure and NMR data of the obtained compound are shown in Table 1.
(4) Synthesis of 1-benzyl-3-[(1S) -1-phenylethyl] imidazolidin-2-one (1-1) 1-[(1S) -1 obtained in Example 1 (3) -Phenylethyl] imidazolidin-2-one (123 mg) in N, N-dimethylformamide (2 ml) was added sodium hydride (60% oil suspension, 26 mg), and the mixture was stirred at room temperature for 15 minutes. Benzyl bromide (77 μl) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 3) to obtain the title compound (92 mg) as a colorless oily substance. Table 2 shows the structure and NMR data of the obtained compound.

1-[(1S) -1-phenylethyl] imidazolidin-2-one obtained in Example 1 (3) and n-butyl bromide, cyclohexylmethyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl chloride, Isobutyl bromide, iodomethane, (2-bromoethyl) benzene, 2- (bromomethyl) pyridine, 1- (chloromethyl) naphthalene, 2- (bromomethyl) naphthalene, 1-bromo-4-phenylbutane, 1-adamantyl bromomethyl ketone, 4- (tert-butyl) benzyl bromide, 1-bromo-3-phenylpropane, 4-bromomethylbiphenyl, 4-cyanobenzyl bromide, 5-bromovaleronitrile, 2- (bromomethyl) tetrahydro-2H-pyran, 1 Compounds (1-4) to (1-22) were obtained in the same manner as described above using-(bromomethyl) adamantane. Table 2 shows the structure and NMR data of the obtained compound.
(5) Synthesis of 1-[(1S) -1-phenylethyl] -3- [3- (trifluoromethyl) benzyl] imidazolidin-2-one (1-2) Obtained in Example 1 (3) Sodium hydride (60% oil suspension, 40 mg) was added to a tetrahydrofuran solution (3.3 ml) of 1-[(1S) -1-phenylethyl] imidazolidin-2-one (190 mg), and the mixture was stirred at room temperature for 20 minutes. Stir. 3- (Trifluoromethyl) benzyl bromide (239 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1 to 1: 1) to give the title compound (288 mg) as a colorless oil. Obtained. Table 2 shows the structure and NMR data of the obtained compound.

1-[(1S) -1-phenylethyl] imidazolidin-2-one obtained in Example 1 (3) and benzyl bromoacetate, 4- (trifluoromethyl) benzyl bromide, 2-methylbenzyl bromide, 4 -Methylbenzyl bromide, 3,4-difluorobenzyl bromide, 3-benzyloxybenzyl bromide, 4- (bromomethyl) benzophenone, 9- (bromomethyl) acridine, 2- (trifluoromethyl) benzyl bromide, 3- (bromomethyl)- 5-chlorobenzo [b] thiophene, 1- [3- (bromomethyl) phenyl] -1H-pyrrole, 5- (bromomethyl) benzofurazan, 1- (3-bromopropyl) pyrrole, 2-fluoro-3-methylbenzyl bromide, 2-cyclohexylethyl bromide, 2-chlorobenzyl chloride, 2,6-difluorobenzyl bromide, 2- (difluoromethoxy) benzyl bromide, 2-fluorobenzyl bromide , Β-bromophenetole, methyl 3- (bromomethyl) benzoate, 3- (2-fluorophenoxy) benzyl bromide, 4-chloromethylstilbene, cinnamyl bromide, geranyl bromide, 3- (4-methoxyphenyl) propyl Methanesulfonate (Reference Example 3), 2-bromomethylbiphenyl, 2-methoxybenzyl chloride, 1- (chloromethyl) -2- (2-phenylethyl) benzene (Reference Example 4), 3-chlorobenzyl chloride, 2 -Cyanobenzyl bromide, 2-bromobenzyl bromide, 2,6-dichlorobenzyl bromide, 3-methylbenzyl bromide, 3-methoxybenzyl bromide, 2,6-dimethylbenzyl chloride, 2- (4-fluorophenyl) oxirane, 1 -Bromomethyl-2-[(phenylsulfonyl) methyl] benzene, 1-benzyl-2- (chloromethyl) benzene (2-benzylbenzyl alcohol) And synthesized in the same manner as in Reference Example 4), 2- (trifluoromethoxy) benzyl bromide, 1-bromo-3,3-diphenylpropane, methyl 1- (iodomethyl) benzoate, 3- (2-methylphenyl) Propylmethanesulfonate (synthesized in the same manner as in Reference Example 3 using 3- (2-methylphenyl) propan-1-ol), 3-cyanobenzyl bromide, 2- (chloromethyl) quinoline, 4- (chloro Methyl) thiazole, 4-chloromethyl-3,5-dimethylisoxazole, chloroacetonitrile, 3-nitrobenzyl bromide, 4-nitrobenzyl bromide, 2-nitrobenzyl bromide and compound (1) in the same manner as above. -23) to (1-73) were obtained. Table 2 shows the structure and NMR data of the obtained compound.
(6) Synthesis of 1- [2- (2,4-dichlorophenoxy) benzyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (1-3) Example 1 (3) Sodium hydride (60% oil suspension, 40 mg) was added to a tetrahydrofuran solution (3.3 ml) of 1-[(1S) -1-phenylethyl] imidazolidin-2-one (190 mg) obtained in 1 above. For 20 minutes. 2,4-Dichloro-1- [2- (chloromethyl) phenoxy] benzene (288 mg) was added, and the mixture was stirred at room temperature for 2 hours. Sodium iodide (150 mg) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1 to 1: 1) to give the title compound (167 mg) as a colorless oil. Obtained. Table 2 shows the structure and NMR data of the obtained compound.

Example 2 Synthesis of Compounds (2-1) to (2-25) (1) N- [2- (3-methylphenyl) ethyl] -N ′-[(1S) -1-phenylethyl] ethanediamide (2A -1) In a simple sealed tube, 3-methylphenethylamine (817 mg) was added to a toluene solution (2 ml) of ethyl oxo {[(1S) -1-phenylethyl] amino} acetate (670 mg) obtained in Reference Example 1. In addition, after stirring at 130 ° C. for 4 hours, the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration and washed with methanol to give the title compound (800 mg) as a colorless powder. The structure and NMR data of the obtained compound are shown in Table 1.

Ethyl oxo {[(1S) -1-phenylethyl] amino} acetate obtained in Reference Example 1, α, α-dimethylphenethylamine, 1- (2-aminoethyl) piperidine, 2- (p-tolyl) ethylamine, 2 -Methoxyphenethylamine, 2-methylphenethylamine, 4-phenoxyphenethylamine, (S)-(-)-1- (4-methoxyphenylethylamine), cumylamine, (S) -1- [3- (trifluoromethyl) phenyl] Ethylamine, (S) -1- [4- (trifluoromethyl) phenyl] ethylamine, (S) -1- [2- (trifluoromethyl) phenyl] ethylamine, (R)-(-)-2-phenyl Ricinol, cyclopropylamine, 2- (2-chlorophenyl) ethylamine, 2- (3-chlorophenyl) ethylamine, (S)-(-)-1- (4-chlorophenyl) ethylamine, (S) -1- (2- Fluorophenyl) ethylamine, (S) -1- (4-fluorophenyl) ethylamine, obtained in Reference Example 5 (1S) -1- (2-chlorophenyl) ethylamine, 2- (4-chlorophenyl) ethylamine, 1-phenylcyclopropylamine obtained in Reference Example 6, (S)-(-)-1- (2-naphthyl) The compounds (2A-2) to (2A-25) were obtained in the same manner as described above using ethylamine and (S)-(-)-1- (4-bromophenyl) ethylamine. The structure and NMR data of the obtained compound are shown in Table 1.
(2) Synthesis of N- [2- (3-methylphenyl) ethyl] -N '-[(1S) -1-phenylethyl] ethane-1,2-diamine (2B-1) N- [2- (2-Methylphenyl) ethyl] -N ′-[(1S) -1-phenylethyl] ethanediamide (2A-1) (780 mg) was added to a tetrahydrofuran suspension (10 ml) of hydride (381 mg). Tetrahydrofuran solution (10 ml) was added and stirred for 8 hours. After returning the reaction solution to room temperature, 28% aqueous ammonia was added dropwise under ice cooling. After filtration, the organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to chloroform: methanol = 10: 1) to obtain the title compound (92 mg) as a yellow oily substance. The structure and NMR data of the obtained compound are shown in Table 1.

Using compounds (2A-2) to (2A-14), compounds (2B-2) to (2B-14) were obtained in the same manner as described above. The structure and NMR data of the obtained compound are shown in Table 1.
(3) Synthesis of N-cyclopropyl-N ′-[(1S) -1-phenylethyl] ethane-1,2-diamine (2B-15) N-cyclopropyl-N described in Table 2 under argon atmosphere A mixture of '-[(1S) -1-phenylethyl] ethanediamide (2A-15) (556 mg) and borane-tetrahydrofuran complex (1.20 M tetrahydrofuran solution, 12 ml) was heated to reflux for 6 hours. Once the solvent was distilled off under reduced pressure, a 6M aqueous hydrochloric acid solution was added, and the mixture was heated to reflux for 2 hours. After returning the reaction solution to room temperature, water and sodium hydroxide were added under ice cooling, followed by extraction with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform: methanol = 20: 1) to obtain the title compound (1.38 g) as a pale yellow oily substance. The structure and NMR data of the obtained compound are shown in Table 1.

Compounds (2B-16) to (2B-25) in the table were synthesized by the same method as above using (2A-16) to (2A-25). The structure and NMR data of the obtained compound are shown in Table 1.
(4) Synthesis of 1- [2- (3-methylphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (2-1) Similar to Example 1 (3) N- [2- (2-methylphenyl) ethyl] -N '-[(1S) -1-phenylethyl] ethane-1,2-diamine (2B-1) (87 mg), triphosgene (30 mg) And triethylamine (95 μl) were used to give the title compound (58 mg) as a yellow oil. Table 2 shows the structure and NMR data of the obtained compound.

  Compounds (2-2) to (2-25) were obtained in the same manner as described above using compounds (2B-2) to (2B-25). Table 2 shows the structure and NMR data of the obtained compound.

Example 3 Synthesis of Compounds (3-1) to (3-4) (1) Synthesis of N-benzyl-N ′-[(1S) -1- (1-naphthyl) ethyl] ethanediamide (3A-1) In the same manner as in Example 2 (1), ethyl (benzylamino) (oxo) acetate (566 mg) and (S)-(−)-1- (1-naphthyl) ethylamine (935 mg) obtained in Reference Example 1 were used. The title compound (600 mg) was obtained as a colorless powder used. The structure and NMR data of the obtained compound are shown in Table 1.

Ethyl (benzylamino) (oxo) acetate obtained in Reference Example 1 and (S)-(-)-1- (4-methoxyphenyl) ethylamine, (S)-(-)-1- (2-naphthyl) ethylamine Alternatively, compounds (3A-2) to (3A-4) were obtained in the same manner as described above using (S) -1- (3-methoxyphenyl) ethylamine. The structure and NMR data of the obtained compound are shown in Table 1.
(2) Synthesis of N-benzyl-N ′-[(1S) -1- (1-naphthyl) ethyl] ethane-1,2-diamine (3B-1) In the same manner as in Example 2 (2), Using N-benzyl-N ′-[(1S) -1- (1-naphthyl) ethyl] ethanediamide (3A-1) (600 mg) and lithium aluminum hydride (548 mg), the title compound (210 mg) was obtained as a red oily substance. It was. The structure and NMR data of the obtained compound are shown in Table 1.

Compounds (3B-2) to (3B-4) were obtained in the same manner as described above using compounds (3A-2) to (3A-4). The structure and NMR data of the obtained compound are shown in Table 1.
(3) Synthesis of 1-benzyl-3-[(1S) -1- (1-naphthyl) ethyl] imidazolidin-2-one (3-1) N-benzyl in the same manner as in Example 1 (3) -N '-[(1S) -1- (1-naphthyl) ethyl] ethane-1,2-diamine (3B-1) (180 mg), triphosgene (59 mg) and triethylamine (181 μl) as a light pink oily substance The title compound (110 mg) was obtained. Table 2 shows the structure and NMR data of the obtained compound.

  Compounds (3-2) to (3-4) were obtained in the same manner as described above using compounds (3B-2) to (3B-4). Table 2 shows the structure and NMR data of the obtained compound.

Example 4 Synthesis of Compounds (4-1) to (4-2) (1) Synthesis Reference Example of Ethyl {[(1S) -1- (2-Fluorophenyl) ethyl] amino} (oxo) acetate (4A) (S) -1- (2-fluorophenyl) ethylamine (924 mg), chloroglyoxylic acid ethyl ester (907 mg) and triethylamine (1.39 ml) in the same manner as in 1, and the title compound ( 1.71 g) was obtained. The structure and NMR data of the obtained compound are shown in Table 1.
(2) Synthesis Example 2 of N-[(1S) -1- (2-fluorophenyl) ethyl] -N ′-[(1S) -1- (4-fluorophenyl) ethyl] ethanediamide (4B-1) In the same manner as (1), ethyl {[(1S) -1- (2-fluorophenyl) ethyl] amino} (oxo) acetate (4A) (710 mg) and (S) -1- (4-fluorophenyl) ) Ethylamine (827 mg) was used to give the title compound (779 mg) as a colorless powder. The structure and NMR data of the obtained compound are shown in Table 1.

Ethyl {[(1S) -1- (2-fluorophenyl) ethyl] amino} (oxo) acetate (4A) (653 mg) and (S)-(−)-1- (synthesized in Example 4 (1) Compound (4B-2) was obtained in the same manner as described above using 2-naphthyl) ethylamine (979 mg). The structure and NMR data of the obtained compound are shown in Table 1.
(3) N-[(1S) -1- (2-fluorophenyl) ethyl] -N ′-[(1S) -1- (4-fluorophenyl) ethyl] ethane-1,2-diamine (4C-1 ) N-[(1S) -1- (2-fluorophenyl) ethyl] -N ′-[(1S) -1- (4-fluorophenyl) ethyl in the same manner as in Synthesis Example 2 (3) Ethanediamide (4B-1) (490 mg) and borane-tetrahydrofuran complex (1.20 M in tetrahydrofuran, 9.8 ml) were used to give the title compound (260 mg) as a pale yellow oil. The structure and NMR data of the obtained compound are shown in Table 1.

N-[(1S) -1- (2-fluorophenyl) ethyl] -N ′-[(1S) -1- (2-naphthyl) ethyl] ethanediamide (4B-2) synthesized in Example 4 (2) (814 mg) and borane-tetrahydrofuran complex (1.20 M tetrahydrofuran solution, 15 ml) were used to obtain compound (4C-2) in the same manner as described above. The structure and NMR data of the obtained compound are shown in Table 1.
(4) 1-[(1S) -1- (2-fluorophenyl) ethyl] -3-[(1S) -1- (4-fluorophenyl) ethyl] imidazolidin-2-one (4-1) In the same manner as in Synthesis Example 1 (3), N-[(1S) -1- (2-fluorophenyl) ethyl] -N ′-[(1S) -1- (4-fluorophenyl) ethyl] ethane The title compound (511 mg) was obtained as a colorless powder using -1,2-diamine (4C-1) (650 mg), triphosgene (210 mg) and triethylamine (0.66 ml). Table 2 shows the structure and NMR data of the obtained compound.

  N-[(1S) -1- (2-fluorophenyl) ethyl] -N ′-[(1S) -1- (2-naphthyl) ethyl] ethane-1,2-synthesized in Example 4 (3) Compound (4-2) was obtained in the same manner as above using diamine (4C-2) (651 mg), triphosgene (194 mg) and triethylamine (0.60 ml). Table 2 shows the structure and NMR data of the obtained compound.

Example 5 1-[(1S) -1- (4-methoxyphenyl) ethyl] -3-{(1S) -1- [2- (trifluoromethyl) phenyl] ethyl} imidazolidin-2-one (5 -1) Synthesis (1) Synthesis of Ethyl {[(1S) -1- (4-methoxyphenyl) ethyl] amino} (oxo) acetate (S)-(-)-1 The title compound (3.18 g) was obtained as a brown oily substance using-(4-methoxyphenyl) ethylamine (1.39 g), chloroglyoxylic acid ethyl ester (1.25 g) and triethylamine (1.92 ml).
1H NMR (300 MHz, CHLOROFORM-D) σ 1.38 (t, J = 7.2 Hz, 2 H), 1.55 (d, J = 6.8 Hz, 3 H), 3.80 (s, 3 H), 4.33 (q, J = 7.2 Hz, 2 H), 5.03-5.16 (m, 1 H), 6.82-6.94 (m, 2 H), 7.18-7.33 (m, 3 H).
(2) Synthesis Example 2 of N-[(1S) -1- (4-methoxyphenyl) ethyl] -N ′-{(1S) -1- [2- (trifluoromethyl) phenyl] ethyl} ethanediamide In the same manner as in 1), ethyl {[(1S) -1- (4-methoxyphenyl) ethyl] amino} (oxo) acetate (642 mg) and (S) -1- [2- (trifluoromethyl) phenyl The title compound (454 mg) was obtained as a colorless powder using ethylamine (725 mg).
1H NMR (300 MHz, CHLOROFORM-D) σ 1.44-1.62 (m, 6 H), 3.77 (s, 3 H), 4.89-5.04 (m, 1 H), 5.27-5.45 (m, 1 H), 6.72 -6.90 (m, 2 H), 7.13-7.84 (m, 8 H).
(3) N-[(1S) -1- (4-methoxyphenyl) ethyl] -N '-{(1S) -1- [2- (trifluoromethyl) phenyl] ethyl} ethane-1,2-diamine In the same manner as in Synthesis Example 2 (3), N-[(1S) -1- (4-methoxyphenyl) ethyl] -N ′-{(1S) -1- [2- (trifluoromethyl) Phenyl] ethyl} ethanediamide (454 mg) and borane-tetrahydrofuran complex (1.20 M in tetrahydrofuran, 7.7 ml) were used to give the title compound (270 mg) as a pale yellow oil.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.16-1.42 (m, 6 H), 2.31-2.64 (m, 4 H), 3.52-3.70 (m, 1 H), 3.80 (s, 3 H), 3.92 -4.22 (m, 1 H), 6.70-6.96 (m, 2 H), 7.11-7.42 (m, 3 H), 7.44-7.67 (m, 2 H), 7.68-7.83 (m, 1 H).
(4) 1-[(1S) -1- (4-methoxyphenyl) ethyl] -3-{(1S) -1- [2- (trifluoromethyl) phenyl] ethyl} imidazolidin-2-one (5 -1) In the same manner as in Example 1 (3), N-[(1S) -1- (4-methoxyphenyl) ethyl] -N '-{(1S) -1- [2- (tri Fluoromethyl) phenyl] ethyl} ethane-1,2-diamine (270 mg), triphosgene (74 mg) and triethylamine (0.24 ml) were used to give the title compound (137 mg) as a colorless oil. Table 2 shows the structure and NMR data of the obtained compound.

Example 6 Synthesis of 1-[(1S) -1-phenylethyl] -3-{(1S) -1- [4- (trifluoromethoxy) phenyl] ethyl} imidazolidin-2-one (6-1) (1) Synthesis of ethyl oxo ({(1S) -1- [4- (trifluoromethoxy) phenyl] ethyl} amino) acetate (S) -1-[(4-trifluoro Methoxy) phenyl] ethylamine (0.95 g), chloroglyoxylic acid ethyl ester (0.63 g) and triethylamine (0.97 ml) were used to give the title compound (1.45 g) as a colorless oil.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.39 (t, J = 7.2 Hz, 3 H), 1.50-1.66 (m, 3 H), 4.35 (q, J = 7.2 Hz, 2 H), 4.99-5.27 (m, 1 H), 6.98-7.58 (m, 5 H).
(2) Synthesis of N-[(1S) -1-phenylethyl] -N ′-{(1S) -1- [4- (trifluoromethoxy) phenyl] ethyl} ethanediamide Similar to Example 2 (1) Method with ethyl oxo ({(1S) -1- [4- (trifluoromethoxy) phenyl] ethyl} amino) acetate (730 mg) and (S)-(−)-phenylethylamine (0.61 ml) The title compound (817 mg) was obtained as a powder.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.26-1.74 (m, 6 H), 4.73-5.24 (m, 2 H), 6.96-7.96 (m, 11 H).
(3) Synthesis Example 2 of N-[(1S) -1-phenylethyl] -N ′-{(1S) -1- [4- (trifluoromethoxy) phenyl] ethyl} ethane-1,2-diamine In the same manner as in (3), N-[(1S) -1-phenylethyl] -N ′-{(1S) -1- [4- (trifluoromethoxy) phenyl] ethyl} ethanediamide (817 mg) and borane -The title compound (190 mg) was obtained as a colorless oily substance using a tetrahydrofuran complex (1.20 M tetrahydrofuran solution, 14 ml).
1H NMR (300 MHz, CHLOROFORM-D) σ 1.18-1.47 (m, 6 H), 2.23-2.81 (m, 4 H), 3.36-3.90 (m, 2 H), 6.83-7.56 (m, 9 H) .
(4) Synthesis of 1-[(1S) -1-phenylethyl] -3-{(1S) -1- [4- (trifluoromethoxy) phenyl] ethyl} imidazolidin-2-one (6-1) In the same manner as in Example 1 (3), N-[(1S) -1-phenylethyl] -N ′-{(1S) -1- [4- (trifluoromethoxy) phenyl] ethyl} ethane-1 , 2-diamine (190 mg), triphosgene (53 mg) and triethylamine (0.17 ml) to give the title compound (117 mg) as a colorless oil. Table 2 shows the structure and NMR data of the obtained compound.

Example 7 Synthesis of Compound (7-1) (1) Ethyl {[(1S) -1- (4-hydroxyphenyl) ethyl] amino} (oxo) acetate Synthesis (S) The title compound (1.83 g) was obtained as a colorless powder using -1- (4-hydroxyphenyl) ethylamine (1.04 g), chloroglyoxylic acid ethyl ester (1.04 g) and triethylamine (1.6 ml). .
1H NMR (300 MHz, CHLOROFORM-D) σ 1.37 (t, J = 7.2 Hz, 3 H), 1.54 (d, J = 6.8 Hz, 3 H), 4.34 (q, J = 7.2 Hz, 2 H), 4.95-5.20 (m, 2 H), 6.68-6.88 (m, 2 H), 7.04-7.36 (m, 3 H).
(2) Synthesis of N-[(1S) -1- (4-hydroxyphenyl) ethyl] -N ′-[(1S) -1-phenylethyl] ethanediamide In the same manner as in Example 2 (1), ethyl Title compound as colorless powder using {[(1S) -1- (4-hydroxyphenyl) ethyl] amino} (oxo) acetate (1.83 g) and (S)-(−)-phenylethylamine (2.0 ml) (1.93 g) was obtained.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.32-1.67 (m, 6 H), 4.80-5.25 (m, 2 H), 6.51-6.91 (m, 2 H), 7.02-7.48 (m, 7 H) , 7.51-7.79 (m, 2 H).
(3) Synthesis of 4-{(1S) -1-[(2-{[(1S) -1-phenylethyl] amino} ethyl) amino] ethyl} phenol In the same manner as in Example 2 (3), Borane-tetrahydrofuran complex (1.20M tetrahydrofuran solution, 41 ml) was used to give the title compound (310 mg) as a colorless oil.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.10-1.56 (m, 6 H), 2.10-2.80 (m, 6 H), 3.30-3.85 (m, 2 H), 6.43-6.80 (m, 2 H) , 6.85-7.48 (m, 7 H).
(4) Synthesis of 1-[(1S) -1- (4-hydroxyphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (7-1) Example 1 ( In the same manner as in 3), 4-{(1S) -1-[(2-{[(1S) -1-phenylethyl] amino} ethyl) amino] ethyl} phenol (310 mg), triphosgene (107 mg) and The title compound (78 mg) was obtained as a colorless powder using triethylamine (0.33 ml). Table 2 shows the structure and NMR data of the obtained compound.

Example 8 Synthesis of Compound (8-1) (1) Synthesis of Ethyl {[(1S) -1- (4-nitrophenyl) ethyl] amino} (oxo) acetate (1S) The title compound (4.02 g) was obtained as a colorless oil using -1- (4-nitrophenyl) ethylamine (3.01 g), chloroglyoxylic acid ethyl ester (2.03 g) and triethylamine (5.40 ml). It was.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.39 (t, J = 7.2 Hz, 3 H), 1.60 (d, J = 7.0 Hz, 3 H), 4.36 (q, J = 7.2 Hz, 2 H), 5.13-5.27 (m, 1 H), 7.41 (brs, 1 H), 7.47-7.54 (m, 2 H), 8.18-8.24 (m, 2 H).
(2) Synthesis of N-[(1S) -1- (4-nitrophenyl) ethyl] -N ′-[(1S) -1-phenylethyl] ethanediamide In the same manner as in Example 2 (1), ethyl Title as colorless powder using {[(1S) -1- (4-nitrophenyl) ethyl] amino} (oxo) acetate (4.02 g) and (S)-(−)-phenylethylamine (3.61 g) Compound (3.89 g) was obtained.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.53-1.62 (m, 6 H), 5.01-5.18 (m, 2 H), 7.25-7.39 (m, 5 H), 7.43-7.50 (m, 2 H) , 7.62-7.68 (m, 1 H), 7.77-7.84 (m, 1 H), 8.16-8.22 (m, 2 H).
(3) Synthesis of N-[(1S) -1- (4-nitrophenyl) ethyl] -N ′-[(1S) -1-phenylethyl] ethane-1,2-diamine Example 2 (3) and In a similar manner, N-[(1S) -1- (4-nitrophenyl) ethyl] -N ′-[(1S) -1-phenylethyl] ethanediamide (1.95 g) and borane-tetrahydrofuran complex (1. The title compound (1.47 g) was obtained as a light brown oily substance using 01M tetrahydrofuran solution (45.1 ml).
1H NMR (300 MHz, CHLOROFORM-D) σ 1.33 (d, J = 6.7 Hz, 3 H), 1.37 (d, J = 6.7 Hz, 3 H), 2.42-2.61 (m, 4 H), 3.65-3.79 (m, 2 H), 7.21-7.37 (m, 5 H), 7.42-7.49 (m, 2 H), 8.13-8.20 (m, 2 H).
(4) Synthesis of 1-[(1S) -1- (4-nitrophenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (8-1) Example 1 ( 3) N-[(1S) -1- (4-nitrophenyl) ethyl] -N ′-[(1S) -1-phenylethyl] ethane-1,2-diamine (1.47 g ), Triphosgene (459 mg) and triethylamine (1.44 ml) to give the title compound (1.24 g) as a colorless oil. Table 2 shows the structure and NMR data of the obtained compound.

Example 9 Synthesis of Compounds (9-1) to (9-4)
Synthesis of 1- (3-aminobenzyl) -3-[(1S) -1-phenylethyl] imidazolidin-2-one (9-1) 1- (3-nitrobenzyl synthesized in Example 1 (5) ) -3-[(1S) -1-phenylethyl] imidazolidin-2-one (1-71) (910 mg) in ethanol-water (5: 1) mixture (14 ml) with ammonium chloride (90 mg) and iron Powder (781 mg) was added and heated to reflux for 2 hours. The reaction mixture was cooled and filtered through celite. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1 to 1: 4) to obtain the title compound (730 mg) as a yellow oily substance. Table 2 shows the structure and NMR data of the obtained compound.

  Using the compound (1-72) synthesized in Example 1 (5), the compound (8-1) synthesized in Example 8 (4), and the compound (1-73) synthesized in Example 1 (5) Compounds (9-2) to (9-4) were synthesized in the same manner as above. Table 2 shows the structure and NMR data of the obtained compound.

Example 10 Synthesis of Compounds (10-1) to (10-4) (1) N- [3-({2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} Synthesis of methyl) phenyl] methanesulfonamide (10-1) 1- (3-aminobenzyl) -3-[(1S) -1-phenylethyl] imidazolidin-2-one synthesized in Example 9 (9- 1) Pyridine (97 μl) and methanesulfonyl chloride (77 μl) were sequentially added to a chloroform solution (5 ml) of (295 mg) under ice-cooling, stirred at 0 ° C. for 1 hour, and then stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1 to 1: 3) to obtain the title compound (284 mg) as a pale yellow gum. Table 2 shows the structure and NMR data of the obtained compound.

Using the compounds (9-2) and (9-3) synthesized in Example 9, the compounds (10-2) and (10-3) were synthesized in the same manner as described above. Table 2 shows the structure and NMR data of the obtained compound.
(2) N- [2-({2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} methyl) phenyl] methanesulfonamide (10-4) and N- (methyl Synthesis of Sulfonyl) -N- [2-({2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} methyl) phenyl] methanesulfonamide (10-5) Example 9 To a chloroform solution (3 ml) of 1- (2-aminobenzyl) -3-[(1S) -1-phenylethyl] imidazolidin-2-one (9-4) (174 mg) synthesized in Step 3 and triethylamine (123 μl) Methanesulfonyl chloride (55 μl) was sequentially added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1 to 1: 3) to give the title compound (10-4) (36 mg) and (10 -5) (126 mg) was obtained. Table 2 shows the structure and NMR data of the obtained compound.

Example 11 Synthesis of Compounds (11-1) and (11-2)
Synthesis example of N- [4-((1S) -1- {2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} ethyl) phenyl] acetamide (11-1) 1-[(1S) -1- (4-aminophenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (9-3) (100 mg) in chloroform Triethylamine (54 μl) and acetyl chloride (23 μl) were sequentially added to the solution (2 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to 0: 1) to obtain the title compound (92 mg) as a light brown powder. Table 2 shows the structure and NMR data of the obtained compound.

  Using compound (9-4) synthesized in Example 9, compound (11-2) was synthesized in the same manner as above. Table 2 shows the structure and NMR data of the obtained compound.

Example 12 Synthesis of Compounds (12-1) to (12-2) (1) Synthesis of N, N′-bis [(1S) -1- (2-fluorophenyl) ethyl] ethanediamide (12A-1) Nitrogen Under an atmosphere, (S) -1- (2-fluorophenyl) ethylamine (855 mg) was added to a tetrahydrofuran solution (30 ml) of oxalyl chloride (0.26 ml), and the mixture was heated to reflux for 2 hours. After returning to room temperature, water was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were washed with n-hexane to give the title compound (490 mg) as a colorless solid. The structure and NMR data of the obtained compound are shown in Table 1.

Compound (12A-2) was synthesized in the same manner as described above using oxalyl chloride (0.28 ml) and (S)-(−)-1- (4-fluorophenyl) ethylamine (920 mg). The structure and NMR data of the obtained compound are shown in Table 1.
(2) Synthesis of N, N′-bis [(1S) -1- (2-fluorophenyl) ethyl] ethane-1,2-diamine (12B-1) In the same manner as in Example 2 (3), Using N, N′-bis [(1S) -1- (2-fluorophenyl) ethyl] ethanediamide (12A-1) (490 mg) and borane-tetrahydrofuran complex (1.20 M tetrahydrofuran solution, 9.8 ml) The title compound (260 mg) was obtained as a yellow oil. The structure and NMR data of the obtained compound are shown in Table 1.

Same as above using N, N′-bis [(1S) -1- (4-fluorophenyl) ethyl] ethanediamide (12A-2) (853 mg) and borane-tetrahydrofuran complex (1.20 M tetrahydrofuran solution, 18 ml) Compound (12B-2) was synthesized by the method described above. The structure and NMR data of (12B-2) are shown in Table 1.
(3) Synthesis of 1,3-bis [(1S) -1- (2-fluorophenyl) ethyl] imidazolidin-2-one (12-1) In the same manner as in Example 1 (3), N, Colorless powder using N′-bis [(1S) -1- (2-fluorophenyl) ethyl] ethane-1,2-diamine (12B-1) (260 mg), triphosgene (98 mg) and triethylamine (0.26 ml) To give the title compound (199 mg). Table 2 shows the structure and NMR data of the obtained compound.
Using N, N′-bis [(1S) -1- (4-fluorophenyl) ethyl] ethane-1,2-diamine (12B-2) (540 mg), triphosgene (175 mg) and triethylamine (0.49 ml) Compound (12-2) was obtained in the same manner as above. Table 2 shows the structure and NMR data of the obtained compound.

Example 13 Synthesis of Compounds (13-1) to (13-4) (1) tert-Butyl ((1S) -1-methyl-2-oxo-2-{[(1S) -1-phenylethyl] amino } Synthesis of ethyl) carbamate (13A-1)
1-Hydroxybenzotriazole was added to a solution of (S)-(-)-phenylethylamine (1.21 g) and N- (tert-butoxycarbonyl) -L-alanine (1.89 g) in N, N-dimethylformamide (10 ml). (1.73 g) was added, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.11 g) was added under ice cooling. The mixture was stirred at 0 ° C. for 30 minutes and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1 to 1: 2) to obtain the title compound (2.84 g) as a colorless powder. The structure and NMR data of the obtained compound are shown in Table 1.

(S)-(-)-Phenylethylamine and N- (tert-butoxycarbonyl) -D-alanine, N- (tert-butoxycarbonyl) -D-phenylalanine or (2R) -2-[(tert-butoxycarbonyl) Using amino] butanoic acid, compounds (13A-2) to (13A-4) in the table were obtained in the same manner as described above. The structure and NMR data of the obtained compound are shown in Table 1.
(2) Synthesis of N-[(1S) -1-phenylethyl] -L-alaninamide (13B-1) tert-butyl ((1S) -1-methyl-2 obtained in Example 14 (1) To a solution of 10-oxo-2-{[(1S) -1-phenylethyl] amino} ethyl) carbamate (13A-1) (2.84 g) in ethyl acetate (10 ml) under ice-cooling, 4N hydrochloric acid-ethyl acetate (30 ml) ) Was added dropwise and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 1N aqueous sodium hydroxide solution (130 ml) was added to the aqueous layer to adjust the pH to 9. After extraction with chloroform and drying over anhydrous sodium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The title compound (1.82 g) was obtained as a colorless oil. The structure and NMR data of the obtained compound are shown in Table 1.

Compounds (13B-2) to (13B-4) were synthesized in the same manner as described above using compounds (13A-2) to (13A-4). The structure and NMR data of the obtained compound are shown in Table 1.
(3) Synthesis of (2S) -N-[(1S) -1-phenylethyl] propane-1,2-diamine (13C-1) N-[(1S)-obtained in Example 13 (2) The title compound (1.20 g) was obtained as a colorless oil in the same manner as in Example 1 (2) using 1-phenylethyl] -L-alaninamide (13B-1) (1.82 g). The structure and NMR data of the obtained compound are shown in Table 1.

Compounds (13C-2) to (13C-4) were obtained in the same manner as described above using compounds (13B-2) to (13B-4). The structure and NMR data of the obtained compound are shown in Table 1.
(4) Synthesis of (4S) -4-methyl-1-[(1S) -1-phenylethyl] imidazolidin-2-one (13D-1) (2S)-obtained in Example 13 (3) Using N-[(1S) -1-phenylethyl] propane-1,2-diamine (13C-1) (1.20 g) in the same manner as in Example 1 (3), the title compound ( 1.22 g) was obtained. The structure and NMR data of the obtained compound are shown in Table 1.

Compounds (13D-2) to (13D-4) were synthesized in the same manner as described above using compounds (13C-2) to (13C-4). The structure and NMR data of the obtained compound are shown in Table 1.
(5) Synthesis of (4S) -3-benzyl-4-methyl-1-[(1S) -1-phenylethyl] imidazolidin-2-one (13-1) Obtained in Example 13 (4) Using (4S) -4-methyl-1-[(1S) -1-phenylethyl] imidazolidin-2-one (13D-1) (204 mg) in the same manner as in Example 1 (4), colorless The title compound (83 mg) was obtained as an oily substance. Table 2 shows the structure and NMR data of the obtained compound.

  Compounds (13-2) to (13-4) were synthesized in the same manner as described above using compounds (13D-2) to (13D-4). Table 2 shows the structure and NMR data of the obtained compound.

Example 14 Synthesis of Compounds (14-1) to (14-2) (1) Synthesis of ethyl N-1-adamantyl glycinate (14A-1)
Ethyl chloroacetate (343 mg) and potassium iodide (465 mg) were added to an ethanol solution (30 ml) of 1-adamantanamine (508 mg), and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to chloroform: methanol = 20: 1 to 5: 1) to give the title as a colorless oily substance. Compound (280 mg) was obtained. The structure and NMR data of the obtained compound are shown in Table 1.

Using (S)-(-)-1-phenylpropylamine, the compound (14A-2) shown in the table was obtained in the same manner as above. The structure and NMR data of the obtained compound are shown in Table 1.
(2) Synthesis of N-1-adamantyl-N-[(1S) -1-phenylethyl] glycinamide (14B-1) Ethyl N-1-adamantyl glycinate (14A-1) (280 mg) in toluene solution ( (S)-(−)-1-phenylethylamine (301 μl) was added to 1 ml), and the mixture was heated to reflux for 7 hours. Once the solvent was distilled off under reduced pressure, the mixture was stirred at 130 ° C. for 3 hours. (S)-(−)-1-Phenylethylamine (0.75 ml) was added, the mixture was returned to room temperature for 9 hours at 130 ° C. and stirred overnight, then heated to 130 ° C. and stirred for 12 hours. Chloroform was added to the reaction solution, and the mixture was washed with 0.5N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent: n-hexane: ethyl acetate = 2: 1 to 1: 1 to chloroform: methanol = 30: 1 to 20: 1) to give the title compound as a pale yellow oily substance ( 235 mg) was obtained. The structure and NMR data of the obtained compound are shown in Table 1.

Compound (14B-2) was synthesized in the same manner as above using compound (14A-2) and benzylamine. The structure and NMR data of the obtained compound are shown in Table 1.
(3) Synthesis of N-1-adamantyl-N ′-[(1S) -1-phenylethyl] ethane-1,2-diamine (14C-1) In the same manner as in Example 1 (2), N— The title compound (58 mg) was obtained as a yellow oil from 1-adamantyl-N-[(1S) -1-phenylethyl] glycinamide (14B-1) (217 mg) and lithium aluminum hydride (209 mg). The structure and NMR data of the obtained compound are shown in Table 1.

Compound (14C-2) was obtained in the same manner as above using compound (14B-2). The structure and NMR data of the obtained compound are shown in Table 1.
(4) Synthesis of 1- (1-adamantyl) -3-[(1S) -1-phenylethyl] imidazolidin-2-one (14-1) In the same manner as in Example 1 (3), N— Using 1-adamantyl-N ′-[(1S) -1-phenylethyl] ethane-1,2-diamine (14C-1) (58 mg), triphosgene (19 mg) and triethylamine (59 μl) as a colorless powder, the title compound ( 38 mg) was obtained. Table 2 shows the structure and NMR data of the obtained compound.

  Compound (14-2) was obtained in the same manner as above using compound (14C-2). Table 2 shows the structure and NMR data of the obtained compound.

Example 15 Synthesis of Compounds (15-1) to (15-7) (1) 1-[(1S) -1- [4- (1H-imidazol-1-yl) phenyl] ethyl] -3-[( Synthesis of 1S) -1-phenylethyl] imidazolidin-2-one (15-1) 1-[(1S) -1- (4-bromophenyl) ethyl] obtained in Example 2 in a simple sealed tube -3-[(1S) -1-phenylethyl] imidazolidin-2-one (2-25) (218 mg) in 1-methyl-2-pyrrolidinone solution (0.78 ml) was mixed with imidazole (79 mg), potassium carbonate ( 160 mg) and copper iodide (11 mg) were added, and the mixture was stirred at 195 ° C. for 2 hours. The reaction mixture was filtered, ethyl acetate was added, and the mixture was washed successively with a 1: 1 mixture of water and saturated brine, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to chloroform: methanol = 50: 1). After the solvent was distilled off under reduced pressure, ethyl acetate was added and washed with water. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (166 mg) as a light brown viscous oil. Table 2 shows the structure and NMR data of the obtained compound.
(2) 1-[(1S) -1-phenylethyl] -3-{(1S) -1- [4- (1H-1,2,4-triazol-1-yl) phenyl] ethyl} imidazolidine- Synthesis of 2-one (15-2) 1-[(1S) -1- (4-bromophenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidine- obtained in Example 2 To a solution of 2-one (2-25) (200 mg) in 1-methyl-2-pyrrolidinone (0.73 ml) was added 1,2,4-triazole (75 mg), potassium carbonate (149 mg) and copper iodide (10 mg). In addition, the reaction was carried out for 3 hours by heating to 195 ° C. using a microwave reactor (Biotage). The reaction mixture was filtered, ethyl acetate was added, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 1: 1 to chloroform: methanol = 20: 1). The obtained crystals were washed with a mixed solution of diethyl ether: n-hexane (1: 3) to give the title compound (103 mg) as a colorless powder. Table 2 shows the structure and NMR data of the obtained compound.

  1-[(1S) -1- (4-Bromophenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (2-25) and pyrrole obtained in Example 2 , Pyrazole, benzimidazole, 4-phenylimidazole or 3-phenyl-1H-pyrazole were used to obtain compounds (15-3) to (15-7) in the table in the same manner as described above. Table 2 shows the structure and NMR data of the obtained compound.

Example 16 Synthesis of 4-((1S) -1- {2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} ethyl) benzonitrile (16-1) Simple sealed tube 1-[(1S) -1- (4-bromophenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (2-25) obtained in Example 2 To a solution of (211 mg) in 1-methyl-2-pyrrolidinone (0.60 ml) was added copper cyanide (92 mg), and the mixture was stirred at 200 ° C. for 3 hours. After returning to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was washed successively with a 1: 1 mixture of water and saturated brine, an aqueous solution of iron chloride III (4.0 g) / concentrated hydrochloric acid (7 ml), and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 2: 1) to obtain the title compound (131 mg) as a light brown oily substance. Table 2 shows the structure and NMR data of the obtained compound.

Example 17 Synthesis of compounds (17-1) and (17-2)
Synthesis of 1-[(1S) -1-phenylethyl] -3-{(1S) -1- [4- (pyridin-2-ylamino) phenyl] ethyl} imidazolidin-2-one (17-1) Of 1-[(1S) -1- (4-aminophenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (9-3) (100 mg) synthesized in Example 9 To a toluene-tert-butyl alcohol (5: 1) mixed solution (3 ml), 2-bromopyridine (52 mg), palladium acetate (1.5 mg), rac-BINAP (8.0 mg), sodium tert-butoxide (43 mg) Were sequentially added, and the mixture was heated to 150 ° C. using a microwave reactor (manufactured by Biotage), and reacted for 30 minutes. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 3: 1 to 1: 2) to obtain the title compound (34 mg) as a pale yellow powder. Table 2 shows the structure and NMR data of the obtained compound.

  Using compound (9-3) synthesized in Example 9 and bromobenzene, compound (17-2) was obtained in the same manner as above. Table 2 shows the structure and NMR data of the obtained compound.

Example 18 2- [4-((1S) -1- {2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} ethyl) phenoxy] acetamide (18-1) 1-[(1S) -1- (4-hydroxyphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (7-1) (7-1) obtained in Synthesis Example 7 2-bromoacetamide (36 mg) and potassium carbonate (50 mg) were added to a solution of N, N-dimethylformamide (2 ml) in 75 mg) and stirred overnight at room temperature, then 2-bromoacetamide (36 mg) and potassium carbonate (50 mg) And stirred at 80 ° C. for 2 hours. After returning to room temperature, the reaction solution was filtered, and ethyl acetate was added. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 2: 1), and the resulting crystal was mixed with n-hexane: ethyl acetate (1: 1) mixed solution. Washing gave the title compound (19 mg) as a colorless powder. Table 2 shows the structure and NMR data of the obtained compound.

Example 19 Synthesis of compounds (19-1) to (19-2)
Synthesis of 1- (2-hydroxybenzyl) -3-[(1) -1-phenylethyl] imidazolidin-2-one (19-1) 1- (2- Methoxybenzyl) -3-[(1) -1-phenylethyl] imidazolidin-2-one (1-50) (105 mg) in a chloroform solution (2.0 ml) under ice cooling with boron tribromide (1. (0M hexane solution) (0.41 ml) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 5: 1) to obtain the title compound (96 mg) as a colorless viscous oily substance. Table 2 shows the structure and NMR data of the obtained compound.

  1-[(1) -1- (4-methoxyphenyl) ethyl] -3-[(1) -1-phenylethyl] imidazolidin-2-one (2-9) and three obtained in Example 2 Compound (19-2) was obtained in the same manner as above using boron bromide (1.0 M hexane solution) (0.77 ml). Table 2 shows the structure and NMR data of the obtained compound.

Example 20 Synthesis of Compounds (20-1), (20-2a) and (20-2b) (1) Synthesis of 1- (1-chloroethyl) -2-methoxybenzene In the same manner as in Reference Example 4, The title compound (3.20 g) was obtained as a colorless oil using (2-methoxyphenyl) ethanol (2.92 g), methanesulfonyl chloride (1.49 ml) and triethylamine (3.21 ml).
1H NMR (300 MHz, CHLOROFORM-D) σ 1.81 (d, J = 6.8 Hz, 3 H), 3.87 (s, 3 H), 5.61 (q, J = 6.8 Hz, 1 H), 6.85-7.03 (m , 2 H), 7.23-7.32 (m, 1 H), 7.50-7.57 (m, 1 H).
(2) Synthesis of 1- [1- (2-methoxyphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (20-1) Obtained in Example 1 (3) Sodium hydride (60% oil suspension, 528 mg) was added to a tetrahydrofuran solution (40 ml) of the obtained 1-[(1S) -1-phenylethyl] imidazolidin-2-one (2.28 g) at room temperature. Stir for 20 minutes. 1- (1-Chloroethyl) -2-methoxybenzene (2.25 g) was added and stirred overnight at room temperature. Heated to reflux for 9 hours. Sodium hydride (240 mg) and sodium iodide (2.05 g) were added to the reaction solution, and the mixture was further heated to reflux for 9 hours. The residue obtained by distilling off the reaction solution under reduced pressure was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1 to 1: 1) to give two kinds of title compounds as colorless oily substances. A mixture of diastereomers (1.43 g) was obtained. Table 2 shows the structure and NMR data of the obtained compound.
(3) Synthesis of 1- [1- (2-hydroxyphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (20-2a) and (20-2b)
1- [1- (2-methoxyphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (20-1) (1.43 g) in chloroform solution (22 ml) Boron bromide (1.0 M hexane solution) (5.29 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 5: 1 to 1: 1), and the diastereomer as the title compound (430-2a) (430 mg) was obtained as a colorless powder. ), (20-2b) (385 mg). Table 2 shows the structure and NMR data of the obtained compound.

Example 21 Synthesis of compounds (21-1) and (21-2)
Synthesis of 1- [1- (2-methoxyphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (21-1) 1 obtained in Example 20 (3) -[1- (2-hydroxyphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (20-2a) (120 mg) in tetrahydrofuran (2 ml) was added to sodium hydride (2 ml). 60% oil suspension, 19 mg) was added, and the mixture was stirred at room temperature for 15 minutes. Iodomethane (36 μl) was added and stirred at room temperature for 1.5 hours. The residue obtained by evaporating the reaction solution under reduced pressure was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 4: 1 to 1: 1) to give the title compound (113 mg) as a pale yellow oily substance. Obtained. Table 2 shows the structure and NMR data of the obtained compound.

  Using 1- [1- (2-hydroxyphenyl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (20-2b) (diastereomer of (20-2a)) In the same manner as described above, (21-2) which is a diastereomer of (21-1) was obtained. Table 2 shows the structure and NMR data of the obtained compound.

Example 22 Synthesis of Compound (22-1)
N-methyl-N- [4-((1S) -1- {2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} ethyl) phenyl] methanesulfonamide (22- 1) Synthesis of N- [4-((1S) -1- {2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} ethyl synthesized in Example 10 (1) ) Phenyl] methanesulfonamide (10-3) (100 mg) in tetrahydrofuran (1.3 ml) was added sodium hydride (60% oil suspension, 12 mg), stirred at room temperature for 15 minutes, and iodomethane (24 μl). ) And stirred at room temperature for 2.5 days. Sodium hydride (12 mg) and iodomethane (24 μl) were added, and the mixture was heated to reflux for 3 hours. The reaction solution was distilled off under reduced pressure, N, N-dimethylformamide (1.3 ml), sodium hydride (12 mg) and iodomethane (24 μl) were successively added, and the mixture was stirred at 130 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 2: 1 to 1: 9) to obtain the title compound (87 mg) as a colorless powder. Table 2 shows the structure and NMR data of the obtained compound.

Example 23 Synthesis of compounds (23-1) to (23-3)
Synthesis of 2-({2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} methyl) benzamide (23-1) 2-({synthesized in Example 1 (5) To a solution of 4-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} methyl) benzonitrile (1-53) (61 mg) in ethanol (4 ml) was added potassium hydroxide (100 mg). In addition, the mixture was heated to reflux for 25.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to chloroform: methanol = 19: 1) to obtain the title compound (21 mg) as a colorless powder. Table 2 shows the structure and NMR data of the obtained compound.

  Using compounds (1-19) and (1-66), compounds (23-2) and (23-3) were synthesized in the same manner as described above. Table 2 shows the structure and NMR data of the obtained compound.

Example 24 Synthesis of Compound (24-1)
Synthesis of 1- [2- (2-oxo-2-piperidin-1-ylethyl) benzyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (24-1) In Example 1 Piperidine solution (0) of the resulting benzyl [2-({2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} methyl) phenyl] acetate (1-23) (67 mg) 3 ml) was stirred at 100 ° C. for 10 hours. Piperidine was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1 to 2: 1 to ethyl acetate: methanol = 20: 1) to give a pale brown oil The title compound (49 mg) was obtained as a substance. Table 2 shows the structure and NMR data of the obtained compound.

Example 25 Synthesis of Compound (25-1)
Synthesis of 1- (3-hydroxybenzyl) -3-[(1S) -1-phenylethyl] imidazolidin-2-one (25-1) 1- [3- (benzyloxy) obtained in Example 1 Benzyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (1-28) (150 mg) in ethanol solution (10 ml) was added with 10% palladium-activated carbon (20 mg) and replaced with hydrogen. Thereafter, the mixture was stirred overnight at room temperature. After filtering the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 3: 1) to give the title compound as a colorless viscous oily substance. (85 mg) was obtained. The structure and NMR data of the obtained compound are shown in Table 2.

Example 26 Synthesis of Compound (26-1)
Synthesis of 3-({2-oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} methyl) benzoic acid (26-1) Methyl 3- (3) obtained in Example 1 {2-Oxo-3-[(1S) -1-phenylethyl] imidazolidin-1-yl} methyl) benzoate (1-43) (104 mg) in methanol solution (0.2 ml) and 5M aqueous sodium hydroxide solution (0.2 ml) was added and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, water (1.0 ml) and 6M aqueous hydrochloric acid solution (0.2 ml) were added. The precipitated crystals were collected by filtration to give the title compound (87 mg) as a colorless powder. Table 2 shows the structure and NMR data of the obtained compound.

Example 27 Synthesis of Compounds (27-1a) and (27-1b) (1) Synthesis of N-methoxy-N-methylisoquinoline-3-carboxamide Isoquinoline-3-carboxyl acid (962 mg) and N, O-dimethyl To a solution of hydroxylamine hydrochloride (599 mg), 1-hydroxybenzotriazole (878 mg) and diisopropylethylamine (1.06 ml) in N, N-dimethylformamide (25 ml) was added 1-ethyl-3- (3-dimethyl) under ice-cooling. Aminopropyl) carbodiimide hydrochloride (1.12 g) was added and stirred overnight at room temperature. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer is dried over anhydrous sodium sulfate, the desiccant is filtered off, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (developing solvent chloroform: methanol = 19: 1 to 9: 1). The title compound (970 mg) was obtained as a colorless solid.
1H NMR (300 MHz, CHLOROFORM-D) σ 3.47 (s, 3 H), 3.81 (s, 3 H), 7.66-7.79 (m, 2 H), 7.92 (d, J = 8.2 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 8.14 (s, 1 H), 9.25 (s, 1 H).
(2) Synthesis of 1-isoquinolin-3-ylethanone Under nitrogen atmosphere, a solution of N-methoxy-N-methylisoquinoline-3-carboxamide (970 mg) in tetrahydrofuran (20 ml) under ice-cooling and 3M methylmagnesium bromide in diethyl ether (3.5 ml) was added dropwise and stirred at the same temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water, extracted with chloroform, and washed with saturated brine. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 5: 1 to 2: 1). The title compound (680 mg) was obtained as a colorless solid.
1H NMR (300 MHz, CHLOROFORM-D) σ 2.84 (s, 3 H), 7.71-7.82 (m, 2 H), 7.98-8.10 (m, 2 H), 8.49 (s, 1 H), 9.30 (s , 1 H).
(3) Synthesis of 1-isoquinolin-3-ylethanol
Sodium borohydride (396 mg) was added to a solution of 1-isoquinolin-3-ylethanone (0.68 g) in ethanol (30 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and saturated aqueous ammonium chloride solution (15 ml) was added and stirred under ice cooling. The mixture was extracted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the desiccant is filtered off, the solvent is distilled off under reduced pressure, and the resulting residue is subjected to silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 5: 1 to 1: 1). The title compound (0.37 g) was obtained as a colorless solid.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.62 (d, J = 6.4 Hz, 3 H), 3.74 (s, 1 H), 5.07 (q, J = 6.4 Hz, 1 H), 7.55-7.63 (m , 1 H), 7.65 (s, 1 H), 7.67-7.74 (m, 1 H), 7.79-7.86 (d, J = 8.5 Hz, 1 H), 7.98 (d, J = 8.1 Hz, 1 H) , 9.22 (s, 1 H).
(4) Synthesis of 3- (1-chloroethyl) isoquinoline
Triethylamine (0.59 ml) and lithium chloride (143 mg) were added to a solution of 1-isoquinolin-3-ylethanol (0.37 g) in chloroform (15 ml), and then methanesulfonyl chloride (0.25 ml) was added dropwise under ice cooling. And stirred at room temperature for 4 hours. Lithium chloride (91 mg) and methanesulfonyl chloride (0.17 ml) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform and washed with saturated brine. After drying the organic layer over anhydrous sodium sulfate, the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 9: 1 to 2: 1). ) To give the title compound (0.17 g) as a pale yellow oil.
1H NMR (300 MHz, CHLOROFORM-D) σ 2.00 (d, J = 6.8 Hz, 3 H), 5.34 (q, J = 6.8 Hz, 1 H), 7.59-7.66 (m, 1 H), 7.69-7.75 (m, 1 H), 7.79 (s, 1 H), 7.84 (d, J = 8.2 Hz, 1 H), 7.99 (d, J = 8.6 Hz, 1 H), 9.26 (s, 1 H).
(5) Synthesis of 1- (1-isoquinolin-3-ylethyl) -3-[(1S) -1-phenylethyl] imidazolidin-2-one (27-1a) and (27-1b) Example 1 ( 1-[(1S) -1-phenylethyl] imidazolidin-2-one (191 mg) obtained in 3) was washed with n-hexane, sodium hydride (60% oil suspension, 63 mg) in N, N -It added to the dimethylformamide solution (5 ml), and stirred at room temperature for 20 minutes. 3- (1-Chloroethyl) isoquinoline (0.17 g) obtained in Example 27 (4) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 9: 1 to 1: 1) and then preparative TLC (developing solvent n-hexane: ethyl acetate = 1: 1). Purification gave the title compound (27-1a) (49 mg), colorless viscous oily substance (27-1b) (35 mg) as a colorless powder. Table 2 shows the structure and NMR data of the obtained compound.

Example 28 Synthesis of compounds (28-1a) and (28-1b) (1) Synthesis of 1-quinolin-2-ylethanol In a nitrogen atmosphere, 2-quinolinecarboxaldehyde (2.08 g) in tetrahydrofuran (100 ml) To the solution was added dropwise 3M methylmagnesium bromide in diethyl ether (8.9 ml) at -50 ° C, and the mixture was stirred at -30 ° C for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with n-hexane to give the title compound (1.72 g) as a brown solid.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.59 (d, J = 6.4 Hz, 3 H), 5.00-5.10 (m, 2 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.52-7.58 (m, 1 H), 7.70-7.77 (m, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 8.09 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 8.5 Hz, 1 H).
(2) Synthesis of 1-quinolin-2-ylethyl methanesulfonate In the same manner as in Reference Example 3, 1-quinolin-2-ylethanol (1.72 g), triethylamine (3.5 ml), methanesulfonyl chloride (1. 15 ml) gave the title compound (2.50 g) as a brown oil.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.86 (d, J = 5.9 Hz, 3 H), 2.95 (s, 3 H), 5.92-6.01 (m, 1 H), 7.55-7.67 (m, 2 H ), 7.72-7.88 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 8.25 (d, J = 8.1 Hz, 1 H).
(3) Synthesis of 1-[(1S) -1-phenylethyl] -3- (1-quinolin-2-ylethyl) imidazolidin-2-one (28-1a) and (28-1b) Example 1 ( 1-[(1S) -1-phenylethyl] imidazolidin-2-one (241 mg) obtained in 3) was washed with n-hexane, sodium hydride (60% oil suspension, 80 mg) in N, N -It added to the dimethylformamide solution (8 ml), and stirred at room temperature for 20 minutes. 1-Quinolin-2-ylethyl methanesulfonate (310 mg) obtained in Example 28 (2) was added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 9: 1 to 2: 1) and then preparative TLC (developing solvent n-hexane: ethyl acetate = 1: 1). Purification gave the title compound (28-1a) (39 mg) as a pale yellow viscous oil. Further purification was performed to obtain (28-1b) (35 mg) as a pale yellow viscous oily substance. Table 2 shows the structure and NMR data of the obtained compound.

Example 29 Synthesis of Compound (29-1) (1) Synthesis of N-methoxy-N-methylquinoline-6-carboxamide In the same manner as in Example 27 (1), 6-quinolinecarboxyl acid (1.31 g ), N, O-dimethylhydroxylamine hydrochloride (885 mg), 1-hydroxybenzotriazole (1.16 g), triethylamine (1.3 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( The title compound (1.21 g) was obtained as a colorless oily substance using 1.74 g).
1H NMR (300 MHz, CHLOROFORM-D) σ 1.69 (s, 12 H), 3.13 (s, 4 H), 7.04-7.48 (m, 10 H).
(2) Synthesis of 1-quinoline-6-ylethanone In the same manner as in Example 27 (2), N-methoxy-N-methylquinoline-6-carboxamide (1.21 g) and 3M methylmagnesium bromide in diethyl ether The title compound (880 mg) was obtained as a brown solid using (3.7 ml).
1H NMR (300 MHz, CHLOROFORM-D) σ 2.75 (s, 3 H), 7.46-7.54 (m, 1 H), 8.14-8.20 (m, 1 H), 8.25-8.33 (m, 3 H), 8.43 -8.50 (m, 1 H).
(3) Synthesis of 1-quinolin-6-ylethanol The title compound as a colorless solid using 1-quinolin-6-ylethanone (880 mg) and sodium borohydride (486 mg) in the same manner as in Example 27 (3) (620 mg) was obtained.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.60 (d, J = 6.4 Hz, 3 H), 5.06-5.18 (m, 1 H), 7.37-7.45 (m, 1 H), 7.70-7.78 (m, 1 H), 7.80-7.84 (m, 1 H), 8.06-8.20 (m, 2 H), 8.87-8.94 (m, 1 H).
(4) Synthesis of 6- (1-chloroethyl) quinoline 1-quinolin-6-ylethanol (620 mg), triethylamine (1.0 ml) and methanesulfonyl chloride (0.42 ml) were used in the same manner as in Reference Example 4. The title compound (325 mg) was obtained as a yellow oil.
1H NMR (300 MHz, CHLOROFORM-D) σ 1.95 (d, J = 6.8 Hz, 3 H), 5.29 (q, J = 6.8 Hz, 1 H), 7.39-7.48 (m, 1 H), 7.77-7.86 (m, 2 H), 8.07-8.21 (m, 2 H), 8.89-8.96 (m, 1 H).
(5) Synthesis of 1-[(1S) -1-phenylethyl] -3- (1-quinolin-6-ylethyl) imidazolidin-2-one (29-1) The same method as in Example 27 (5) 1-[(1S) -1-phenylethyl] imidazolidin-2-one (244 mg) obtained in Example 1 (3), sodium hydride washed with n-hexane (60% oil suspension, 77 mg) and 6- (1-chloroethyl) quinoline (163 mg) to give a mixture of two diastereomers (186 mg) as the title compound as a pale pink viscous oil. Table 2 shows the structure and NMR data of the obtained compound.

Example 30 Synthesis of Compounds (30-1a) and (30-1b) (1) Synthesis of 1- (1-benzothien-5-yl) ethanol In the same manner as in Example 28 (1), 1-benzothiophene The title compound (1.90 g) was obtained as a colorless solid using -5-carbaldehyde (1.31 g) and 3M methylmagnesium bromide in diethyl ether (8.0 ml).
1H NMR (300 MHz, CHLOROFORM-D) σ 1.56 (d, J = 6.4 Hz, 3 H), 5.04 (q, J = 6.4 Hz, 1 H), 7.21-7.50 (m, 3 H), 7.78-7.94 (m, 2 H).
(2) of 1- [1- (1-benzothien-5-yl) ethyl] -3-[(1S) -1-phenylethyl] imidazolidin-2-one (30-1a) and (30-1b) Composition
Triethylamine (0.25 ml) and methanesulfonyl chloride (0.11 ml) were added to a tetrahydrofuran solution (5 ml) of 1- (1-benzothien-5-yl) ethanol (211 mg) at −20 ° C. for 40 minutes at the same temperature. Stir. This reaction solution was washed with 1-[(1S) -1-phenylethyl] imidazolidin-2-one (224 mg) obtained in Example 1 (3) and n-hexane (72% oil suspension). Turbidity, 94 mg) was added to a tetrahydrofuran solution (5 ml) under ice cooling, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 0.1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 to 5: 1) to obtain the title compound (30-1a) (58 mg) as a colorless viscous oily substance. It was. Further purification was performed to obtain (30-1b) (32 mg) as a colorless powder. Table 2 shows the structure and NMR data of the obtained compound.

Example 31 Synthesis of Compound (31-1) (1) Synthesis of 1-quinolin-3-ylethanol In the same manner as in Example 28 (1), 3-quinolinecarboxaldehyde (1.03 g) and 3M methyl were synthesized. The title compound (1.11 g) was obtained as a colorless oily substance using a diethyl bromide solution of magnesium bromide (4.4 ml).
1H NMR (300 MHz, CHLOROFORM-D) σ 1.64 (d, J = 6.5 Hz, 3 H), 5.16 (m, 1 H), 7.46-7.62 (m, 1 H), 7.64-7.77 (m, 1 H ), 7.79-7.86 (m, 1 H), 8.05-8.19 (m, 2 H), 8.93 (d, J = 2.2 Hz, 1 H).
(2) Synthesis of 1-[(1S) -1-phenylethyl] -3- (1-quinolin-3-ylethyl) imidazolidin-2-one (31-1) The same method as in Example 30 (2) 1-quinolin-3-ylethanol (309 mg), triethylamine (0.37 ml), methanesulfonyl chloride (0.17 ml), 1-[(1S) -1-phenyl obtained in Example 1 (3) Ethyl] imidazolidin-2-one (339 mg) and sodium hydride washed with n-hexane (72% oil suspension, 142 mg) as a mixture of two diastereomers of the title compound as a light brown solid (31 -1) (46 mg) was obtained. Table 2 shows the structure and NMR data of the obtained compound.
Table 1

Table 2

Test example [11βHSD1 inhibition test]
The test compound was evaluated as follows.
Human liver microsome (Tissue Transformation Technologies) as an enzyme source was added to a reaction solution obtained by adding 200 nM NADPH in 30 mM TrisHCl (pH 7.4) / 1 mM EDTA buffer at 10 μg / ml, and a test compound was further added. Thereafter, the reaction was started by adding a cortisone solution as a substrate so that the final concentration was 100 nM. After incubation at 37 ° C. for 80 minutes, the reaction was stopped by adding 18β glycyrrhetinic acid, a non-specific inhibitor, at a final concentration of 100 μM. The amount of cortisol produced was quantified using a detection kit (Nippon Schering Co., Ltd.) based on the HTRF (Homogeneous Time-Resolved Fluorescence) method. This system detects fluorescence resonance energy transfer between the anti-cortisol antibody labeled with europium and the cortisol labeled with XL665. When unlabeled cortisol is added, the binding signal is attenuated by competitive reaction. . At this time, a standard curve was prepared with cortisol of known concentration attached to the kit, and the amount of cortisol produced by the reaction was evaluated. Assume that cortisol production in wells that do not contain enzyme is the background, cortisol production in wells that do not contain compound is 100% enzyme activity, and evaluate each compound for each dilution series from 50 μM to a common ratio of 3 to calculate IC50 values did.

Compound number IC50
1-1 16nM
1-5 17nM
1-10 4.9nM
1-31 5.9nM
3-3 2.9nM
27-1a 3.7nM

According to the present invention, it is possible to provide a compound having an excellent 11β-HSD1 inhibitory activity, and the compound of the present invention can be used as an active ingredient of a pharmaceutical having a sufficient therapeutic effect as an 11β-HSD1 inhibitory action.

Claims (9)

Formula (1)

[Where:
A is a basic ring of an aromatic hydrocarbon compound; a basic ring of a compound obtained by condensing an aromatic hydrocarbon compound and a saturated ring compound; a basic ring of an aromatic heterocyclic compound; or an aromatic heterocyclic compound and a saturated ring compound are condensed. The basic ring of the compound
R ¹ and R ² are the same or different and each represents a hydrogen atom; a halogen atom; or a C _1-6 alkyl group;
R ³ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, a nitro group, a C _1-6 alkyl group; a halogen atom and C _1-6 alkyl substituted with 1 to 3 groups selected from a hydroxyl group A C _1-6 alkoxy group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group; a heteroaryl group; a heteroaryl group substituted with a phenyl group; or formula (2)
-X ²¹ -Y ²¹ -R ²¹ (2)
(Wherein X ²¹ is an oxygen atom; formula —NR ²² —; formula —NR ²³ CO—; or formula —NR ²⁴ SO ₂ — (wherein R ²² , R ²³ and R ²⁴ are the same or different, hydrogen atom;. showing a or C _1-6 alkyl group) indicates, Y ²¹ is a single bond; indicates or C _1-6 alkylene group, R ²¹ is a hydrogen atom; or heteroaryl group; a carbamoyl group; an aryl group A group represented by:
R ⁴ represents a halogen atom; a C _1-6 alkyl group; or a C _1-6 alkyl group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group;
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom; a C _1-6 alkyl group; a C _1-6 alkyl group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group; or a benzyl group Show
R ⁷ is, C _1-6 alkyl group; a halogen atom, a hydroxyl group, C _1-6 alkyl group substituted with 1 to 3 groups selected from cyano group and diphenylmethyl group; C _2-10 alkenyl group; C _3-10 cycloalkyl group; C _3-10 cycloalkyl C _1-3 alkyl group; cinnamyl group; phenoxyethyl group; benzyloxycarbonylmethyl group; formula (3)
-X ³¹ -Y ³¹ -R ³¹ (3)
(Wherein X ³¹ represents a C _1-6 alkylene group, Y ³¹ represents a single bond; an oxygen atom; a formula —CO—; a formula —CO ₂ —; or a formula —OCO—, and R ³¹ represents C _{3 − A} cycloalkyl group; or a saturated heterocyclic group); or a group represented by formula (4)

(Wherein X ⁴¹ , X ⁴² and X ⁴³ are the same or different and represent a single bond; or a C _1-4 alkylene group, and R ⁴¹ represents a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a heteroaryl group. An amino group; a diC _1-3 alkylamino group; a C _1-3 alkoxy group; a carbamoylmethoxy group; or a cyanomethoxy group, n represents 0 or 1, and B represents a basic ring of an aromatic hydrocarbon compound; Or a basic ring of an aromatic heterocyclic compound,
R ⁴² and R ⁴³ are the same or different and each represents a hydrogen atom; a halogen atom; a C _1-6 alkyl group; or a C _1-6 alkoxy group,
R ⁴⁴ is selected from a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, an amino group, a carboxyl group, a C _1-6 alkyloxycarbonyl group, a C _1-6 alkyl group, a halogen atom and a hydroxyl group. pieces of C is substituted with a group _1-6 alkyl group; C _1-6 alkoxy groups; C _1-6 alkoxy group substituted with 1 to 3 groups selected from a halogen atom and a hydroxyl group; a heteroaryl group; phenyl A phenoxy group substituted with 1 to 3 halogen atoms; a styryl group; a phenylsulfonylmethyl group; or the formula (5)
-X ⁵¹ -Y ⁵¹ -R ⁵¹ (5)
(Wherein X ⁵¹ is an oxygen atom; C _1-6 alkylene group; formula —CO—; formula —NR ⁵² —; formula —NR ⁵³ CO—; formula —CONR ⁵⁴ —; formula —NR ⁵⁵ SO ₂ —; formula —N (SO ₂ R ⁵⁶ ) SO ₂ —; or —CH ₂ SO ₂ — (wherein R ⁵² , R ⁵³ , R ⁵⁴ , R ⁵⁵ and R ⁵⁶ are the same or different and represent a hydrogen atom; or C . _{of 1-6} represents an alkyl group) represents, Y ⁵¹ is a single bond; Table in showing a or a heteroaryl group); indicates or C _1-6 alkylene group, R ⁵¹ is a hydrogen atom; a carbamoyl group; an aryl group. Represents a group. ) Is represented. Or a pharmaceutically acceptable salt or hydrate thereof or a solvate thereof (wherein, in the formula (1), A represents a benzene ring, R ¹ , R ² , R ³ , R ⁵ and R ⁶ are hydrogen atoms, R ⁴ is a methyl group, and R ⁷ is an unsubstituted 1-phenethyl group. A pharmaceutical comprising the imidazolidinone derivative according to claim 1 or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient. The medicament according to claim 2, for preventing or treating a disease or condition that can be ameliorated by inhibiting 11β-HSD1. The medicament according to claim 3, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is diabetes. The medicament according to claim 3, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is metabolic syndrome. The medicament according to claim 3, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is obesity. The medicament according to claim 3, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is hypertension. The medicament according to claim 3, wherein the disease or condition that can be ameliorated by inhibiting 11β-HSD1 is arteriosclerosis. The medicament according to claim 3, wherein the disease or condition that can be improved by inhibiting 11β-HSD1 is hyperlipidemia.