JP4805552B2 - Fused ring compounds - Google Patents

Description

  The present invention relates to a novel fused ring compound having a GPR40 receptor function regulating action.

The amino acid sequence of human-derived GPR40 and the DNA encoding it are described (Patent Document 1 and Non-Patent Document 1).
It is known that a carboxylic acid containing an aromatic ring or a derivative thereof has various physiological activities.
Alkanoic acid derivatives are known (Patent Document 2).
An isoxazole derivative having an action of promoting insulin secretion and an action of lowering blood glucose and useful for the prevention and treatment of diabetes is known (Patent Document 3).
A nitrogen-containing 5-membered heterocyclic compound that has a blood glucose lowering action and a blood lipid lowering action and is useful for the prevention and treatment of diabetes is known (Patent Document 4).
An alkoxyiminoalkanoic acid derivative having a blood glucose lowering action and a blood lipid lowering action and useful for the prevention and treatment of diabetes is known (Patent Document 5).
An oxyiminoalkanoic acid derivative having a blood glucose lowering action and a blood lipid lowering action and useful for the prevention and treatment of diabetes is known (Patent Document 6).
A 1,3-azole derivative having a retinoid-related receptor function regulating action and useful for the prevention and treatment of diabetic complications is known (Patent Document 7).
An oxyiminoalkanoic acid derivative having a blood glucose lowering action and a blood lipid lowering action and useful for the prevention and treatment of diabetes is known (Patent Document 8).
An oxazole derivative that has an insulin secretion promoting action and a blood glucose lowering action and is useful for the prevention and treatment of diabetes is known (Patent Document 9).
A benzofuran derivative having a blood glucose and blood lipid lowering action is known (Patent Document 10).
It has been reported that fatty acids bind to GPR40 (Patent Document 11).

WO2000 / 22129 JP 2002-265457 A JP 2002-212171 A JP 2001-226350 A JP 2001-199971 A JP 2000-198772 A Japanese Unexamined Patent Publication No. 2000-80086 JP 2000-34266 A JP 09-323983 A Japanese Patent Laid-Open No. 08-311065 WO02 / 057783 Biochem Biophys Res Commun. 1997, Oct 20; 239 (2)

  An object of the present invention is to provide a novel fused ring compound having a GPR40 receptor function-regulating action and useful as an insulin secretion promoter or a preventive / therapeutic agent for diabetes.

  As a result of intensive studies, the inventors of the present invention have unexpectedly superior GPR40 receptor agonist activity based on the specific chemical structure of the compound represented by the following formula (I), It has excellent physical properties as pharmaceuticals such as stability and has been found to be a safe and useful pharmaceutical as a preventive / therapeutic agent for mammalian GPR40 receptor-related pathologies or diseases. The present invention has been completed based on the above.

［式中、Arは置換されていてもよい環状基を、
環Aはさらに置換されていてもよい環（但し、該環はチアゾール、オキサゾール、イミダ
ゾールおよびピラゾールでない）を、
XaおよびXbは独立して、結合手または主鎖の原子数が1ないし5個のスペーサーを、
XcはO、S、SOまたはSO₂を、

環Bは5ないし7員環を、
Xdは結合手、CHまたはCH₂を、
・・・・・・は、Xdが結合手またはCH₂であるとき単結合を、XdがCHであるとき二重結合
を、
R¹は置換されていてもよいヒドロキシ基を示す。
ただし、
(i)環Aがベンゼンであるとき、Arで示される環状基はキノリニル基でなく、
(ii)環Bが5ないし7員芳香環であるとき、環Aで示される環はチオフェンまたはフランでなく、
(iii)環Bがベンゼンであるとき、環Aで示される環は5員芳香族複素環でなく、
(iv)環Bがシクロヘキサンであるとき、Xdは結合手でない。］で表わされる化合物［ただ
し、
［6−(4−ビフェニリル)メトキシ−2−テトラリン］酢酸；
［6−(4−ビフェニリル)メトキシ−2−テトラリン］酢酸メチル；
［7−(4−ビフェニリル)メトキシ−1,2,3,4−テトラヒドロ−2−オキソ−3−キノリン］
酢酸；および
［7−(4−ビフェニリル)メトキシ−1,2,3,4−テトラヒドロ−2−オキソ−3−キノリン］
酢酸メチルを除く］またはその塩（以下、化合物（Ｉ）と略記する場合もある）；
［２］化合物（Ｉ）のプロドラッグ；
［３］Arで示される環状基が芳香族炭化水素基である化合物（Ｉ）；
［４］Xaが結合手である化合物（Ｉ）；
［５］環Aがベンゼンである化合物（Ｉ）；
［６］Xbが−ＣＨ_２−である化合物（Ｉ）；
［７］XcがOである化合物（Ｉ）；
［８］

である化合物（Ｉ）；
［９］環Bが5ないし7員非芳香環である化合物（Ｉ）；
［１０］環Bがシクロペンタンまたはテトラヒドロフランである前記［９］記載の化合物
；
［１１］XdがCH₂である化合物（Ｉ）；
［１２］R¹がヒドロキシ基である化合物（Ｉ）；
［１３］式

［式中、Ar¹は置換されていてもよいフェニル基または置換されていてもよいインダニル
基を、
Xa¹は結合手または主鎖の原子数が1ないし5個のスペーサーを、
環A²はさらに置換されていてもよいベンゼン環を、
環B²は5ないし7員環を示す。］で表わされる化合物（Ｉ）；
［１４］式

［式中、Ar²は置換されていてもよいチアゾリル基を、
Xa²は結合手または主鎖の原子数が1ないし5個のスペーサーを、
環A³はさらに置換されていてもよいベンゼン環を、
環B²は5ないし7員環を示す。］で表わされる化合物（Ｉ）；
［１５］化合物（Ｉ）またはそのプロドラッグを含有してなる医薬；
［１６］糖尿病の予防・治療剤である前記［１５］記載の医薬；
［１７］化合物（Ｉ）またはそのプロドラッグを含有してなるインスリン分泌促進剤；
［１８］式

［式中、環A¹は置換されていてもよい環を、
Xbは結合手または主鎖の原子数が1ないし5個のスペーサーを、
XcはO、S、SOまたはSO₂を、

環B¹は5ないし7員非芳香環を、
Xdは結合手、CHまたはCH₂を、
・・・・・・は、Xdが結合手またはCH₂であるとき単結合を、XdがCHであるとき二重結合
を、
R¹は置換されていてもよいヒドロキシ基を示す。］で表わされる化合物もしくはその塩（以下、化合物（Ｉ’）と略記する場合もある）またはそのプロドラッグを含有してなるＧＰＲ４０受容体機能調節剤；
［１９］哺乳動物に対して、化合物（Ｉ’）またはそのプロドラッグの有効量を投与することを特徴とする、該哺乳動物におけるＧＰＲ４０受容体機能調節方法；
［２０］ＧＰＲ４０受容体機能調節剤の製造のための、化合物（Ｉ’）またはそのプロドラッグの使用；を提供する。 That is, the present invention
[1] Formula

[In the formula, Ar represents an optionally substituted cyclic group,
Ring A represents a ring which may be further substituted (provided that the ring is not thiazole, oxazole, imidazole and pyrazole),
Xa and Xb independently represent a spacer having a bond or main chain atom number of 1 to 5,
Xc is O, S, SO or SO ₂ ,

Ring B is a 5- to 7-membered ring,
Xd is a bond, CH or CH ₂ ,
・ ・ ・ ・ ・ ・ Is a single bond when Xd is a bond or CH ₂ and a double bond when Xd is CH,
R ¹ represents an optionally substituted hydroxy group.
However,
(i) when ring A is benzene, the cyclic group represented by Ar is not a quinolinyl group,
(ii) when ring B is a 5- to 7-membered aromatic ring, the ring represented by ring A is not thiophene or furan;
(iii) When ring B is benzene, the ring represented by ring A is not a 5-membered aromatic heterocycle,
(iv) When ring B is cyclohexane, Xd is not a bond. A compound represented by the formula [However,
[6- (4-biphenylyl) methoxy-2-tetralin] acetic acid;
[6- (4-biphenylyl) methoxy-2-tetralin] methyl acetate;
[7- (4-biphenylyl) methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline]
Acetic acid; and [7- (4-biphenylyl) methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline]
Excluding methyl acetate] or a salt thereof (hereinafter sometimes abbreviated as compound (I));
[2] Prodrug of compound (I);
[3] Compound (I) in which the cyclic group represented by Ar is an aromatic hydrocarbon group;
[4] Compound (I) wherein Xa is a bond;
[5] Compound (I) wherein ring A is benzene;
[6] Compound (I) wherein Xb is —CH ₂ —;
[7] Compound (I) wherein Xc is O;
[8]

Compound (I) which is
[9] Compound (I) wherein ring B is a 5- to 7-membered non-aromatic ring;
[10] The compound according to the above [9], wherein ring B is cyclopentane or tetrahydrofuran;
[11] Compound (I) wherein Xd is CH ₂ ;
[12] Compound (I) wherein R ¹ is a hydroxy group;
[13] Formula

[Wherein Ar ¹ represents an optionally substituted phenyl group or an optionally substituted indanyl group;
Xa ¹ is a spacer having 1 to 5 atoms in the bond or main chain,
Ring A ² represents an optionally substituted benzene ring,
Ring B ² represents a 5- to 7-membered ring. A compound (I) represented by the formula:
[14] Formula

[In the formula, Ar ² represents an optionally substituted thiazolyl group,
Xa ² is a spacer having 1 to 5 atoms in the bond or main chain,
Ring A ³ represents an optionally substituted benzene ring,
Ring B ² represents a 5- to 7-membered ring. A compound (I) represented by the formula:
[15] A medicament comprising compound (I) or a prodrug thereof;
[16] The medicament according to the above [15], which is a preventive / therapeutic agent for diabetes;
[17] An insulin secretagogue comprising compound (I) or a prodrug thereof;
[18] Formula

[Wherein ring A ¹ represents an optionally substituted ring,
Xb is a spacer having 1 to 5 atoms in the bond or main chain,
Xc is O, S, SO or SO ₂ ,

Ring B ¹ is a 5- to 7-membered non-aromatic ring,
Xd is a bond, CH or CH ₂ ,
・ ・ ・ ・ ・ ・ Is a single bond when Xd is a bond or CH ₂ and a double bond when Xd is CH,
R ¹ represents an optionally substituted hydroxy group. Or a salt thereof (hereinafter sometimes abbreviated as compound (I ′)) or a prodrug thereof, a GPR40 receptor function modulator;
[19] A method for regulating GPR40 receptor function in a mammal, which comprises administering an effective amount of compound (I ′) or a prodrug thereof to the mammal;
[20] Use of compound (I ′) or a prodrug thereof for the manufacture of a GPR40 receptor function modulator.

  The compound of the present invention has an excellent GPR40 receptor function regulating action, and is useful as an insulin secretagogue and a preventive / therapeutic agent for diabetes.

  Unless otherwise specified, the “halogen atom” in the present specification includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Unless otherwise specified, examples of the “optionally substituted hydrocarbon group” in the present specification include “optionally substituted C _1-6 alkyl group” and “optionally substituted C”. “ _2-6 alkenyl group”, “optionally substituted C _2-6 alkynyl group”, “optionally substituted C _3-8 cycloalkyl group”, “optionally substituted C _6-14 aryl” Group ”,“ optionally substituted C _7-16 aralkyl group ”and the like.
The “C _1-6 alkyl group” in the present specification is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl unless otherwise specified. Etc.
The “C _2-6 alkenyl group” in the present specification is, for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexene unless otherwise specified. -1-yl and the like can be mentioned.
Examples of the “C _2-6 alkynyl group” in the present specification include 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl and the like, unless otherwise specified. It is done.
Unless otherwise specified, examples of the “C _3-8 cycloalkyl group” in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Examples of the “C _6-14 aryl group” in the present specification include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like, unless otherwise specified. Can be mentioned. The C _6-14 aryl may be partially saturated. Examples of the partially saturated C _6-14 aryl include tetrahydronaphthyl.
Unless otherwise specified, the “C _7-16 aralkyl group” in the present specification includes, for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropylene. , 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl and the like.

As used herein, “optionally substituted hydroxy group” is, for example, “hydroxy group”, “optionally substituted C _1-10 alkoxy group”, “substituted” unless otherwise specified. And optionally substituted heterocyclic oxy group ”,“ optionally substituted C _6-14 aryloxy group ”,“ _optionally substituted C _7-16 aralkyloxy group ”and the like.
Unless otherwise specified, examples of the “C _1-6 alkoxy group” in the present specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like. In addition, examples of the “C _1-10 alkoxy group” in the present specification include heptyloxy, octyloxy, nonyloxy, decyloxy and the like in addition to the C _1-6 alkoxy group.
Unless otherwise specified, examples of the “C _1-6 alkoxy-C _1-6 alkoxy group” in the present specification include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
Examples of the “heterocyclic oxy group” in the present specification include a hydroxy group substituted with a “heterocyclic group” described later. Preferable examples of the heterocyclic oxy group include tetrahydropyranyloxy, thiazolyloxy, pyridyloxy, pyrazolyloxy, oxazolyloxy, thienyloxy, furyloxy and the like.
Unless otherwise specified, examples of the “C _6-14 aryloxy group” in the present specification include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
Unless otherwise specified, examples of the “C _7-16 aralkyloxy group” in the present specification include benzyloxy and phenethyloxy.

Unless otherwise specified, examples of the “optionally substituted mercapto group” in the present specification include “mercapto group”, “optionally substituted C _1-10 alkylthio group”, and “substituted”. And optionally substituted heterocyclic thio group ”,“ _optionally substituted C _6-14 arylthio group ”,“ _optionally substituted C _7-16 aralkylthio group ”and the like.
Unless otherwise specified, examples of the “C _1-6 alkylthio group” in the present specification include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and the like. Further, the “C _1-10 alkylthio group” in the present specification
In addition to the C _1-6 alkylthio group, heptylthio, octylthio, nonylthio, decylthio and the like can be mentioned.
Examples of the “heterocyclic thio group” in the present specification include a mercapto group substituted with a “heterocyclic group” described later. Preferable examples of the heterocyclic thio group include tetrahydropyranylthio, thiazolylthio, pyridylthio, pyrazolylthio, oxazolylthio, thienylthio, furylthio and the like.
Examples of the “C _6-14 arylthio group” in the present specification include phenylthio, 1-naphthylthio, 2-naphthylthio and the like, unless otherwise specified.
Unless otherwise specified, examples of the “C _7-16 aralkylthio group” in the present specification include benzylthio and phenethylthio.

As used herein, the “heterocyclic group” is, for example, 1 or 2 selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom, and 1 to 4 unless otherwise specified. 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group, preferably (i) a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group, (ii) 5 to 10
Member non-aromatic heterocyclic group and the like. Of these, a 5- or 6-membered aromatic heterocyclic group is preferable. Specifically, for example, thienyl (eg, 2-thienyl, 3-thienyl), furyl (eg, 2-furyl, 3-furyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (Example: 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (example: 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazinyl, pyrimidinyl (example: 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl ( Examples: 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (Example: 1-triazolyl, 2-triazolyl), tetrazolyl, pyridazinyl (example: 3-pyridazini , 4-pyridazinyl), isothiazolyl (eg: 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), isoxazolyl (eg: 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), indolyl (eg: 1-indolyl, 2- Indolyl, 3-indolyl), 2-benzothiazolyl, 2-benzoxazolyl, benzimidazolyl (eg, 1-benzoimidazolyl, 2-benzimidazolyl), benzo [b] thienyl (eg, 2-benzo [b] thienyl, 3-benzo [B] thienyl), benzo [b] furanyl (eg, 2-benzo [b] furanyl, 3-benzo [b] furanyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl) , 8-quinolyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl) Aromatic heterocyclic groups such as ryl, 4-isoquinolyl, 5-isoquinolyl); for example, pyrrolidinyl (eg 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (eg 2-oxazolidinyl), imidazolinyl (eg 1 -Imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (eg: 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (eg: 1-piperazinyl, 2-piperazinyl), morpholinyl (eg: 2-morpholinyl, 3-morpholinyl, 4-morpholinyl), thiomorpholinyl (eg, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl), and non-aromatic heterocyclic groups such as tetrahydropyranyl.

Unless otherwise specified, examples of the “C _1-6 alkyl-carbonyl group” in the present specification include acetyl, isobutanoyl, isopentanoyl and the like.
Unless otherwise specified, examples of the “C _1-6 alkoxy-carbonyl group” in the present specification include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
Examples of the “C _3-8 cycloalkyl-carbonyl group” in the present specification include, for example, cyclopentylcarbonyl, cyclohexylcarbonyl and the like, unless otherwise specified.
Unless otherwise specified, examples of the “C _6-14 aryl-carbonyl group” in the present specification include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
Unless otherwise specified, examples of the “C _7-16 aralkyl-carbonyl group” in the present specification include phenylacetyl, 2-phenylpropanoyl, and the like.
Examples of the “C _6-14 aryloxy-carbonyl group” in the present specification include phenyloxycarbonyl, naphthyloxycarbonyl and the like, unless otherwise specified.
Unless otherwise specified, examples of the “C _7-16 aralkyloxy-carbonyl group” in the present specification include benzyloxycarbonyl, phenethyloxycarbonyl and the like.
As used herein, “nitrogen-containing heterocyclic-carbonyl group” includes, for example, pyrrolidinylcarbonyl, piperidinocarbonyl and the like, unless otherwise specified.

Examples of the “C _1-6 alkylsulfonyl group” in the present specification include methylsulfonyl, ethylsulfonyl and the like, unless otherwise specified.
Examples of the “C _6-14 arylsulfonyl group” in the present specification include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like, unless otherwise specified.

Examples of the “C _1-6 alkylsulfinyl group” in the present specification include methylsulfinyl, ethylsulfinyl and the like, unless otherwise specified.
Unless otherwise specified, examples of the “C _6-14 arylsulfinyl group” in the present specification include phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like.

Unless otherwise specified, the “optionally esterified carboxyl group” in the present specification includes, for example, carboxyl, C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- Butoxycarbonyl etc.), C
Examples thereof include _6-14 aryloxy-carbonyl groups (eg, phenoxycarbonyl etc.), C _7-16 aralkyloxy-carbonyl groups (eg: benzyloxycarbonyl, phenethyloxycarbonyl etc.) and the like.

Unless otherwise specified, the “optionally halogenated C _1-6 alkyl group” in the present specification includes the above “C ₁ optionally substituted with 1 to 5 above“ halogen atoms ”. _{A -6} alkyl group ". For example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, trifluoromethyl and the like can be mentioned.
Unless otherwise specified, the “optionally halogenated C _1-6 alkoxy group” in the present specification includes the above “C ₁ optionally substituted with 1 to 5 above“ halogen atoms ”. _-6 alkoxy group ". Examples include methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy and the like.

Unless otherwise specified, the “mono- or di-C _1-6 alkyl-amino group” in the present specification includes an amino group mono- or di-substituted with the above “C _1-6 alkyl group”. Can be mentioned. For example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like can be mentioned.
Unless otherwise specified, the “mono- or di-C _6-14 aryl-amino group” in the present specification includes an amino group mono- or di-substituted with the above “C _6-14 aryl group”. Can be mentioned. For example, phenylamino, diphenylamino, 1-naphthylamino, 2-naphthylamino and the like can be mentioned.
Unless otherwise specified, the “mono- or di-C _7-16 aralkyl-amino group” in the present specification includes an amino group mono- or di-substituted with the above “C _7-16 aralkyl group”. Can be mentioned. For example, benzylamino, phenethylamino and the like can be mentioned.
Unless otherwise specified, the “N—C _1-6 alkyl-N—C _6-14 aryl-amino group” in the present specification is the above “C _1-6 alkyl group” and the above “C _6-14 ”. And an amino group substituted with an “aryl group”. For example, N-methyl-N-phenylamino, N-ethyl-N-phenylamino and the like can be mentioned.
Unless otherwise specified, the “N—C _1-6 alkyl-N—C _7-16 aralkyl-amino group” in the present specification is the above “C _1-6 alkyl group” and the above “C _7-16 ”. And an amino group substituted with an “aralkyl group”. For example, N-methyl-N-benzylamino, N-ethyl-N-benzylamino and the like can be mentioned.

Unless otherwise specified, the “mono- or di-C _1-6 alkyl-carbamoyl group” in the present specification includes a carbamoyl group mono- or di-substituted with the above “C _1-6 alkyl group”. Can be mentioned. Examples thereof include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like.
Unless otherwise specified, the “mono- or di-C _6-14 aryl-carbamoyl group” in the present specification includes a carbamoyl group mono- or di-substituted with the above “C _6-14 aryl group”. Can be mentioned. Examples thereof include phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like.
Unless otherwise specified, the “mono- or di-C _3-8 cycloalkyl-carbamoyl group” in the present specification is a carbamoyl mono- or di-substituted with the above “C _3-8 cycloalkyl group”. Groups. For example, cyclopropylcarbamoyl etc. are mentioned.
Unless otherwise specified, the “mono- or di-C _7-16 aralkyl-carbamoyl group” in the present specification includes a carbamoyl group mono- or di-substituted with the above “C _7-16 aralkyl group”. Can be mentioned. For example, benzylcarbamoyl etc. are mentioned.
Unless otherwise specified, the “mono- or di-5 to 7-membered heterocyclic-carbamoyl group” in the present specification includes a carbamoyl group mono- or di-substituted with a 5- to 7-membered heterocyclic group. It is done. Here, as the 5- to 7-membered heterocyclic group, a heterocyclic group containing 1 or 2 kinds and 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom Is mentioned. Preferable examples of the “mono- or di-5 to 7-membered heterocyclic-carbamoyl group” include 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like. It is done.

Unless otherwise specified, the “mono- or di-C _1-6 alkyl-sulfamoyl group” in the present specification includes a sulfamoyl group mono- or di-substituted with the above “C _1-6 alkyl group”. Examples thereof include methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like.
Unless otherwise specified, the “mono- or di-C _6-14 aryl-sulfamoyl group” in the present specification includes a sulfamoyl group mono- or di-substituted with the above “C _6-14 aryl group”. Examples thereof include phenylsulfamoyl, diphenylsulfamoyl, 1-naphthylsulfamoyl, 2-naphthylsulfamoyl and the like.
Unless otherwise specified, the “mono- or di-C _7-16 aralkyl-sulfamoyl group” in the present specification includes a sulfamoyl group mono- or di-substituted with the above “C _7-16 aralkyl group”. Can be mentioned. For example, benzylsulfamoyl etc. are mentioned.

In the present specification, “optionally substituted C _1-6 alkyl group”, “optionally substituted C _2-6 alkenyl group”, “optionally substituted C _2-6 alkynyl group”, “Optionally substituted C _1-10 alkoxy group (including optionally substituted C _1-6 alkoxy group)” and “optionally substituted C _1-10 alkylthio group (optionally substituted) (Including a good C _1-6 alkylthio group) ”includes, for example, (1) a halogen atom; (2) a hydroxy group; (3) an amino group; (4) a nitro group; (5) a cyano group; , Hydroxy group, amino group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, mono- or di-C _1-6 alkyl-amino group, C _6-14 aryl group, mono- or di _{-C 6-14} aryl - amino _{Group, C 3-8} cycloalkyl _{group, C 1-6} alkoxy _{groups, C 1-6} alkoxy _{-C 1-6 alkoxy, C 1-6} alkylthio _{group, C 1-6} alkylsulfinyl _{group, C 1-6} alkyl Sulfonyl group, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _6-14 aryl-carbamoyl group, sulfamoyl group , A heterocyclic group optionally substituted with 1 to 3 substituents selected from a mono- or di-C _1-6 alkyl-sulfamoyl group and a mono- or di-C _6-14 aryl-sulfamoyl group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl); (7) mono - or di _{-C 1-6} alkyl - A Amino group; (8) mono - or di _{-C 6-14} aryl - amino group; (9) mono- - or di _{-C 7-16} aralkyl - amino group; (10) N-
A C _1-6 alkyl-N—C _6-14 aryl-amino group; (11) a N—C _1-6 alkyl-N—C _7-16 aralkyl-amino group; (12) a C _3-8 cycloalkyl group; (13) an optionally halogenated C _1-6 alkoxy group; (14) a C _1-6 alkylthio group; (15) a C _1-6 alkylsulfinyl group; (16) a C _1-6 alkylsulfonyl group; 17) an optionally esterified carboxyl group; (18) a C _1-6 alkyl-carbonyl group; (19) a C _3-8 cycloalkyl-carbonyl group; (20) a C _6-14 aryl-carbonyl group; (21) a carbamoyl group; (22) a thiocarbamoyl group; (23) a mono- or di-C _1-6 alkyl-carbamoyl group; (24) a mono- or di-C _6-14 aryl-carbamoyl group; -Or di-5 to 7 members Heterocyclic - carbamoyl group, (26) which may be substituted with a carboxyl C _1-6 alkyl - carbonylamino group (e.g. acetylamino, propionylamino); (27) a halogen atom, hydroxy group, an amino group, a nitro Group, cyano group, optionally halogenated C _1-6 alkyl group, mono- or di-C _1-6 alkyl-amino group, C _6-14 aryl group, mono- or di-C _6-14 aryl -Amino group, C _3-8 cycloalkyl group, C _1-6 alkoxy group, C _1-6 alkoxy-C _1-6 alkoxy group, C _1-6 alkylthio group, C _1-6 alkylsulfinyl group, C _{1- 6} alkylsulfonyl group, esterified or unprotected carboxyl group, a carbamoyl group, thiocarbamoyl group, mono- - or di -C _1-6 alkyl - Karubamoi Group, mono - or di _{-C 6-14} aryl - carbamoyl group, a sulfamoyl group, a mono- - or di _{-C 1-6} alkyl - sulfamoyl group and mono - or di _{-C 6-14} aryl - 1 selected from sulfamoyl group _{Or a} C _6-14 aryloxy group _optionally substituted with three substituents; (28) a halogen atom, a hydroxy group, an amino group, a nitro group, a cyano group, or a halogenated C _1-6 Alkyl group, mono- or di-C _1-6 alkyl-amino group, C _6-14 aryl group, mono- or di-C _6-14 aryl-amino group, C _3-8 cycloalkyl group, C _1-6 Alkoxy group, C _1-6 alkoxy-C _1-6 alkoxy group, C _1-6 alkylthio group, C _1-6 alkylsulfinyl group, C _1-6 alkylsulfonyl group, ester Optionally substituted carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _6-14 aryl-carbamoyl group, sulfamoyl group, mono- Or a C _6-14 aryl group _optionally substituted by 1 to 3 substituents selected from a di-C _1-6 alkyl-sulfamoyl group and a mono- or di-C _6-14 aryl-sulfamoyl group; (30) sulfamoyl group; (31) mono- or di-C _1-6 alkyl-sulfamoyl group; (32) mono- or di-C _6-14 aryl-sulfamoyl group; Halogen atom, hydroxy group, amino group, nitro group, cyano group, C _1-6 alkyl group which may be halogenated, mono- or di-C _1-6 alkyl Ru-amino group, C _6-14 aryl group, mono- or di-C _6-14 aryl-amino group, C _3-8 cycloalkyl group, C _1-6 alkoxy group, C _1-6 alkoxy-C _{1- 6} alkoxy group, C _1-6 alkylthio group, C _1-6 alkylsulfinyl group, C _1-6 alkylsulfonyl group, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _6-14 aryl-carbamoyl group, sulfamoyl group, mono- or di-C _1-6 alkyl-sulfamoyl group and mono- or di-C _6-14 aryl- it 1 selected from sulfamoyl group 3 may be substituted with a substituent C _7-16 aralkyloxy group; a 1 selected from such Five substituents may be at substitutable positions respectively,
“C _1-6 alkyl group”, “C _2-6 alkenyl group”, “C _2-6 alkynyl group”, “C _1-10 alkoxy group (including C _1-6 alkoxy group)” and “C _{1- 10} alkylthio groups (including C _1-6 alkylthio groups) ”.

In the present specification, “optionally substituted C _3-8 cycloalkyl group”, “ _optionally substituted C _6-14 aryl group”, “ _optionally substituted C _7-16 aralkyl group” , “Optionally substituted heterocyclic group”, “optionally substituted heterocyclic oxy group”, “optionally substituted C _6-14 aryloxy group”, “ _optionally substituted C” _“7-16 aralkyloxy group”, “ _optionally substituted heterocyclic thio group”, “ _optionally substituted C _6-14 arylthio group” and “ _optionally substituted C _7-16 aralkylthio group” "Is, for example, (1) a halogen atom; (2) a hydroxy group; (3) an amino group; (4) a nitro group; (5) a cyano group; (6) an optionally substituted C _1-6 alkyl group (7) C _2-6 alkeni which may be substituted (8) an optionally substituted C _2-6 alkynyl group;
(9) Halogen atom, hydroxy group, amino group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, mono- or di-C _1-6 alkyl-amino group, C _6-14 Aryl group, mono- or di-C _6-14 aryl-amino group, C _3-8 cycloalkyl group, C _1-6 alkoxy group, C _1-6 alkoxy-C _1-6 alkoxy group, C _1-6 alkylthio Group, C _1-6 alkylsulfinyl group, C _1-6 alkylsulfonyl group, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono _-Or di-C _6-14 aryl-carbamoyl, sulfamoyl, mono- or di-C _1-6 alkyl-sulfamoyl and mono- or di-C _{6 A} C _6-14 aryl group _optionally substituted by 1 to 3 substituents selected from _-14 aryl-sulfamoyl groups; (10) halogen atom, hydroxy group, amino group, nitro group, cyano group, halogenated group An _optionally substituted C _1-6 alkyl group, a mono- or di-C _1-6 alkyl-amino group, a C _6-14 aryl group, a mono- or di-C _6-14 aryl-amino group, a C _{3- 8} cycloalkyl group, C _1-6 alkoxy group, C _1-6 alkoxy-C _1-6 alkoxy group, C _1-6 alkylthio group, C _1-6 alkylsulfinyl group, C _1-6 alkylsulfonyl group, esterification Carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _6-14 aryl Substituted with 1 to 3 substituents selected from a ru-carbamoyl group, a sulfamoyl group, a mono- or di-C _1-6 alkyl-sulfamoyl group and a mono- or di-C _6-14 aryl-sulfamoyl group. which may _{C 6-14} aryloxy group, (11) a halogen atom, hydroxy group, an amino group, a nitro group, a cyano group, a _{C 1-6} alkyl group which may be halogenated, mono- - or di _{-C 1- 6} alkyl-amino group, C _6-14 aryl group, mono- or di-C _6-14 aryl-amino group, C _3-8 cycloalkyl group, C _1-6 alkoxy group, C _1-6 alkoxy-C _{1 -6 alkoxy, C 1-6} alkylthio _{group, C 1-6} alkylsulfinyl _{group, C 1-6} alkylsulfonyl group, a carboxyl group which may be esterified, Carbamoyl group, thiocarbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _6-14 aryl-carbamoyl group, sulfamoyl group, mono- or di-C _1-6 alkyl-sulfamoyl A C _7-16 aralkyloxy group _optionally substituted by 1 to 3 substituents selected from a group and a mono- or di-C _6-14 aryl-sulfamoyl group; (12) halogen atom, hydroxy group, amino Group, nitro group, cyano group, optionally halogenated C _1-6 alkyl group, mono- or di-C _1-6 alkyl-amino group, C _6-14 aryl group, mono- or di-C _{6 -14} aryl-amino group, C _3-8 cycloalkyl group, C _1-6 alkoxy group, C _1-6 alkoxy-C _1-6 alkoxy group, C _1-6 al Kirthio group, C _1-6 alkylsulfinyl group, C _1-6 alkylsulfonyl group, optionally esterified carboxyl group, carbamoyl group, thiocarbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, 1 to 3 selected from mono- or di-C _6-14 aryl-carbamoyl group, sulfamoyl group, mono- or di-C _1-6 alkyl-sulfamoyl group and mono- or di-C _6-14 aryl-sulfamoyl group Heterocyclic groups optionally substituted with one substituent (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl); (13) mono- or di-C _1-6 alkyl-amino groups; (14) mono - or di _{-C 6-14} aryl - amino group; (15) mono - or di _{-C 7-16} aralkyl - amino group; 16) _{N-C 1-6} alkyl _{-N-C 6-14} aryl - amino group; (17) _{N-C 1-6} alkyl _{-N-C 7-16} aralkyl - amino group; _{(18) C 3-8} (19) optionally substituted C _1-6 alkoxy group; (20) C _1-6 alkylthio group; (21) C _1-6 alkylsulfinyl group; (22) C _1-6 alkylsulfonyl A group; (23) an optionally esterified carboxyl group; (24) a C _1-6 alkyl-carbonyl group; (25) a C _3-8 cycloalkyl-carbonyl group; (26) a C _6-14 aryl-carbonyl group. (27) a carbamoyl group; (28) a thiocarbamoyl group; (29) a mono- or di-C _1-6 alkyl-carbamoyl group; (30) a mono- or di-C _6-14 aryl-carbamoyl group; 31) Mono- or di-5 to 7 Selected from the like; heterocyclic - carbamoyl group, (32) sulfamoyl group; (33) mono - or di _{-C 1-6} alkyl - sulfamoyl group; a sulfamoyl group - (34) mono - or di _{-C 6-14} aryl 1 to 5 substituents each may have a substitutable position,
“C _3-8 cycloalkyl group”, “C _6-14 aryl group”, “C _7-16 aralkyl group”, “heterocyclic group”, “heterocyclic oxy group”, “C _6-14 aryloxy group” , “C _7-16 aralkyloxy group”, “heterocyclic thio group”, “C _6-14 arylthio group” and “C _7-16 aralkylthio group”.

Unless otherwise specified, the “optionally substituted amino group” in the present specification is (1
) An optionally substituted C _1-6 alkyl group; (2) an optionally substituted C _2-6 alkenyl group; (3) an optionally substituted C _2-6 alkynyl group; (4) substituted (3) an optionally substituted C _3-8 cycloalkyl group; (5) an optionally substituted C _6-14 aryl group; (6) an optionally substituted C _1-6 alkoxy group; (8) an optionally substituted heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl); (9) a sulfamoyl group; (10) mono- or di-C _1-
6 alkyl-sulfamoyl groups; (11) amino groups optionally substituted with 1 or 2 substituents selected from mono- or di-C _6-14 aryl-sulfamoyl groups and the like. Further, when the “optionally substituted amino group” is an amino group substituted with two substituents, these substituents may form a nitrogen-containing heterocyclic ring together with the adjacent nitrogen atom. Good. The “nitrogen-containing heterocycle” includes, for example, at least one nitrogen atom in addition to a carbon atom as a ring-constituting atom, and further contains 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom And a 5- to 7-membered nitrogen-containing heterocycle which may be used. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine and the like.

Unless otherwise specified, the “optionally substituted acyl group” in the present specification has the formula: —COR ² , —CO—OR ² , —SO ₂ R ² , —SOR ² , —PO (OR ² ) (OR ³ ), —CO—NR ^2a R ^3a and —CS—NR ^2a R ^3a [wherein R ² and R ³ are the same or different and represent a hydrogen atom or an optionally substituted hydrocarbon group; Or represents an optionally substituted heterocyclic group, and R ^2a and R ^3a are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group , R ^2a and R ^3a together with the adjacent nitrogen atom may form an optionally substituted nitrogen-containing heterocyclic ring].

The “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R ^2a and R ^3a together with the adjacent nitrogen atom is, for example, at least one nitrogen other than a carbon atom as a ring-constituting atom. Examples thereof include a 5- to 7-membered nitrogen-containing heterocyclic ring which contains an atom and may further contain 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Preferable examples of the nitrogen-containing heterocyclic ring include pyrrolidine, imidazolidine, pyrazolidine,
Examples include piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, and oxazolidine.
The nitrogen-containing heterocycle may have 1 to 2 substituents at substitutable positions. Examples of such a substituent include a hydroxy group, an optionally halogenated C _1-6 alkyl group, a C _6-14 aryl group, a C _7-16 aralkyl group, and the like.

Preferable examples of the “optionally substituted acyl group” include formyl group; carboxyl group; carbamoyl group; C _1-6 alkyl-carbonyl group; C _1-6 alkoxy-carbonyl group; C _3-8 cycloalkyl -Carbonyl group; C _6-14 aryl-carbonyl group; C _7-16 aralkyl-carbonyl group; C _6-14 aryloxy-carbonyl group; C _7-16 aralkyloxy-carbonyl group; mono- or di-C _{1- 6} alkylcarbamoyl group; mono- - or di _{-C 6-14} aryl - carbamoyl group; mono- - or di _{-C 3-8} cycloalkyl - carbamoyl groups; mono- - or di _{-C 7-16} aralkyl - carbamoyl group; _{C 1 -6} alkylsulfonyl group; C _6-14 arylsulfonyl group _optionally substituted with a nitro group; nitrogen-containing heterocycle - carbonyl _{group; C 1-6} alkylsulfinyl _{group; C 6-14} arylsulfinyl group; thiocarbamoyl group; a sulfamoyl group; mono- - or di _{-C 1-6} alkyl - sulfamoyl group; mono- - or di _{-C 6-14} Aryl-sulfamoyl group; mono- or di-C _7-16 aralkyl-sulfamoyl group; and the like.

Below, the definition of each symbol in Formula (I) and (I ') is explained in full detail.
Ar represents a cyclic group which may be substituted. Here, examples of the “cyclic group” include a C _3-8 cycloalkyl group, an aromatic hydrocarbon group (eg, C _6-14 aryl group), a heterocyclic group, and the like. Preferred examples of the “cyclic group” include cyclopropyl, cyclohexyl, phenyl, naphthyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, benzo [b] thienyl, indolyl, indanyl and the like. Can be mentioned.
The cyclic group represented by Ar is preferably an aromatic hydrocarbon group (eg, C _6-14 aryl group), more preferably phenyl.
The cyclic group represented by Ar may have, for example, 1 to 5, preferably 1 to 3 substituents at substitutable positions. As the “substituent”, those exemplified as the substituent in the aforementioned “optionally substituted C _3-8 cycloalkyl group” can be used. When the cyclic group has two or more substituents, each substituent may be the same or different.
The substituent is preferably a halogen atom; a cyano group; an optionally halogenated C _1-6 alkyl group; a C _6-14 aryl group; a hydroxy group; a C _3-8 cycloalkyl group; A C _1-10 alkoxy group optionally substituted with 1 to 3 substituents selected from a C _1-6 alkoxy group and the like; a heterocyclic oxy group (preferably tetrahydropyranyloxy); C _7-16 An aralkyloxy group; a carboxyl group; a C _1-6 alkyl-carbonyl group; a C _6-14 aryl-carbonyl group;

Examples of the “ring” represented by ring A and ring A ¹ include aromatic rings such as aromatic hydrocarbons and aromatic heterocycles; non-aromatic rings such as alicyclic hydrocarbons and nonaromatic heterocycles.
As an aromatic hydrocarbon, a C6-C14 aromatic hydrocarbon is mentioned, for example. Preferable examples of the aromatic hydrocarbon include benzene, naphthalene, anthracene, phenanthrene, acenaphthylene and the like.
As the aromatic heterocycle, for example, a 5- to 7-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as a ring constituent atom or condensed An aromatic heterocyclic ring is mentioned. Examples of the condensed aromatic heterocycle include those 5- to 7-membered monocyclic aromatic heterocycles, 6-membered rings containing 1 to 2 nitrogen atoms, benzene rings or 5-membered containing 1 sulfur atom. Examples thereof include a ring condensed with a ring.
Preferable examples of the aromatic heterocyclic ring include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, isoxazole, isothiazole, oxazole, thiazole, oxadiazole, thiadiazole, triazole, tetrazole, quinoline. Quinazoline, quinoxaline, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, indole, 1H-indazole, 1H-pyrrolo [2,3-b] pyrazine, 1H-pyrrolopyridine, 1H-imidazopyridine, 1H-imidazo Examples include pyrazine, triazine, isoquinoline, and benzothiadiazole.
Examples of the alicyclic hydrocarbon include saturated or unsaturated alicyclic hydrocarbons having 3 to 12 carbon atoms such as cycloalkane, cycloalkene, and cycloalkadiene.
Preferable examples of cycloalkane include cycloalkanes having 3 to 10 carbon atoms such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, bicyclo [2.2.1] heptane, bicyclo [2.2. .2] Octane, bicyclo [3.2.1] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, bicyclo [4.2.1] nonane, bicyclo [4.3. .1] Decane and the like can be mentioned.
Preferable examples of the cycloalkene include a cycloalkene having 3 to 10 carbon atoms such as cyclobutene, cyclopentene, cyclohexene and the like.
Preferable examples of the cycloalkadiene include cycloalkadiene having 4 to 10 carbon atoms, such as 2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene and the like.
As the non-aromatic heterocycle, for example, a 5- to 7-membered monocyclic non-aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms Or a condensed non-aromatic heterocyclic ring is mentioned. Examples of the condensed non-aromatic heterocycle include these 5- to 7-membered monocyclic non-aromatic heterocycle and a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or one sulfur atom. And a ring condensed with a 5-membered ring.
Suitable examples of the non-aromatic heterocyclic ring include dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, pyrrolidine, pyrroline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, hexamethyleneimine, oxazolidine, thiazolidine, imidazolidine, imidazoline , Tetrahydrofuran, azepane, oxepane, tetrahydropyridine and the like.

Among the above rings, aromatic rings such as benzene, pyrazole, thiazole, oxazole, furan, thiophene, oxadiazole, triazole, tetrazole, pyrimidine, benzimidazole, and indole are preferable, and benzene is particularly preferable.
However, the ring represented by ring A is not thiazole, oxazole, imidazole or pyrazole.

The “ring” represented by ring A and ring A ¹ may have, for example, 1 to 5, preferably 1 to 3 substituents at substitutable positions. As the “substituent”, those exemplified as the substituent in the aforementioned “optionally substituted C _3-8 cycloalkyl group” can be used. When the ring has two or more substituents, each substituent may be the same or different.
The substituent is preferably a halogen atom, a C _7-16 aralkyl group, a C _6-14 aryl group, a C _1-10 alkoxy group, a C _7-16 aralkyloxy group, or the like.
Ring A is preferably benzene.

In addition, the “ring” represented by ring A ¹ may have a substituent represented by the formula: Ar—Xa— (the symbols have the same meaning as described above).
Ring A ¹ is preferably ring A having a substituent represented by the formula: Ar—Xa— (the symbols are as defined above).

Xa and Xb independently represent a spacer having a bond or a main chain having 1 to 5 atoms.
For example, when Xa is a spacer having 1 to 5 atoms in the main chain, the “main chain” means a divalent straight chain connecting Ar and ring A, and the “number of main chain atoms” is , And count so that the atoms of the main chain are minimized.
Similarly, when Xb is a spacer having 1 to 5 atoms in the main chain, the “main chain” means ring A.
And the number of main chain atoms is counted so that the number of main chain atoms is minimized.
The “main chain” is composed of 1 to 5 atoms selected from a carbon atom and a hetero atom (for example, an oxygen atom, a sulfur atom, a nitrogen atom, etc.), and may be saturated or unsaturated. Carbon atoms and sulfur atoms may be oxidized.

Examples of the “spacer having 1 to 5 atoms in the main chain” include (1) — (CH ₂ ) _k − (k is an integer of 1 to 5);
_{(2) - (CH 2)} k1 -Q- (CH 2) k2 - [k1 and k2 independently an integer of 0 to 4 is and k1 + k2 = 0 to 4 integer; Q is O, S (O) _k3 (k3 represents an integer of 0 to 2),
CO or N (R ⁴ ) (R ⁴ represents a hydrogen atom or a substituent)];
(3) — (CH ₂ ) _k ⁴ —NR ⁴ CO— (CH ₂ ) _{k 5} — (k 4 and k 5 are each independently an integer of 0 to 3, and k 4 + k 5 = 0 to 3 and R ⁴ is the same as above. Show significance).
As the substituent represented by R ⁴ , those exemplified as the substituent in the aforementioned “optionally substituted C _3-8 cycloalkyl group” can be used. Among these, an optionally substituted C _1-6 alkyl group (preferably a C _1-6 alkyl group, a C _7-16 aralkyl group, etc.) and a C _3-8 cycloalkyl group are preferable.

As a specific example of “a spacer having 1 to 5 atoms in the main chain”,
_{(1a) -CH 2 -, -} CH 2 CH 2 -, - CH 2 CH 2 CH 2 -;
(2a) —O—, —CH ₂ O—, —CH ₂ CH ₂ O—, —OCH ₂ —, —O—CH ₂ C
_{H 2 -, - O-CH} 2 CH 2 CH 2 -;
_{(2b) -S -, - CH} 2 S -, - CH 2 CH 2 S -, - SCH 2 -, - SCH 2 C
_{H 2 -, - S-CH} 2 CH 2 CH 2 -;
(2c) -CO -, - CO -CH 2 -;
(2d) —NH—CH ₂ —, —, each having a substituent selected from a C _1-6 alkyl group, a C _7-16 aralkyl group, and a C _3-8 cycloalkyl group on the N atom, _{NH-CH 2 CH 2 -,} - CH 2 NH- or _{-CH 2 -NH-CH 2 CH 2} -;
(3a) —CH ₂ —NH—CO—;

Xa is preferably a bond; —O—; —S—; —CH ₂ —; —CO—; —CH ₂ O—; —CH ₂ S—; C _1-6 alkyl group and C ₇ on the N atom -CH ₂ NH- which may have a substituent selected from _-16 aralkyl groups; -OCH _2- ; -SCH _2- ; from a C _1-6 alkyl group and a C _7-16 aralkyl group on the N atom Optionally substituted —NH—CH ₂ —; —CH ₂ CH ₂ O—; —CH ₂ CH ₂ S—; C _1-6 alkyl group and C _7-16 aralkyl on N atom A —CH ₂ —NH—CO— which may have a substituent selected from a group; Xa is more preferably a bond.
Xb is preferably _{-CH 2 -; - CH 2 CH} 2 -; - CO-CH 2 -; - CH 2 CH 2 CH 2 -; - O-CH 2 CH 2 -; - S-CH 2 CH 2 - _{; -O-CH 2 CH 2 CH} 2 -; - S-CH 2 CH 2 CH 2 -; has on the N atom _{C 3-8} substituents selected from cycloalkyl group and _{C 7-16} aralkyl groups, respectively good _-NH-CH 2 be the CH ₂ - or _{-CH 2 -NH-CH 2 CH 2} -; and the like. Xb is more preferably —CH ₂ —.

Xc represents O, S, SO or SO ₂ and is preferably O.

Examples of the “5- to 7-membered ring” represented by ring B include those that are 5- to 7-membered rings among the rings exemplified as ring A. Among them, C5-C7 cycloalkane (preferably cyclopentane, cyclohexane, cycloheptane), C5-C7 cycloalkene (preferably cyclopentene, cyclohexene), 5- to 7-membered monocyclic non-aromatic 5- to 7-membered non-aromatic rings such as heterocycles (preferably tetrahydrofuran, oxepane) are preferred.
Ring B is more preferably cyclopentane or tetrahydrofuran, and particularly preferably tetrahydrofuran.
A suitable combination of ring D and ring B includes a case where ring D is benzene and ring B is cyclopentane or tetrahydrofuran (ring B is preferably tetrahydrofuran).
That is,

As the “5- to 7-membered non-aromatic ring” for ring B ¹ , those exemplified as the aforementioned ring B can be mentioned.
Ring B ¹ is preferably cyclopentane or tetrahydrofuran, more preferably tetrahydrofuran.
A suitable combination of ring D and ring B ¹ includes a case where ring D is benzene and ring B ¹ is cyclopentane or tetrahydrofuran (ring B ¹ is preferably tetrahydrofuran). That is,

Xd represents a bond, CH or CH ₂ , preferably CH ₂ .
R ¹ is preferably a hydroxy group or a C _1-6 alkoxy group, more preferably a hydroxy group.

In formula (I):
(i) when ring A is benzene, the cyclic group represented by Ar is not a quinolinyl group,
(ii) when ring B is a 5- to 7-membered aromatic ring, the ring represented by ring A is not thiophene or furan;
(iii) When ring B is benzene, the ring represented by ring A is not a 5-membered aromatic heterocycle,
(iv) When ring B is cyclohexane, Xd is not a bond.
The compound represented by formula (I) is:
[6- (4-biphenylyl) methoxy-2-tetralin] acetic acid;
[6- (4-biphenylyl) methoxy-2-tetralin] methyl acetate;
[7- (4-biphenylyl) methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline]
Acetic acid; and [7- (4-biphenylyl) methoxy-1,2,3,4-tetrahydro-2-oxo-3-quinoline]
Contains no methyl acetate.

XdがCH₂；かつ
R¹がヒドロキシ基またはＣ_１−６アルコキシ基（好ましくはヒドロキシ基）；である化合物。 Preferable examples of compound (I) include the following compounds.
[Compound A]
Ar is a halogen atom; a cyano group; an optionally halogenated C _1-6 alkyl group; a C _6-14 aryl group; a hydroxy group; a C _3-8 cycloalkyl group, an optionally halogenated C _{1 A} C _1-10 alkoxy group optionally substituted with 1 to 3 substituents selected from a _-6 alkoxy group and the like; a heterocyclic oxy group (preferably tetrahydropyranyloxy); a C _7-16 aralkyloxy group; C _1-6 alkyl-carbonyl group; C _6-14 aryl-carbonyl group; an aromatic hydrocarbon group optionally having 1 to 3 substituents selected from the group (preferably C _{6-6 14} aryl group; more preferably phenyl);
Ring A is a halogen atom, a C _7-16 aralkyl group, a C _6-14 aryl group, a C _1-10
An aromatic ring (preferably benzene, furan, thiophene, oxadiazole, triazole, tetrazole, pyrimidine, optionally having 1 to 3 substituents selected from an alkoxy group, a C _7-16 aralkyloxy group, etc. Benzimidazole, indole; more preferably benzene);
Xa is a _{bond; -O -; - S -;} - CH 2 -; - CO -; - CH 2 O -; - CH 2 S-; C 1-6 alkyl group and a _{C 7-16} on the N atom —CH ₂ NH— which may have a substituent selected from an aralkyl group; —OCH ₂ —; —SCH ₂ —; selected from a C _1-6 alkyl group and a C _7-16 aralkyl group on the N atom Optionally substituted —NH—CH ₂ —; —CH ₂ CH ₂ O—; —CH ₂ CH ₂ S—; or a C _1-6 alkyl group and a C _7-16 aralkyl group on the N atom an optionally substituted _-CH 2 -NH-CO- also selected from (preferably a bond);
Xb _{is, -CH 2 -; - CH 2} CH 2 -; - CO-CH 2 -; - CH 2 CH 2 CH 2 -; - O-CH 2 CH 2 -; - S-CH 2 CH 2 -; - O—CH ₂ CH ₂ CH ₂ —; —S—CH ₂ CH ₂ CH ₂ —; or each having a substituent selected from a C _3-8 cycloalkyl group and a C _7-16 aralkyl group on the N atom. May be —NH—CH ₂ CH ₂ — or —CH ₂ —NH—CH ₂ CH ₂ — (preferably —CH ₂ —);
Xc is O;

Xd is CH ₂ ; and
A compound in which R ¹ is a hydroxy group or a C _1-6 alkoxy group (preferably a hydroxy group);

［式中、Ar¹は置換されていてもよいフェニル基または置換されていてもよいインダニル
基を、
Xa¹は結合手または主鎖の原子数が1ないし5個のスペーサーを、
環A²はさらに置換されていてもよいベンゼン環を、
環B²は5ないし7員環を示す。］で表わされる化合物（以下、化合物（Ｉ−2）と略記する
場合もある）。
ここで、Ar¹は、好ましくはハロゲン原子、ニトロ基、カルボキシル基、ハロゲン化さ
れていてもよいＣ_１−６アルキル基、ヒドロキシ−Ｃ_１−６アルキル基、カルボキシ−Ｃ_１−６アルキルカルボニルアミノ−Ｃ_１−６アルキル基、ハロゲン化されていてもよいＣ_１−６アルコキシ基、Ｃ_６−１４アリール基、Ｃ_６−１４アリールオキシ基およびＣ_７−１６アラルキルオキシ基から選ばれる置換基をそれぞれ有していてもよいフェニル基またはインダニル基である。なかでもハロゲン原子、ニトロ基、カルボキシ基、ハロゲン化されていてもよいＣ_１−６アルキル基、ヒドロキシ−Ｃ_１−６アルキル基、カルボキシ−Ｃ_１−６アルキルカルボニルアミノ−Ｃ_１−６アルキル基、ハロゲン化されていてもよいＣ
_１−６アルコキシ基、Ｃ_６−１４アリール基、Ｃ_６−１４アリールオキシ基およびＣ_７−１６アラルキルオキシ基から選ばれる置換基を有していてもよいフェニル基が好ましく、特にハロゲン原子およびハロゲン化されていてもよいＣ_１−６アルキル基から選ばれる置換基を有していてもよいフェニル基が好ましい。
Xa¹は、好ましくは結合手、−Ｏ−、−ＣＨ_２−Ｏ−、−ＣＯ−、−ＣＯＮＨ−、−Ｎ
（ＣＨ_３）ＣＨ_２−、−Ｓ−ＣＨ_２−、−Ｃ＝Ｃ−などである。特に、結合手、−Ｏ−または−ＣＨ_２−Ｏ−が好ましい。
環A²は、好ましくはさらにＣ_１−６アルキル基で置換されていてもよいベンゼン環である。 [Compound B]
formula

[Wherein Ar ¹ represents an optionally substituted phenyl group or an optionally substituted indanyl group;
Xa ¹ is a spacer having 1 to 5 atoms in the bond or main chain,
Ring A ² represents an optionally substituted benzene ring,
Ring B ² represents a 5- to 7-membered ring. ] (It may abbreviate as compound (I-2) hereafter).
Here, Ar ¹ is preferably a halogen atom, a nitro group, a carboxyl group, an optionally halogenated C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, or a carboxy-C _1-6 alkylcarbonylamino. A substituent selected from a -C _1-6 alkyl group, an optionally halogenated C _1-6 alkoxy group, a C _6-14 aryl group, a C _6-14 aryloxy group and a C _7-16 aralkyloxy group; Each of them may be a phenyl group or an indanyl group. Among them, a halogen atom, a nitro group, a carboxy group, an optionally halogenated C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a carboxy-C _1-6 alkylcarbonylamino-C _1-6 alkyl group , C which may be halogenated
_A phenyl group which may have a substituent selected from a _1-6 alkoxy group, a C _6-14 aryl group, a C _6-14 aryloxy group and a C _7-16 aralkyloxy group is preferable, and particularly a halogen atom and a halogen atom The phenyl group which may have a substituent selected from a C _1-6 alkyl group which may be formed is preferable.
Xa ¹ is preferably a bond, —O—, —CH ₂ —O—, —CO—, —CONH—, —N.
(CH ₃ ) CH ₂ —, —S—CH ₂ —, —C═C— and the like. In particular, a bond, —O— or —CH ₂ —O— is preferable.
Ring A ² is preferably a benzene ring which may be further substituted with a C _1-6 alkyl group.

In formula (I-2) and formulas (I-4), (I-1) and (I-3) described later,

［式中、Ar²は置換されていてもよいチアゾリル基を、
Xa²は結合手または主鎖の原子数が1ないし5個のスペーサーを、
環A³はさらに置換されていてもよいベンゼン環を、
環B²は5ないし7員環を示す。］で表わされる化合物（以下、化合物（Ｉ−4）と略記する
場合もある）。
ここで、Ar²は、好ましくはＣ_６−１４アリール基およびＣ_１−６アルキル基から選ば
れる置換基を有していてもよいチアゾリル基（例、２−チアゾリル基）である。
Xa²は、好ましくは−Ｎ（Ｒ⁵）−（ＣＨ_２）ｍ−または−Ｓ−（ＣＨ_２）ｍ−（Ｒ⁵は
水素原子またはＣ_１−６アルキル基を、ｍは０ないし３の整数を示す）が好ましく、なかでも−Ｎ（Ｒ⁵）−（ＣＨ_２）ｍ−が好ましい。
Ｒ⁵としては、メチル、エチル、プロピルなどのＣ_１−３アルキル基が好ましく、特に
メチルが好ましい。
環A³は、好ましくはベンゼン環である。 [Compound C]
formula

[In the formula, Ar ² represents an optionally substituted thiazolyl group,
Xa ² is a spacer having 1 to 5 atoms in the bond or main chain,
Ring A ³ represents an optionally substituted benzene ring,
Ring B ² represents a 5- to 7-membered ring. ] (It may hereafter abbreviate as a compound (I-4)).
Here, Ar ² is preferably a thiazolyl group (eg, 2-thiazolyl group) which may have a substituent selected from a C _6-14 aryl group and a C _1-6 alkyl group.
Xa ² is preferably —N (R ⁵ ) — (CH ₂ ) m— or —S— (CH ₂ ) m— (R ⁵ is a hydrogen atom or a C _1-6 alkyl group, and m is 0 to 3. An integer) is preferable, and —N (R ⁵ ) — (CH ₂ ) m— is particularly preferable.
R ⁵ is preferably a C _1-3 alkyl group such as methyl, ethyl or propyl, and particularly preferably methyl.
Ring A ³ is preferably a benzene ring.

[Compound D]
{6-[(2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -1,2,3,4-tetrahydronaphthalen-1-yl} acetic acid (Example 11);
8-[(2 ′, 6′-dimethylbiphenyl-3-yl) methoxy] -2,3,4,5-tetrahydro-1-benzooxepin-4-carboxylic acid (Example 13);
{5-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1H-inden-1-yl}
Acetic acid (Example 17);
{6-[(2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid (Example 33);
(6-{[3- (2-methyl-1-naphthyl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid (Example 47);
[6-({4-[(2-phenyl-1H-indol-1-yl) methyl] benzyl} oxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid (Example 66);
(6-{[4 ′-(benzyloxy) -2 ′, 6′-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid (Example 70);
(6-{[4 '-(2-Ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid (Example 72) );
(6-{[4 ′-(2-Ethoxyethoxy) -2 ′, 6′-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) calcium acetate (Examples) 73); and
(6-{[6- (Benzyloxy) -2 ′, 6′-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid (Example 75).

［式中、環A⁴は置換されていてもよいベンゼン環を、
pおよびqは独立して置換されていてもよい炭素数０ないし４の炭素鎖を、
Xb¹は結合手または主鎖の原子数が1ないし5個のスペーサーを、
Xc³はO、S、SOまたはSO₂を、
環B²は5ないし7員環を示す。］で表わされる化合物またはその塩（以下、化合物（Ｉ−1
）と略記する場合もある）。
ここで、環A⁴は好ましくは、（１）ハロゲン原子、（２）Ｃ_１−６アルキル基、（３）Ｃ_１−６アルコキシ基、（４）ハロゲン原子、Ｃ_１−６アルキルまたはＣ_１−６アルコキシで置換されていてもよいＣ_６−１４アリール基、（５）Ｃ_６−１４アリールオキシ基および（６）Ｃ_７−１６アラルキルオキシ基から選ばれる置換基を有していてもよいベンゼン環である。

Xb¹は好ましくは結合手である。
Xc³は好ましくはOである。 The present invention further provides a compound represented by the following formula (I-1) and a compound represented by the formula (I-3).
formula

[Wherein ring A ⁴ represents an optionally substituted benzene ring,
p and q independently represent an optionally substituted carbon chain having 0 to 4 carbon atoms,
Xb ¹ is a spacer having 1 to 5 atoms in the bond or main chain,
Xc ³ is O, S, SO or SO ₂ ,
Ring B ² represents a 5- to 7-membered ring. Or a salt thereof (hereinafter referred to as compound (I-1
)).
Here, the ring A ⁴ is preferably (1) a halogen atom, (2) a C _1-6 alkyl group, (3) a C _1-6 alkoxy group, (4) a halogen atom, C _1-6 alkyl or C _{1. It} may have a substituent selected from a C _6-14 aryl group optionally substituted with _-6 alkoxy, (5) C _6-14 aryloxy group and (6) C _7-16 aralkyloxy group. Benzene ring.

Xb ¹ is preferably a bond.
Xc ³ is preferably O.

［式中、環A⁵は置換されていてもよいベンゼン環を、
環A⁶は置換されていてもよい5員複素環を、
環B²は5ないし7員環を示す。］で表わされる化合物またはその塩（以下、化合物（Ｉ−3
）と略記する場合もある）。
ここで、

は、好ましくはハロゲン原子（例、塩素原子）およびハロゲン化されていてもよいＣ_１−６アルキル基（例、メチル、トリフルオロメチル）から選ばれる置換基をそれぞれ有していてもよい、

である。 formula

[Wherein ring A ⁵ represents an optionally substituted benzene ring,
Ring A ⁶ represents an optionally substituted 5-membered heterocyclic ring,
Ring B ² represents a 5- to 7-membered ring. Or a salt thereof (hereinafter referred to as compound (I-3
)).
here,

Each preferably has a substituent selected from a halogen atom (eg, chlorine atom) and an optionally halogenated C _1-6 alkyl group (eg, methyl, trifluoromethyl).

It is.

As a salt of the compound (compound (I), compound (I ′), compound (I-1), compound (I-2), compound (I-3), compound (I-4), etc.) used in the present invention Examples thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine. And the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, p-toluenesulfonic acid and the like.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
Of the above-mentioned salts, pharmaceutically acceptable salts are preferable.

Compound used in the present invention or a salt thereof (Compound (I), Compound (I ′), Compound (I-1), Compound (I-2), Compound (I-3), Compound (I-4), etc.) A prodrug (hereinafter sometimes abbreviated as the compound of the present invention) is a compound that is converted to the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, or hydrolyzed. The compound which raise | generates etc. and changes to this invention compound, The compound which raise | generates a hydrolysis etc. by stomach acid etc. and changes to this invention compound.
As a prodrug of the compound of the present invention, a compound in which the amino group of the compound of the present invention is acylated, alkylated or phosphorylated (for example, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); compounds of the present invention Compounds in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethyl A carbonylated compound, etc.); the carboxy group of the compound of the present invention is esterified, Amidated compounds (for example, the carboxy group of the compound of the present invention is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalated And the like. (E.g., dimethyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound, etc.); A compound in which the carboxy group of the inventive compound is esterified with a C _1-6 alkyl group such as methyl, ethyl or tert-butyl is preferably used. These compounds can be produced from the compound of the present invention by a method known per se.
In addition, the prodrug of the compound of the present invention changes to the compound of the present invention under physiological conditions as described in Hirokawa Shoten 1990 "Pharmaceutical Development" Vol. 7, Molecular Design, pages 163 to 198. Also good.

Below, the manufacturing method of this invention compound is demonstrated.
Unless otherwise specified, each symbol in the schematic diagram in the following reaction formula has the same meaning as described above. Each compound in the reaction formula includes a case where a salt is formed as long as the reaction is not inhibited. Examples of the salt include the same salts as those of the compound used in the present invention.
The compound obtained in each reaction can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation). And can be easily purified by chromatography, etc.).

［式中、Ｘｃ^１はＯまたはＳを、Ｘｃ²はＳＯまたはＳＯ₂を、Ｒ^１ａは置換されていてもよいＣ_１−６アルコキシ基を、Ｌはヒドロキシ基もしくは脱離基を示す］
Ｌで示される脱離基としては、例えばハロゲン原子、ハロゲン化されていてもよいＣ_１−６アルキルスルホニルオキシ基（例：メタンスルホニルオキシ、エタンスルホニルオキシ、トリクロロメタンスルホニルオキシ、トリフルオロメタンスルホニルオキシ）、置換基を有していてもよいＣ_６−１０アリールスルホニルオキシ基［例えば、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基およびニトロ基から選ばれる置換基を１〜３個有していてもよいＣ_６−１０アリールスルホニルオキシ基（例：フェニルスルホニルオキシ、ナフチルスルホニルオキシ）など。好ましくは、フェニルスルホニルオキシ基、ｍ−ニトロフェニルスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基など］、アシルオキシ基（例：トリクロロアセトキシ、トリフルオロアセトキシ）などが挙げられる。 Compound (I) (for example, compounds represented by the following formulas (Ia), (Ia ′), (Ib) and (Ib ′) (compound (Ia), compound (Ia ′), compound (Ib), compound ( Ib ′) can be produced according to, for example, the method shown in the following reaction scheme 1 or a method analogous thereto.
Reaction formula 1

[Wherein, Xc ¹ represents O or S, Xc ² represents SO or SO ₂ , R ^1a represents an optionally substituted C _1-6 alkoxy group, and L represents a hydroxy group or a leaving group]
As the leaving group represented by L, for example, a halogen atom, an optionally halogenated C _1-6 alkylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy) An optionally substituted C _6-10 arylsulfonyloxy group [for example, having 1 to 3 substituents selected from a C _1-6 alkyl group, a C _1-6 alkoxy group, and a nitro group. A C _6-10 arylsulfonyloxy group (eg, phenylsulfonyloxy, naphthylsulfonyloxy) and the like which may be used. Preferred examples include phenylsulfonyloxy group, m-nitrophenylsulfonyloxy group, p-toluenesulfonyloxy group and the like], acyloxy groups (eg, trichloroacetoxy, trifluoroacetoxy) and the like.

<Step 1> Compound (Ia) is a compound represented by formula (II) and a compound represented by formula (III) (
It can be produced by reacting compound (II) and compound (III), respectively).
(I) When L is a hydroxy group, the compound (Ia) is subjected to the Mitsunobu reaction (for example, described in Synthesis, page 1-27, 1981, etc.) with the compound (II) and the compound (III). Can be manufactured. In the reaction, compound (II) and compound (III) are converted into azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipiperidine, and triphenylphosphine, tributyl. The reaction is carried out in the presence of phosphines such as phosphine.
The amount of the azodicarboxylates and phosphines to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (II).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; aromatics such as benzene and toluene Aromatic hydrocarbons; saturated hydrocarbons such as cyclohexane and hexane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; dichloromethane, chloroform, carbon tetrachloride, 1, Halogenated hydrocarbons such as 2-dichloroethane; Nitriles such as acetonitrile and propionitrile; Ketones such as acetone and ethyl methyl ketone; Solvents such as sulfoxides such as dimethyl sulfoxide or a mixed solution thereof And the like are preferable.
The amount of compound (III) to be used is about 0.5 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (II).
The reaction time is usually 5 minutes to 100 hours, preferably 30 minutes to 72 hours. The reaction temperature is usually -20 to 200 ° C, preferably 0 to 100 ° C.

(Ii) When L is a leaving group, the compound (Ia) can be produced by reacting the compound (II) and the compound (III) in the presence of a base.
Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as barium hydroxide; alkali metals such as sodium carbonate, potassium carbonate and cesium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate; acetates such as sodium acetate and ammonium acetate; aromatic amines such as pyridine and lutidine; triethylamine, tripropylamine, tributylamine, N-ethyldiisopropylamine, cyclohexyldimethylamine, 4 -Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine; alkali metal hydrides such as sodium hydride and potassium hydride; And metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide; alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide It is done.
The amount of the base to be used is about 1 to about 10 mol, preferably about 1 to about 3 mol, per 1 mol of compound (II).
This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, those similar to the above “in the case where L is a hydroxy group” are used.
The amount of compound (III) to be used is about 0.8 to about 10 mol, preferably about 0.9 to about 2 mol, per 1 mol of compound (II). Also,
The reaction time is usually 10 minutes to 12 hours, preferably 20 minutes to 6 hours. The reaction temperature is generally −70 to 150 ° C., preferably −20 to 100 ° C.

<Step 2A> Compound (Ib) can be produced by subjecting compound (Ia) to a hydrolysis reaction.
The hydrolysis reaction is performed according to a conventional method using an acid or a base.
Examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trichloride and boron tribromide; and organic acids such as trifluoroacetic acid and p-toluenesulfonic acid. Here, the Lewis acid can be used in combination with thiol or sulfide.
Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as barium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methoxide C 1-6 alkali metal alkoxides such as sodium ethoxide and potassium tert-butoxide; organic bases (including hydrates) such as triethylamine, imidazole and formamidine.
The amount of the acid and base to be used is about 0.5 to about 10 mol, preferably about 0.5 to about 6 mol, per 1 mol of compound (Ia).
The hydrolysis reaction is performed without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol; aromatic hydrocarbons such as benzene and toluene; saturated hydrocarbons such as cyclohexane and hexane; formic acid, Organic acids such as acetic acid; ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dichloromethane, chloroform, carbon tetrachloride, 1,2 -Halogenated hydrocarbons such as dichloroethane; Nitriles such as acetonitrile and propionitrile; Ketones such as acetone and methyl ethyl ketone; Sulfoxides such as dimethyl sulfoxide; Solvents such as water or a mixed solvent thereof are preferable.
The reaction time is usually 10 minutes to 100 hours, preferably 10 minutes to 24 hours. The reaction temperature is usually −10 to 200 ° C., preferably 0 to 120 ° C.

<Step 3A> Compound (Ia ′) oxidizes compound (Ia) in which Xc ¹ is S (for example, 4th edition Experimental Chemistry Course, Vol. 24, 350-352, pages 363-366 (The Chemical Society of Japan) Ed) and the like.
The oxidation reaction is usually performed according to a conventional method using an oxidizing agent.
Examples of the oxidizing agent include hydrogen peroxide, peracetic acid, sodium metaperiodate, potassium permanganate, sodium perborate, metachloroperbenzoic acid (MCPBA), acyl nitrate, dinitrogen tetroxide, halogen, N-bromo. Examples include succinimide (NBS) and N-chlorosuccinimide (NCS).
The amount of the oxidizing agent to be used is about 0.5 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (Ia).
The oxidation reaction is carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol; aromatic hydrocarbons such as benzene and toluene; organic acids such as acetic acid and trifluoroacetic acid; dichloromethane, Halogenated hydrocarbons such as chloroform, carbon tetrachloride and 1,2-dichloroethane; solvents such as water or mixed solvents thereof are preferred.
The reaction time is usually 10 minutes to 100 hours, preferably 10 minutes to 24 hours. The reaction temperature is usually -20 to 150 ° C, preferably 0 to 100 ° C.

<Step 2B> Compound (Ib ′) can be produced by subjecting the compound represented by formula (Ia ′) to a hydrolysis reaction.
This reaction can be carried out in the same manner as in Step 2A or according to a method analogous thereto.

<Step 3B> Compound (Ib ′) is a compound represented by formula (Ib) (compound in which Xc ¹ is S)
Can be produced by subjecting to an oxidation reaction.
The oxidation reaction can be performed in the same manner as in Step 3A or according to a method analogous thereto.

Compound (II) used in Reaction Scheme 1 is, for example, Journal of Medicinal Chemistry (J. Med. Chem.), 39, 4928-4934, 1996; Bioorganic and Medicinal Chemistry (Bioorg. Med. Chem.). 9, Vol. 1325-13
35, 2001; Heterocycles, 41, 647-650,
1995; Journal of Medicinal Chemistry (J. Med. Chem.) 43, 2049-2063, 2000; Journal of Chemical Society Perkin Trans. 1, 2895- It can be produced according to the method described in page 2900, 1996 or the like, or a method analogous thereto.

［式中、Ｌ¹は脱離基を、Ｒ⁶は水素原子または置換されていてもよいＣ_１−６アルコキシ基を、Ｍは水素原子または金属（例えばカリウム、ナトリウム、リチウム、マグネシウム、銅、水銀、亜鉛、タリウム、ホウ素、スズなどを示し、これらは錯化していてもよい）を示す］
Ｌ¹で示される脱離基としては、前記Ｌとして例示したものが用いられる。 Compound (III) used in Reaction Scheme 1 can be easily obtained as a commercial product, and can also be produced according to a method known per se.
For example, among the compounds (III), Xa is — (CH ₂ ) _k1 -Q— (CH ₂ ) _k2 − (the symbols are as defined above), and Xb is Xba—CH ₂ (Xba is a bond or main bond). Compound (III ′) (which may be abbreviated as “Compound (III ′)” hereinafter), which is a spacer having a chain atom number of 1 to 4 atoms, is, for example, the method shown in Reaction Scheme 2 or a modification thereof It can be manufactured according to the method.
The “spacer having 1 to 4 atoms in the main chain” represented by Xba is the “spacer having 1 to 5 atoms in the main chain” exemplified as Xa, and “the number of atoms in the main chain is 1”. "Three things" are used.
Reaction formula 2

[Wherein, L ¹ represents a leaving group, R ⁶ represents a hydrogen atom or an optionally substituted C _1-6 alkoxy group, M represents a hydrogen atom or a metal (for example, potassium, sodium, lithium, magnesium, copper, Mercury, zinc, thallium, boron, tin, etc., which may be complexed)]
As the leaving group for L ¹ , those exemplified for the aforementioned L can be used.

<Step 4> Compound (VI) is prepared by reacting (i) compound (IV-1) with compound (V-1) or (ii) compound (IV-2) and compound (V-2). It can manufacture by making these react. Hereinafter, unless specifically limited, compound (IV-1) and compound (IV-2) are collectively referred to as compound (IV), and compound (V-1) and compound (V-2) are not particularly limited. As long as it is collectively referred to as compound (V).
The reaction between compound (IV) and compound (V) is usually performed in the presence of a base. As the base,
For example, alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; carbonic acid Alkali metal carbonates such as sodium and potassium carbonate; alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide and sodium tert-butoxide; For example, trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2. ] Organic bases such as octane and 1,8-diazabicyclo [5.4.0] -7-undecene; Organic lithiums such as methyllithium, n-butyllithium, sec-butyllithium and tert-butyllithium; Lithium diisopropyl And lithium amides such as amides (including hydrates).
The reaction between compound (IV) and compound (V) is advantageously carried out using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol; dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether Ethers such as ethylene glycol-dimethyl ether; esters such as ethyl formate, ethyl acetate, and n-butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; n-hexane, benzene, toluene, and the like Hydrocarbons; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide; nitriles such as acetonitrile and propionitrile; dimethylsulfo Sulfoxides such as Sid; sulfolane; hexamethylphosphoramide; and solvent, or a mixed solvent such as water is preferred.
The reaction between the compound (IV) and the compound (V) can be promoted using a metal catalyst. As the metal catalyst, metal complexes having various ligands are used. For example, palladium compounds [eg, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) chloride. Palladium (II), dichlorobis (triethylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, palladium acetate (II) and 1
, 1′-bis (diphenylphosphino) ferrocene complex, etc.]; nickel compounds [eg, tetrakis (triphenylphosphine) nickel (0), bis (triethylphosphine) chloride
Nickel (II), bis (triphenylphosphine) nickel (II) chloride, etc.]; Rhodium compounds (eg, tris (triphenylphosphine) rhodium (III) chloride); Cobalt compounds; Copper (II) and the like]; platinum compounds and the like. Of these, palladium compounds, nickel compounds and copper compounds are preferred. The amount of these metal catalysts to be used is about 0.000001 to about 5 mol, preferably about 0.0001 to about 1 mol, per 1 mol of compound (IV). When a metal catalyst unstable to oxygen is used in this reaction, the reaction is preferably performed in an inert gas (for example, argon gas or nitrogen gas) stream.
The amount of compound (V) to be used is about 0.1 to about 10 mol, preferably about 0.5 to about 2 mol, per 1 mol of compound (IV). The amount of the base to be used is about 1 to about 20 mol, preferably about 1 to about 5 mol, per 1 mol of compound (IV).
The reaction temperature is -10 to 250 ° C, preferably 0 to 150 ° C. The reaction time varies depending on the type of compound (IV), compound (V), metal catalyst, base or solvent, reaction temperature, etc.
Minutes to 200 hours, preferably 5 minutes to 100 hours.

<Step 5> Compound (III ′) can be produced from compound (VI).
Compound (III ′) in which L is a hydroxy group can be produced by subjecting compound (VI) to a reduction reaction.
The reduction reaction is usually performed according to a conventional method using a reducing agent.
Examples of the reducing agent include metal hydrides such as aluminum hydride, diisobutylaluminum hydride and tributyltin hydride; sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, lithium aluminum hydride and the like. Metal-hydrogen complex compounds; Borane complexes such as borane tetrahydrofuran complex and borane dimethyl sulfide complex; alkylboranes such as texylborane and diciamylborane; diboranes; metals such as zinc, aluminum, tin and iron; alkali metals / liquids such as sodium and lithium Examples include ammonia (Birch reduction).
The amount of reducing agent used is appropriately determined depending on the type of reducing agent. For example, the amount of metal hydride, metal hydrogen complex compound, borane complex, alkylborane or diborane used is about 0.25 to about 10 moles, preferably about 0.5 to about 10 moles per mole of compound (VI). The amount of the metal (including the alkali metal used in Birch reduction) is about 1 to about 20 equivalents, preferably about 1 to about 5 equivalents, per 1 mol of compound (VI).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol; diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1 Ethers such as 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene and toluene; saturated hydrocarbons such as cyclohexane and hexane; N, N-dimethylformamide and N, N-dimethylacetamide Amides such as hexamethylphosphoric triamide; solvents such as formic acid, acetic acid, propanoic acid, trifluoroacetic acid, organic acids such as methanesulfonic acid, and mixed solvents thereof are preferred.
While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min to 100 hr, preferably 30 min to 50 hr. The reaction temperature is usually -20 to 100 ° C, preferably 0 to 80 ° C.

Compound (III ′) in which L is a leaving group can be produced by reacting compound (III ′) in which L is a hydroxy group with a halogenating agent or sulfonylating agent.
Examples of the halogenating agent include thionyl chloride and phosphorus tribromide. Compound (III ′) in which L is a halogen atom (eg, chlorine, bromine, etc.) by reaction with a halogenating agent
) Can be manufactured.
The reaction of compound (III ′) with a halogenating agent is usually performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether, diisopropyl ether, tert-butyl methyl ether , Ethers such as tetrahydrofuran, dioxane, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, n-butyl acetate, and tert-butyl acetate. An excessive amount of a halogenating agent may be used as a solvent.
The amount of the halogenating agent to be used is generally about 1 to about 10 mol per 1 mol of compound (III ′). The reaction temperature is usually -20 to 100 ° C. The reaction time is usually 0.5 to 24 hours.
Examples of the sulfonylating agent include methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like. By reaction with a sulfonylating agent, a compound (III ′) in which L is, for example, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, or the like can be produced.
The amount of the sulfonylating agent to be used is generally about 1 to about 10 mol per 1 mol of compound (III ′).
The reaction of compound (III ′) with a sulfonylating agent is usually carried out in the presence of a base in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether, diisopropyl ether, tert-butyl methyl ether , Ethers such as tetrahydrofuran, dioxane, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, n-butyl acetate, and tert-butyl acetate.
Examples of the base include amines such as triethylamine and N-methylmorpholine; and alkali metal salts such as sodium hydrogen carbonate, potassium hydrogen carbonate and potassium carbonate.
The amount of the base to be used is generally about 1 to about 10 mol per 1 mol of compound (III ′).
The reaction temperature is usually -20 to 100 ° C. The reaction time is usually 0.5 to 24 hours.

Compound (I-2) can be produced, for example, according to the method shown in the following reaction scheme 3 or a method analogous thereto.
Reaction formula 3

<Step 6> Compound (IX) can be produced in the same manner as in Step 1 from compound (VII) and compound (VIII).
Compound (VII) and compound (VIII) can be easily obtained commercially,
It can also be produced according to a method known per se or a method analogous thereto.
<Step 7> Compound (I-2) can be produced in the same manner as in Step 2A from compound (IX).

Compound (I-4) can be produced, for example, according to the method shown in the following reaction scheme 4 or a method analogous thereto.
Reaction formula 4

<Step 8> Compound (XI) can be produced in the same manner as in Step 1 from compound (VII) and compound (X).
Compound (X) is easily commercially available, and can also be produced according to a method known per se or a method analogous thereto.
<Step 9> Compound (I-4) can be produced from compound (XI) in the same manner as in Step 2A.

Among compounds (I-4), a compound in which Xa ² is —N (R ⁵ ) — (CH ₂ ) m— is produced, for example, according to the method shown in the following Reaction Scheme 5 or a method analogous thereto. You can also.
Reaction formula 5

<Step 10> Compound (XIII) can be produced in the same manner as in Step 1 from compound (VII) and compound (XII).
<Step 11> Among compounds (XV), a compound in which Xa is —N (R ⁵ ) — (CH ₂ ) m—
In the same manner as in Step 4, it can also be produced from compound (XIII) and compound (XIV).
Compounds (XII) and (XIV) which are commercially available can be easily obtained, and can also be produced according to a method known per se or a method analogous thereto.
<Step 12> Among compounds (I-4), the compound in which Xa is —N (R ⁵ ) — (CH ₂ ) m— is the same as in Step 2A, and Xa is —N (R ⁵ ) — (CH ₂ ) It can be produced from compound (XV) which is m-.

Below, the manufacturing method of compound (I-1) and compound (I-3) is demonstrated.
Compound (I-1) can be produced, for example, according to the method shown in the following reaction scheme 6 or a method analogous thereto.
Compounds (XVI), (XVII), (XVIII) and (XIX) can be easily obtained commercially, and can also be produced according to a method known per se or a method analogous thereto.

Reaction formula 6

Compound (XVII) can be produced by reducing the carbonyl group of compound (XVI).
Examples of the reducing agent used for the reduction include those exemplified in Step 5 above. The amount of reducing agent used is, for example, compound (XVI) 1 in the case of metal hydrides and metal hydrogen complex compounds.
About 1 to about 10 moles, preferably about 1 to about 5 moles per mole, and in the case of borane complexes, alkylboranes or diborane, about 1 to about 10 moles per mole of compound (XVI), preferably Is about 1 to about 5 moles, and in the case of metals, about 1 to about 20 equivalents, preferably about 1 to about 5 equivalents. In this reaction, Lewis acids may be used if desired. Examples of the “Lewis acids” include aluminum chloride, aluminum bromide, titanium (IV) chloride, tin (II) chloride, zinc chloride, boron trichloride, boron tribromide, boron trifluoride and the like. The amount of the Lewis acid to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (XVI).
It can also be reduced by a hydrogenation reaction. In this case, for example, a catalyst such as palladium carbon, platinum (IV) oxide, Raney nickel, Raney cobalt or the like is used. The amount of the catalyst to be used is about 5 to about 1000% by weight, preferably about 10 to about 3%, per 1 mol of compound (XVI).
00% by weight. Various hydrogen sources can be used instead of gaseous hydrogen. Examples of the “hydrogen source” include formic acid, ammonium formate, triethylammonium formate, sodium phosphinate, hydrazine and the like. The amount of the hydrogen source to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (XVI).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, but alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4 -Ethers such as dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide , Solvents such as organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid or a mixed solvent thereof are preferable.
While the reaction time varies depending on the kind and amount of reducing agent used or the activity and amount of catalyst, it is generally about 1 hour to about 100 hours, preferably about 1 hour to about 50 hours. The reaction temperature is usually about −20 to about 120 ° C., preferably about 0 to about 80 ° C. When a hydrogenation catalyst is used, the hydrogen pressure is usually about 1 to about 100 atmospheres.

Compound (XVIII) can be produced by converting the hydroxy group of compound (XVII) to a “leaving group”.
When the “leaving group” represented by L is a halogen atom, examples of the halogenating agent used for halogenation include halogenated thionyls such as thionyl chloride and thionyl bromide, halogens such as phosphoryl chloride and phosphoryl bromide. Phosphoryl halides, phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide, phosphorus tribromide and other halogenated phosphorus, oxalyl halides such as oxalyl chloride, and phosgene. The halogenating agent is used in an amount of about 0.1 to about 30 mol, preferably about 0.2 to about 10 mol, per 1 mol of compound (XVII).
This reaction is carried out in the presence of a base if desired. Examples of the “base” include triethylamine, tripropylamine, tributylamine, N-ethyldiisopropylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N -Tertiary amines such as methyl morpholine. The base is used in an amount of about 1 to about 20 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XVII).
This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, hydrocarbons such as benzene, toluene, cyclohexane, hexane, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- Ethers such as dimethoxyethane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, halogenated carbonization such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane A solvent such as hydrogen or a mixed solvent thereof is preferable.
The reaction time is usually about 10 minutes to about 12 hours, preferably about 10 minutes to about 5 hours. The reaction temperature is generally about −10 to about 200 ° C., preferably about −10 to about 120 ° C.
In the case where the “leaving group” represented by L is a C _1-6 alkylsulfonyloxy group which may be halogenated or a C _6-10 arylsulfonyloxy group which may have a substituent, a sulfonylating agent Examples thereof include halogenated C _1-6 alkylsulfonyl such as methanesulfonyl chloride, halogenated C _6-10 arylsulfonyl such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, and the like. The sulfonylating agent is used in an amount of about 1 to about 20 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XVII).

This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, hydrocarbons such as benzene, toluene, cyclohexane, hexane, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- Solvents such as ethers such as dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, esters such as methyl acetate, ethyl acetate, butyl acetate, or a mixed solvent thereof. preferable.
This reaction is carried out in the presence of a base if desired. Examples of the “base” include triethylamine, tripropylamine, tributylamine, N-ethyldiisopropylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N -Tertiary amines such as methylmorpholine, inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, ammonium acetate And basic salts. The base is used in an amount of about 1 to about 20 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XVII).
The reaction time is usually about 10 minutes to about 12 hours, preferably about 10 minutes to about 5 hours. The reaction temperature is usually about −30 to about 150 ° C., preferably about −20 to about 100 ° C.
Compound (XX) can be produced by condensing compound (XVIII) and compound (XIX) in the presence of a base when Xb ¹ -Xc ³ is an oxygen atom or a sulfur atom.

Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and ammonium acetate. Salts, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, N-ethyldiisopropylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, Tertiary amines such as N-methylpyrrolidine and N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide , Na Potassium methoxide, sodium ethoxide, sodium tert- butoxide, and metal alkoxides such as potassium tert- butoxide. These bases are used in an amount of about 1-10 mol, preferably about 1-3 mol, per 1 mol of compound (XVIII).
This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1, Ethers such as 4-dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, etc. Amides, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, esters such as methyl acetate, ethyl acetate, and butyl acetate, and dimethyl sulfoxide Sulfoxides, such as solvent, or a mixed solvent thereof, such as water is preferred.
The reaction time is usually about 10 minutes to about 12 hours, preferably about 20 minutes to about 6 hours. The reaction temperature is usually about −50 to about 150 ° C., preferably about −20 to about 100 ° C.

Compound (XX) can also be produced by condensing compound (XVII) and compound (XIX) in the presence of a dehydrating agent, if desired, when Xb ¹ -Xc ³ is an oxygen atom or a sulfur atom.
Examples of the dehydrating agent used in this reaction include hydrochloric acid, sulfuric acid, phosphoric acid, potassium hydrogen sulfate, oxalic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ether complex and other acidic catalysts, Examples thereof include basic catalysts such as sodium and potassium hydroxide. Further, for example, carbodiimides such as N, N′-dicyclohexylcarbodiimide, alumina, sodium dioxide, phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, etc. may be used. Good. These acids and bases are present in an amount of about 0.1 per mol of compound (XIX).
-10 mol, preferably about 0.1-5.0 mol.
This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, but for example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and organic such as formic acid and acetic acid. Preferred are acids, hydrocarbons such as benzene, toluene, cyclohexane, hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, or a mixed solvent thereof. .
The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually 0 to 200 ° C, preferably 0 to 150 ° C.

Compound (XX) can also be produced by subjecting compound (XVII) and compound (XIX) to Mitsunobu reaction when Xb ¹ -Xc ³ is an oxygen atom.
This reaction is carried out in the same manner as in Step 1.

  Compound (I-1) can be produced in the same manner as in Step 2A from compound (XX).

化合物（XXI）は市販されているものを容易に入手でき、また、自体公知の方法または
これらに準じた方法に従って製造することもできる。
化合物（XXII）は、化合物（VII）と化合物（XXI）から工程１と同様にして製造するこ
とができる。
化合物（Ｉ−３）は、化合物（XXII）から工程２Ａと同様にして製造することができる。 Compound (I-3) of the present invention can be produced, for example, according to the method shown in the following Reaction Scheme 7 or a method analogous thereto.
Reaction formula 7

Compound (XXI) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.
Compound (XXII) can be produced in the same manner as in Step 1 from compound (VII) and compound (XXI).
Compound (I-3) can be produced from compound (XXII) in the same manner as in Step 2A.

In each of the above reactions, when the raw material compound has an amino group, carboxyl group, hydroxy group, or mercapto group as a substituent, a protective group generally used in peptide chemistry or the like may be introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction.
Examples of the protecting group for the amino group include a formyl group; a C _1-6 alkyl-carbonyl group (for example, acetyl, propionyl, etc.) each optionally having a substituent, a benzoyl group, and a C _1-6 alkoxy-carbonyl. Groups (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), etc.), allyloxycarbonyl groups (Alo
c), phenyloxycarbonyl group, fluorenylmethyloxycarbonyl group (Fmoc), C _7-10 aralkyloxy-carbonyl group (eg benzyloxycarbonyl etc.), trityl group, phthaloyl group, dithiasuccinoyl group, N , N-dimethylaminomethylene group and the like are used. Here, examples of the substituent include a phenyl group, a halogen atom, a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, valeryl, etc.),
An optionally halogenated C _1-6 alkoxy group, a nitro group or the like is used, and the number of substituents is about 1 to 3.

As the protecting group for the carboxyl group, for example, a C _1-6 alkyl group, an allyl group, a benzyl group, a phenyl group, a trityl group, a trialkylsilyl group, etc., each of which may have a substituent, are used. Here, as the substituent, for example, a halogen atom, a formyl group, a C _1-6 alkyl-carbonyl group (for example, acetyl, propionyl, butylcarbonyl, etc.)
An optionally halogenated C _1-6 alkoxy group, a nitro group, a C _1-6 alkyl group, a C _6-10 aryl group (eg, phenyl, naphthyl, etc.) and the like, and the number of substituents is 1 Or about three.
Examples of the protecting group for the hydroxy group include a formyl group, or a C _1-6 alkyl group, a C _7-10 aralkyl group, and a C _1-6 alkyl-carbonyl group (for example, acetyl, each optionally having a substituent). Propionyl etc.), benzoyl group, phenyloxycarbonyl group, C _7-10 aralkyloxy-carbonyl group (eg benzyloxycarbonyl etc.), C _7-10 aralkyl-carbonyl group (eg benzylcarbonyl etc.), tetrahydropyranyl group , Tetrahydrofuranyl group, furanyl group, silyl group and the like are used. Here, examples of the substituent include a halogen atom, a C _1-6 alkyl group, a C _7-10 aralkyl group (eg, benzyl), a C _6-10 aryl group (eg, phenyl, naphthyl etc.), C _{1- A 6} alkoxy group, a nitro group or the like is used, and the number of substituents is about 1 to 4.
Examples of the protecting group for the mercapto group include a C _1-6 alkyl group and a C _7-20 aralkyl group (for example, benzyl, trityl) each optionally having a substituent. Here, as the substituent, for example, a halogen atom, a C _1-6 alkyl group, a phenyl group, a C _7-10 aralkyl group (for example, benzyl etc.), a C _1-6 alkoxy group, a nitro group, etc. are used. The number of groups is 1 to 4.

As a method for removing the protecting group, a method known per se or a method similar thereto is used. For example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate ( II) or the like or a reduction reaction is used.
In each of the above reaction steps, if desired, hydrolysis reaction, deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, and substituent exchange reaction are each independently performed. Alternatively, the compound of the present invention can be synthesized by performing a combination of two or more thereof. As these reactions, for example, a method described in New Experimental Chemistry Course 14, Vol. 15, 1977 (Maruzen Publishing) is adopted.

When the desired product is obtained in the free state by the above reaction, it may be converted into a salt according to a conventional method. When it is obtained as a salt, it may be converted into a free form or other salt according to a conventional method. You can also. The compound of the present invention thus obtained can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like.
When the compound of the present invention exists as a configurational isomer (configuration isomer), diastereomer, conformer or the like, each can be isolated by the above-described separation and purification means, if desired. When the compound of the present invention is a racemate, it can be separated into an S form and an R form by a conventional optical resolution means.
When a stereoisomer exists in the compound of the present invention, the case where this isomer is a single isomer or a mixture thereof is also included in the present invention.
The compound of the present invention may be a hydrate or non-hydrate.
The compound of the present invention may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S) and the like.

The compound of the present invention or a prodrug thereof has a GPR40 receptor function-modulating action, particularly GPR40 receptor agonist activity, has low toxicity and has few side effects, and therefore is a safe GPR40 receptor function regulator, preferably Useful as a GPR40 agonist.
The compound of the present invention or a prodrug thereof has an excellent GPR40 receptor function regulating action on mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). Therefore, it is useful as a regulator of physiological functions involving the GPR40 receptor or a prophylactic / therapeutic agent for a disease state or disease involving the GPR40 receptor.
Specifically, the compound of the present invention or a prodrug thereof is useful as an insulin secretion regulator (preferably an insulin secretagogue), a hypoglycemic agent, and a pancreatic β cell protective agent.
In particular, the compounds of the present invention and their prodrugs are useful as blood glucose level-dependent insulin secretagogues based on their GPR40 receptor agotanist activity. That is, the compounds of the present invention and prodrugs thereof are useful as insulin secretagogues that do not cause hypoglycemia, unlike sulfonylureas.
Further, the compound of the present invention or a prodrug thereof is, for example, diabetic, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction, skin disease, Arthropathy, osteopenia, arteriosclerosis, thrombotic disease, dyspepsia, memory learning disorder, obesity, hypoglycemia, hypertension, edema, insulin resistance, unstable diabetes, fat atrophy, insulin allergy, insulinoma, lipotoxicity, Hyperinsulinemia, diseases such as cancer, especially diabetes, impaired glucose tolerance, ketosis, acidosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, sexual dysfunction, skin disease, joint It is useful as a prophylactic / therapeutic agent for diseases such as symptom, osteopenia, arteriosclerosis, thrombotic disease, dyspepsia and memory learning disorder. Here, diabetes includes insulin-dependent (type I) diabetes, non-insulin-dependent (type II) diabetes and gestational diabetes. Hyperlipidemia includes hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia, and the like.

Regarding the criteria for determining diabetes, a new criterion was reported in 1999 by the Japan Diabetes Society.
According to this report, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. This is a state in which the blood glucose level (glucose concentration in venous plasma) is at least 200 mg / dl as needed. In addition, it does not correspond to the above-mentioned diabetes, and “a fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl. A state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
As for the criteria for determining diabetes, new criteria were reported from ADA (American Diabetes Association) in 1997 and from WHO in 1998.
According to these reports, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.
According to the above report, glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl, and a 75-g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose) is a state where the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.
The compound of the present invention or a prodrug thereof is also used as a prophylactic / therapeutic agent for diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above new criteria. . Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.

The compound of the present invention or a prodrug thereof has low toxicity, and the compound of the present invention or a prodrug thereof is used as it is or a pharmacologically acceptable carrier in accordance with a method known per se generally used as a method for producing a pharmaceutical preparation. For example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release pharmaceutical preparations, It can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.).
The content of the compound of the present invention in the pharmaceutical preparation is about 0.01 to about 100% by weight of the whole preparation. The dose varies depending on the administration subject, administration route, disease, symptom, and the like. For example, for a diabetic patient (body weight: about 60 kg), about 0.0 as an active ingredient [the compound of the present invention] per day.
1 to about 30 mg / kg body weight, preferably about 0.1 to about 20 mg / kg body weight, more preferably about 1 to about 20 mg / kg body weight may be orally administered in 1 to several times a day.

Examples of the pharmacologically acceptable carrier that may be used in the production of the medicament of the present invention include various organic or inorganic carrier substances that are conventionally used as a preparation material. For example, excipients, lubricants in solid preparations, Examples include binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers, and soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
Examples of soothing agents include benzyl alcohol.
Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

Furthermore, the compound of the present invention or a prodrug thereof can be used in combination with a drug other than the compound of the present invention.
Examples of a drug that can be used in combination with the compound of the present invention (hereinafter sometimes abbreviated as a concomitant drug) include, for example, other therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, anti-obesity agents Agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, immunomodulators, anti-inflammatory agents, antithrombotic agents, osteoporosis treatment agents, antibacterial agents, antifungal agents, antiprotozoal agents, antibiotics, antitussives / stagnation agents, sedatives , Anesthetic, anti-ulcer, tranquilizer, antipsychotic, antitumor, muscle relaxant, antiepileptic, antidepressant, antiallergic, cardiotonic, antiarrhythmic, vasodilator, vasoconstrictor , Narcotic antagonist, vitamin drug, vitamin derivative, anti-asthma drug, anti-dementia drug, frequent urination / urinary incontinence drug, dysuria drug, atopic dermatitis drug, allergic rhinitis drug, pressor drug, endotoxin antagonist Drug or antibody, signal transduction inhibitor, inflammatory mediator Tar action inhibitors, inflammatory mediator action suppressing antibodies, anti-inflammatory mediator action suppressing drugs, anti-inflammatory mediator action suppressing antibodies. Specific examples include the following.

Other therapeutic agents for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragments or derivatives (eg, INS-1 etc.), oral insulin preparations, etc., insulin sensitivity enhancers (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Reglixane (JTT-501), Netoglitazone (MCC-555), GI-262570, KRP-297, FK-614, Riboglitazone (CS-011), (γE) -γ- [[[4-[(5-Methyl-2-phenyl-4-oxazolyl) methoxy] phenyl] methoxy] imino] benze Nbutanoic acid, etc., WO99 / 58510
Compounds described in (for example (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid), compounds described in WO01 / 38325, Tesaglitazar (AZ-242), Ragaglitazar (NN-622), Muraglitazar (BMS-298585), ONO-5816, BM-13-1258, LM-4156, MBX-102, LY- 519818, MX-6054, LY-510929, Balaglitazone (NN-2344), T-131 or a salt thereof, THR-0921), α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate, etc.) , Biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylsulfonylates (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopi Amide, glimepiride, etc.), repaglinide, senagrinide, mitiglinide or its calcium salt hydrate, nateglinide, etc.], GLP-1 receptor agonist [eg, GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin- 4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ , CJC-1131, etc.], dipeptidyl peptidase IV inhibitor (eg, NVP-DPP-278, PT-100, P32) / 98, P93 / 01, NVP-DPP-728, LAF237, TS-021, etc.), β3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9679, AZ40140, etc.), Amylin agonist (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitor (eg, vanadic acid, etc.), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist) ), SGLT (sodium-glucose cotransporter) inhibitors (eg, T-1095, etc.), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, etc.), adiponectin or agonists thereof, IKK inhibitors (eg, AS- 2868), leptin resistance improving drug, somatostatin receptor agonist (compound described in WO01 / 25228, WO03 / 42204, compound described in WO98 / 44921, WO98 / 45285, WO99 / 22735, etc.), glucokinase activator ( Examples include Ro-28-1675).
Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minarerestat (ARI-509), CT-112, etc.), nerves Nutritional factor and its increasing drug (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg 4- (4-chlorophenyl) -2- (2-methyl-1- Imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole etc.), protein kinase C (PKC) inhibitors (eg LY-333531 etc.), AGE inhibitors (eg ALT-945, pimagedin) , Pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, ALT-711, pyridorin, pyridoxa Active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, thioprid, etc.), somatostatin receptor agonists (BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitors Etc.

Antihyperlipidemic agents include statins that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or their salts (eg, sodium salt, etc.)), squalene synthase inhibition Agents (eg, compounds described in WO97 / 10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxy) Phenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrates (eg, bezafibrate, clofibrate) , Simfibrate, clinofibrate, etc.), antioxidants (eg, lipoic acid, probucol) and the like.
Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, losartan, candesartan cilexetil, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1-[[2 ' -(2,5-Dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid Etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), clonidine and the like.
Examples of anti-obesity agents include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex; MCH receptor antagonist (Eg, SB-568849; SNAP-7941; compounds included in WO01 / 82925 and WO01 / 87834, etc.); neuropeptide Y antagonists (eg, CP-422935, etc.); cannabinoid receptor antagonists (eg, SR-141716) SR-147778, etc.); Ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498 etc.), pancreatic lipase inhibitor (eg, orlistat, ATL-962 etc.), β3 agonist (eg, CL) -316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), peptidic appetite suppressant Example, leptin, CNTF
(Ciliary neurotrophic factor) etc.), cholecystokinin agonists (eg, lynchtrypto, FPL-15849 etc.), antifeedants (eg, P-57 etc.) and the like.
Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, Methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, Examples include ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), Plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like can be mentioned. Of these, 5-fluorouracil derivatives such as furuluron or neofluturon are preferable.
Examples of immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques ( Examples include interferons, interleukins (IL), etc., colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), and interleukins such as IL-1, IL-2, IL-12 among others. Is preferred.
Examples of the anti-inflammatory drug include non-steroidal anti-inflammatory drugs such as aspirin, acetaminophen, and indomethacin.
Examples of the antithrombotic agent include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban), thrombus Soluble drugs (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride)
Cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, etc.).
Examples of osteoporosis therapeutic agents include alfacalcidol, calcitriol, elcatonin, salmon calcitonin salmon, estriol, ipriflavone, pamidronate disodium. ), Alendronate sodium hydrate, incadronate disodium, and the like.
Examples of vitamin drugs include vitamin B1 and vitamin B12.
Examples of the anti-dementia agent include tacrine, donepezil, rivastigmine, galantamine and the like.
For example, flavoxate hydrochloride is a therapeutic drug for frequent urination and urinary incontinence.
), Oxybutynin hydrochloride, propiverine hydrochloride and the like.
Examples of dysuria therapeutic agents include acetylcholinesterase inhibitors (eg, distigmine).

Furthermore, drugs that have been shown to improve cachexia in animal models and clinically, ie, cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, 49, 5935-5939, 1989] ], Progesterone derivatives (e.g.,
Megesterol acetate) [Journal of Clinical Oncology, Vol. 12, 213-225, 1994], carbohydrate steroids (eg, dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinol drugs (The literature is the same as above), fat metabolism improving agent (eg, eicosapentaenoic acid, etc.) [British Journal of Cancer, Vol. 68, pages 314-318, 1993], growth Antibodies against hormones, IGF-1, or cachexia-inducing factors such as TNF-α, LIF, IL-6, and oncostatin M can also be used in combination with the preparation of the present invention.
Furthermore, glycation inhibitors (eg, ALT-711, etc.), nerve regeneration promoters (eg, Y-128, VX853, prosaptide, etc.), antidepressants (eg, desipramine, amitriptyline, imipramine), antiepileptic drugs (eg,
Eg, lamotrigine), antiarrhythmic drug (eg, mexiletine), acetylcholine receptor ligand (eg, ABT-594), endothelin receptor antagonist (eg, ABT-627), monoamine uptake inhibitor (eg, tramadol), narcotic Sex analgesics (eg, morphine), GABA receptor agonists (eg, gabapentin), α2 receptor agonists (eg, clonidine), local analgesics (eg, capsaicin), anxiolytics (eg, benzothiazepine) In addition, phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, apomorphine) and the like can also be used in combination with the compound of the present invention.

By combining the compound of the present invention and a concomitant drug,
(1) The dose can be reduced compared to the case where the compound of the present invention or the concomitant drug is administered alone.
(2) A drug to be used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.),
(3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer.
(4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained.
(5) By using the compound of the present invention and the concomitant drug in combination, excellent effects such as a synergistic effect can be obtained.
Hereinafter, when the compound of the present invention and a concomitant drug are used in combination, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject. Alternatively, administration may be performed with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
As the administration form of the compound of the present invention and the concomitant drug, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) separate administration of the compound of the present invention and the concomitant drug Simultaneous administration of the two preparations obtained by formulation into the same administration route, (3) Time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug. (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Formulating the compound of the present invention and the concomitant drug separately Administration of the two types of preparations obtained at different times by different administration routes (for example, the compound of the present invention; administration in the order of concomitant drugs, or administration in the reverse order).

The present invention is further described in detail by the following reference examples, examples, formulation examples and experimental examples, but these examples are merely examples and do not limit the present invention, and the scope of the present invention is not limited. You may change in the range which does not deviate.
In the following Reference Examples and Examples, “room temperature” usually indicates about 10 ° C. to about 35 ° C. % Represents mol / mol% in yield,% by volume for solvents used in chromatography, and% by weight for others. The proton NMR spectrum which cannot be confirmed by broad such as OH and NH protons is not described in the data.
Other abbreviations used in the text have the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl ₃ : Deuterated chloroform
DMSO-d ₆ : Heavy dimethyl sulfoxide
¹ H NMR: Proton nuclear magnetic resonance

In the following Reference Examples and Examples, the melting point, mass spectrum (MS) and nuclear magnetic resonance spectrum (NMR) were measured under the following conditions.
Melting point measuring instrument: Yanagimoto trace melting point measuring instrument or Buch melting point measuring instrument B-545 type was used.
MS measuring instrument: Waters ZMD, Waters ZQ2000 or Micromass Platform II ionization method: Electron Spray Ionization (ESI), or Atmospheric Pressure Chemical Ionization (APCI). ESI was used unless otherwise specified.
NMR measuring instrument: Varian Gemini 200 (200 MHz), Varian Gemini 300 (300 MHz), Bruker Biospin AVANCE 300.

Further, purification by preparative HPLC in Reference Examples and Examples was performed under the following conditions.
Preparative HPLC instrument: Gilson high-throughput purification system Column: YMC Combiprep ODS-A S-5 μm, 20 X 50 mm
Solvent: Liquid A; water containing 0.1% trifluoroacetic acid,
B solution: 0.1% trifluoroacetic acid-containing acetonitrile gradient cycle A: 0.00 minutes (A solution / B solution = 90/10), 1.20 minutes (A solution / B solution = 90/10), 4.75 minutes (A solution / B solution) = 0/100), 7.30 minutes (A liquid / B liquid = 0/100), 7.40 minutes (A liquid / B liquid = 90/10), 7.50 minutes (A liquid / B liquid = 90/10).
Gradient cycle B: 0.00 minutes (A liquid / B liquid = 95/5), 1.00 minutes (A liquid / B liquid = 95/5), 5.20 minutes (A liquid / B liquid = 5/95), 6.40 minutes (A Liquid / B liquid = 5/95), 6.50 minutes (A liquid / B liquid = 95/5), 6.60 minutes (A liquid / B
Liquid = 95/5).
Flow rate: 25 ml / min, detection method: UV 220nm

4-(ベンジルオキシ)-2-ヒドロキシベンズアルデヒド(5.8 g)、4-ブロモ酪酸エチル (7.1 mL)、炭酸カリウム (10.5 g)、よう化ナトリウム (3.8 g) を N,N-ジメチルホルムアミド(50 mL) に加え、室温、一晩撹拌した。水中に注ぎ、酢酸エチルで抽出した。有機層を
水、食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン) で精製し、表題化合物 (8.2 g) を油状
物として得た。
¹H NMR (CDCl₃) δ： 1.26(3H, t), 2.14-2.23(2H, m), 2.53(2H,t), 4.06-4.20(4H, m),
5.12(2H, s), 6.53(1H, d), 6.62(1H, dd), 7.34-7.45(5H, m),7.81(1H, d)。
参考例２ 8-(ベンジルオキシ)-2，3-ジヒドロ-1-ベンゾオキセピン-4-カルボン酸エチル

4-[5-(ベンジルオキシ)-2-ホルミルフェノキシ]酪酸エチル(8.2 g) を炭酸ジエチル (100 mL) に溶かし、カリウム t-ブトキシド (4 g) を加え、室温で一晩撹拌した。1 M 塩
酸を加え濃縮し、酢酸エチルで抽出した。有機層を水、食塩水で洗浄後、硫酸マグネシウムで乾燥した。溶媒を留去し、表題化合物(5.2 g) を粗結晶として得た。一部を酢酸エチル−ヘキサンから再結晶し、結晶を得た。
融点 75-76 ℃。
参考例３ 8-ヒドロキシ-2,3-ジヒドロ-1-ベンゾオキセピン-4-カルボン酸エチル

8- (ベンジルオキシ)-2,3-ジヒドロ-1-ベンゾオキセピン-4-カルボン酸エチル(2.5 g) をトリフルオロ酢酸 (10 mL) に溶かし、42％ 臭化水素酸 (0.5 mL) を加え、60 ℃ で 30 分間加熱した。濃縮後、酢酸エチルで抽出した。有機層を水洗後、1M 水酸化ナトリウ
ム水溶液で逆抽出した。水層を塩酸酸性とし、酢酸エチルで抽出した。有機層を水、食塩水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をエタノール(100 mL)
に溶かし、氷冷下、塩化チオニル (1 mL) を滴下した。室温で一晩撹拌し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン)で精製し、粗結晶を得た。酢酸エチル−ヘキサンから再結晶し、表題化合物 (0.39 g) を結晶として得た。
融点 131-132 ℃。 Reference Example 1 Ethyl 4- [5- (benzyloxy) -2-formylphenoxy] butyrate

4- (Benzyloxy) -2-hydroxybenzaldehyde (5.8 g), ethyl 4-bromobutyrate (7.1 mL), potassium carbonate (10.5 g), sodium iodide (3.8 g) was added to N, N-dimethylformamide (50 mL). ) And stirred overnight at room temperature. Pour into water and extract with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane) to give the title compound (8.2 g) as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t), 2.14-2.23 (2H, m), 2.53 (2H, t), 4.06-4.20 (4H, m),
5.12 (2H, s), 6.53 (1H, d), 6.62 (1H, dd), 7.34-7.45 (5H, m), 7.81 (1H, d).
Reference Example 2 Ethyl 8- (benzyloxy) -2,3-dihydro-1-benzoxepin-4-carboxylate

Ethyl 4- [5- (benzyloxy) -2-formylphenoxy] butyrate (8.2 g) was dissolved in diethyl carbonate (100 mL), potassium t-butoxide (4 g) was added, and the mixture was stirred overnight at room temperature. 1 M Hydrochloric acid was added and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over magnesium sulfate. The solvent was distilled off to give the title compound (5.2 g) as crude crystals. A part was recrystallized from ethyl acetate-hexane to obtain crystals.
Melting point 75-76 ° C.
Reference Example 3 Ethyl 8-hydroxy-2,3-dihydro-1-benzoxepin-4-carboxylate

Dissolve ethyl 8- (benzyloxy) -2,3-dihydro-1-benzoxepin-4-carboxylate (2.5 g) in trifluoroacetic acid (10 mL), add 42% hydrobromic acid (0.5 mL), Heated at 60 ° C. for 30 minutes. After concentration, the mixture was extracted with ethyl acetate. The organic layer was washed with water and back-extracted with 1M aqueous sodium hydroxide solution. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was ethanol (100 mL)
Then, thionyl chloride (1 mL) was added dropwise under ice cooling. The mixture was stirred overnight at room temperature, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane) to obtain crude crystals. Recrystallization from ethyl acetate-hexane gave the title compound (0.39 g) as crystals.
Melting point 131-132 ° C.

8-(ベンジルオキシ)-2,3-ジヒドロ-1-ベンゾオキセピン-4-カルボン酸エチル(3.5 g)
をエタノール (50 mL) に溶かし、10％ パラジウム−炭素 (0.35g) を用いて 3 日間接触還元した。触媒を濾別し、濾液の溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン)で精製し、表題化合物 (2.7 g) を油状物として得た。
¹H NMR (CDCl₃) δ： 1.25(3H, t),2.12-2.25(2H, m), 2.52-2.68(1H, m), 2.89-3.11(2H, m), 3.76-3.88(1H, m), 4.14(2H, q), 4.23-4.34(1H, m), 4.78(1H, s), 6.44-6.50(2H, m), 7.00(1H, d)。
参考例５ 2',6'-ジメチルビフェニル-3-カルバルデヒド

3-ブロモベンズアルデヒド (18.5 g、100 mmol)、(2,6-ジメチルフェニル)ボロン酸(21.0 g、140 mmol) を 1 M 炭酸ナトリウム水溶液 (200 mL)、エタノール (100 mL) およびトルエン (200 mL) の混液に溶解させ、アルゴン置換した後、テトラキス(トリフェニル
ホスフィン)パラジウム(0) (5.78 g、5.00 mmol) を加えた。反応液をアルゴン雰囲気下
、80℃ で 20 時間攪拌した。反応液を冷却後、反応液に水を加え酢酸エチルで希釈し、
不溶物をセライト濾過した。濾液の有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜10%
酢酸エチル／ヘキサン) で精製し、表題化合物 (20.4 g、収率 97%) を無色油状物として得た。
MS m/z 211 (MH⁺)。
参考例６ (2',6'-ジメチルビフェニル-3-イル)メタノール

2',6'-ジメチルビフェニル-3-カルバルデヒド (18.5g、88.0 mmol) を 1,2-ジメトキシエタン (100 mL) およびテトラヒドロフラン (100 mL) の混液に溶解し、氷冷下で水素化ホウ素ナトリウム (1.66 g、44.0 mmol) を加えた後、同温で 3 時間、さらに室温で3 時間撹拌した。反応液に希塩酸を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%〜50% 酢酸エチル／ヘキサン) で精製し、表題化合物 (15.6 g、収率 83%) を無色油状物として得た。
¹H NMR (CDCl₃) δ： 1.66(1H, t, J=5.9Hz), 2.03(6H, s), 4.74(2H, d, J=5.9Hz), 7.07-7.19(5H, m), 7.35(1H, d, J=7.5Hz), 7.43(1H, t, J=7.5Hz)。 Reference Example 4 Ethyl 8-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate

Ethyl 8- (benzyloxy) -2,3-dihydro-1-benzoxepin-4-carboxylate (3.5 g)
Was dissolved in ethanol (50 mL) and catalytically reduced with 10% palladium-carbon (0.35 g) for 3 days. The catalyst was filtered off and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane) to give the title compound (2.7 g) as an oil.
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t), 2.12-2.25 (2H, m), 2.52-2.68 (1H, m), 2.89-3.11 (2H, m), 3.76-3.88 (1H, m ), 4.14 (2H, q), 4.23-4.34 (1H, m), 4.78 (1H, s), 6.44-6.50 (2H, m), 7.00 (1H, d).
Reference Example 5 2 ', 6'-Dimethylbiphenyl-3-carbaldehyde

3-Bromobenzaldehyde (18.5 g, 100 mmol), (2,6-dimethylphenyl) boronic acid (21.0 g, 140 mmol) in 1 M aqueous sodium carbonate (200 mL), ethanol (100 mL) and toluene (200 mL) ), And after purging with argon, tetrakis (triphenylphosphine) palladium (0) (5.78 g, 5.00 mmol) was added. The reaction solution was stirred at 80 ° C. for 20 hours under an argon atmosphere. After cooling the reaction solution, water was added to the reaction solution and diluted with ethyl acetate.
The insoluble material was filtered through Celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane to 10%
Purification with ethyl acetate / hexane) gave the title compound (20.4 g, 97% yield) as a colorless oil.
MS m / z 211 (MH ⁺ ).
Reference Example 6 (2 ', 6'-Dimethylbiphenyl-3-yl) methanol

Dissolve 2 ', 6'-dimethylbiphenyl-3-carbaldehyde (18.5 g, 88.0 mmol) in a mixture of 1,2-dimethoxyethane (100 mL) and tetrahydrofuran (100 mL), and borohydride under ice cooling Sodium (1.66 g, 44.0 mmol) was added, and the mixture was stirred at the same temperature for 3 hours and further at room temperature for 3 hours. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% -50% ethyl acetate / hexane) to give the title compound (15.6 g, yield 83%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 1.66 (1H, t, J = 5.9 Hz), 2.03 (6H, s), 4.74 (2H, d, J = 5.9 Hz), 7.07-7.19 (5H, m), 7.35 (1H, d, J = 7.5Hz), 7.43 (1H, t, J = 7.5Hz).

実施例１の過程で得られた (6-ヒドロキシ-3,4-ジヒドロナフタレン-1-イル)酢酸エチ
ルおよび (2E)-(6-ヒドロキシ-3,4-ジヒドロナフタレン-1(2H)-イリデン)酢酸エチルの混合物(3.34 g、14.4 mmol) をエタノール (70 mL) に溶解させ、10% パラジウム−炭素(50% 含水品、0.2 g) を加えて、水素雰囲気下 (風船圧)、 室温で 18 時間攪拌した。触媒
を濾別し、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (5%〜30%
酢酸エチル／ヘキサン) で精製し、表題化合物 (1.95 g、収率58%) を淡黄色油状物とし
て得た。
MS m/z 235 (MH⁺)。
参考例８ 5-ベンジルオキシ-1-インダノン

［工程１］5-メトキシ-1-インダノン(10.3 g、63.5 mmol) のトルエン (150 mL) 懸濁液
を氷冷し、塩化アルミニウム (16.9 g、127 mmol) を少しずつ加えた後、窒素雰囲気下で4 時間加熱還流した。反応液を室温まで放冷後氷水に注ぎ、有機物を酢酸エチルとテトラヒドロフランの混合溶媒で抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減圧濃縮して5-ヒドロキシ-1-インダノンを黄色結晶として得た。
［工程２］本品をアセトン (120 mL) に懸濁させ、ベンジルブロミド (10.9 g、64.0 mmol) および 炭酸カリウム (12.3 g、88.9mmol) を加えて、窒素雰囲気下、1 時間加熱還流した。反応液を室温まで放冷後、酢酸エチルと水を加えた。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、表題化合物(14.2 g、94%) を淡黄色結晶として得た (酢酸エチルから再結晶)。
MS m/z 239 (MH⁺)。
参考例９ (2E)-[5-(ベンジルオキシ)-2,3-ジヒドロ-1H-インデン-1-イリデン]酢酸エチ
ル

氷冷したホスホノ酢酸トリエチル (4.75 g、21.2 mmol) のトルエン (15 mL) 溶液に水素化ナトリウム (60% 油性、0.848 g、21.2mmol) を少しずつ加えた後、窒素雰囲気下で 50 ℃ まで昇温して 1 時間撹拌した。反応液を氷冷し、5-ベンジルオキシ-1-インダノン
(3.36 g、14.1 mmol) のトルエン (15 mL) 溶液を滴下して 4 時間加熱還流した。室温
まで冷却した後、1M 塩酸を加えて酢酸エチルで抽出した。抽出液を無水硫酸マグネシウ
ムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%〜30% 酢酸
エチル／ヘキサン)で精製し、得られた固体を酢酸エチル−ヘキサンから再結晶して、表
題化合物(2.11 g、収率 49%) を淡黄色プリズム晶として得た。
MS m/z 309 (MH⁺)。 Reference Example 7 (6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) ethyl acetate

(6-Hydroxy-3,4-dihydronaphthalen-1-yl) ethyl acetate and (2E)-(6-hydroxy-3,4-dihydronaphthalene-1 (2H) -ylidene obtained in the process of Example 1 ) A mixture of ethyl acetate (3.34 g, 14.4 mmol) was dissolved in ethanol (70 mL), 10% palladium-carbon (50% water-containing product, 0.2 g) was added, and hydrogen atmosphere (balloon pressure) at room temperature was added. Stir for 18 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (5% -30%
Purification with ethyl acetate / hexane) afforded the title compound (1.95 g, 58% yield) as a pale yellow oil.
MS m / z 235 (MH ⁺ ).
Reference Example 8 5-Benzyloxy-1-indanone

[Step 1] A suspension of 5-methoxy-1-indanone (10.3 g, 63.5 mmol) in toluene (150 mL) was ice-cooled and aluminum chloride (16.9 g, 127 mmol) was added little by little, followed by a nitrogen atmosphere. The mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, poured into ice water, and the organic matter was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-hydroxy-1-indanone as yellow crystals.
[Step 2] This product was suspended in acetone (120 mL), benzyl bromide (10.9 g, 64.0 mmol) and potassium carbonate (12.3 g, 88.9 mmol) were added, and the mixture was heated to reflux for 1 hour in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (14.2 g, 94%) as pale yellow crystals (recrystallized from ethyl acetate).
MS m / z 239 (MH ⁺ ).
Reference Example 9 (2E)-[5- (Benzyloxy) -2,3-dihydro-1H-indene-1-ylidene] ethyl acetate

To a solution of ice-cooled triethyl phosphonoacetate (4.75 g, 21.2 mmol) in toluene (15 mL) was added sodium hydride (60% oily, 0.848 g, 21.2 mmol) little by little, and the temperature was raised to 50 ° C under a nitrogen atmosphere. Warmed and stirred for 1 hour. The reaction mixture is ice-cooled and 5-benzyloxy-1-indanone
A solution of (3.36 g, 14.1 mmol) in toluene (15 mL) was added dropwise and heated to reflux for 4 hours. After cooling to room temperature, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% -30% ethyl acetate / hexane), and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (2.11 g, yield 49%) as a pale yellow Obtained as prismatic crystals.
MS m / z 309 (MH ⁺ ).

(2E)-[5-(ベンジルオキシ)-2,3-ジヒドロ-1H-インデン-1-イリデン]酢酸エチル(2.10 g、6.81 mmol) のエタノール (20 mL) 溶液に 10% パラジウム−炭素(50% 含水品、0.5 g)
を加え、水素雰囲気下 (風船圧)、 室温で 24 時間攪拌した。触媒を濾別し、濾液を減
圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (5%〜30% 酢酸エチル／ヘキサン) で精製し、表題化合物 (1.45 g、収率97%) を無色油状物として得た。
¹H NMR (CDCl₃) δ： 1.28(3 H, t, J=7.1Hz), 1.69-1.81(1H, m), 2.32-2.44(2H, m), 2.71(1H, dd, J=15.3, 5.8Hz), 2.77-2.94(2H, m), 3.46-3.56(1H, m), 4.18(2H, q, J=7.1Hz), 4.71(1H, s), 6.62(1H, dd, J=8.1, 2.2Hz), 6.70(1H, d, J=2.2Hz), 7.02(1H, d,
J=8.1Hz)。
参考例１１ 4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}安息香酸メチル

参考例３８と同様にして、4-フェニル-N-プロピル-1,3-チアゾール-2-アミンおよび4-(ブロモメチル)安息香酸メチルから表題化合物を無色油状物として得た。収率 75%。
¹H NMR (CDCl₃) δ： 0.93(3H, t, J=7.7Hz), 1.64-1.74(2H, m), 3.40(2H, t,J=7.7Hz),
3.91(3H, s), 4.85(2H, s), 6.72(1H, s), 7.23-7.42(5H, m), 7.82-7.85(2H, m), 7.99-8.01(2H, m)。
参考例１２ (4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}フェ
ニル)メタノール

参考例４１と同様にして、4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}安息香酸メチルから表題化合物を無色油状物として得た。収率 67%。
¹H NMR (CDCl₃) δ： 0.93(3H, t, J=7.4Hz), 1.62(1H, t, J=5.8Hz), 1.64-1.74(2H, m), 3.40(2H, t, J=7.7Hz), 4.69(2H, d, J=5.8Hz), 4.79(2H, s), 6.70(1H, s), 7.24-7.39(7H, m), 7.84-7.87(2H, m)。 Reference Example 10 (5-Hydroxy-2,3-dihydro-1H-inden-1-yl) ethyl acetate

(2E)-[5- (Benzyloxy) -2,3-dihydro-1H-indene-1-ylidene] ethyl acetate (2.10 g, 6.81 mmol) in ethanol (20 mL) in 10% palladium-carbon (50 % Water-containing product, 0.5 g)
And stirred for 24 hours at room temperature under a hydrogen atmosphere (balloon pressure). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% -30% ethyl acetate / hexane) to give the title compound (1.45 g, yield 97%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 1.28 (3 H, t, J = 7.1 Hz), 1.69-1.81 (1H, m), 2.32-2.44 (2H, m), 2.71 (1H, dd, J = 15.3, 5.8Hz), 2.77-2.94 (2H, m), 3.46-3.56 (1H, m), 4.18 (2H, q, J = 7.1Hz), 4.71 (1H, s), 6.62 (1H, dd, J = 8.1 , 2.2Hz), 6.70 (1H, d, J = 2.2Hz), 7.02 (1H, d,
J = 8.1Hz).
Reference Example 11 4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} methyl benzoate

In the same manner as in Reference Example 38, the title compound was obtained as a colorless oil from 4-phenyl-N-propyl-1,3-thiazol-2-amine and methyl 4- (bromomethyl) benzoate. Yield 75%.
¹ H NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.7Hz), 1.64-1.74 (2H, m), 3.40 (2H, t, J = 7.7Hz),
3.91 (3H, s), 4.85 (2H, s), 6.72 (1H, s), 7.23-7.42 (5H, m), 7.82-7.85 (2H, m), 7.99-8.01 (2H, m).
Reference Example 12 (4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} phenyl) methanol

In the same manner as in Reference Example 41, the title compound was obtained as a colorless oil from methyl 4-{[(4-phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} benzoate. Yield 67%.
¹ H NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.62 (1H, t, J = 5.8 Hz), 1.64-1.74 (2H, m), 3.40 (2H, t, J = 7.7Hz), 4.69 (2H, d, J = 5.8Hz), 4.79 (2H, s), 6.70 (1H, s), 7.24-7.39 (7H, m), 7.84-7.87 (2H, m).

氷冷した4-ホスホノクロトン酸トリエチル (24.0 g、95.9 mmol) のテトラヒドロフラ
ン (100 mL) 溶液に水素化ナトリウム (60% 油性、3.84g、96.0 mmol) を少しずつ加えた後、窒素雰囲気下で 30 分間撹拌した。反応液に 3-メトキシベンズアルデヒド (12.3 g
、90.0 mmol)のテトラヒドロフラン (100 mL) 溶液を滴下して室温で 2 時間攪拌し、N,N-ジメチルホルムアミド (50 mL) を加えてさらに 18 時間攪拌した。反応液を減圧濃縮し
、1M 塩酸を加えて酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減
圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (10%〜30% 酢酸エチル／ヘキ
サン)で精製し、表題化合物 (7.70 g、収率 37%) を黄色油状物として得た。
MS m/z 233 (MH⁺)。
参考例１４ 5-(3-メトキシフェニル)ペンタン酸エチル

参考例１０と同様にして、(2E,4E)-5-(3-メトキシフェニル)ペンタ-2,4-ジエン酸エチ
ルから表題化合物を無色油状物として得た。収率 77%。
¹H NMR (CDCl₃) δ： 1.25(3H, t, J=7.2Hz), 1.60-1.72(4H, m), 2.32(2H, t, J=7.0Hz), 2.61(2H, t, J=7.0Hz), 3.80(3H, s), 4.12(2H, q, J=7.2Hz), 6.72-6.78(3H, m), 7.16-7.22(1H, m)。
参考例１５ 5-(3-メトキシフェニル)ペンタン酸

5-(3-メトキシフェニル)ペンタン酸エチル (6.01 g、25.4 mmol) のエタノール (50 mL) およびテトラヒドロフラン (50 mL) 混合溶液に2 M 水酸化ナトリウム水溶液 (25 mL) を加え、室温で 3 時間撹拌した。反応液に水を加え、1 M 塩酸で酸性にして、酢酸エチ
ルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮して、表題化合物 (5.28 g、収率 99%) を赤茶色油状物として得た。
¹H NMR (CDCl₃) δ： 1.66-1.70(4H, m), 2.36-2.41(2H, m), 2.59-2.64(2H, m), 3.80(3H, s), 6.72-6.78(3H, m), 7.17-7.22(1H, m)。 Reference Example 13 (2E, 4E) -5- (3-methoxyphenyl) penta-2,4-dienoic acid ethyl ester

To a solution of ice-cooled triethyl 4-phosphonocrotonate (24.0 g, 95.9 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (60% oily, 3.84 g, 96.0 mmol) little by little, and under a nitrogen atmosphere. Stir for 30 minutes. To the reaction mixture, 3-methoxybenzaldehyde (12.3 g
, 90.0 mmol) in tetrahydrofuran (100 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hr. N, N-dimethylformamide (50 mL) was added, and the mixture was further stirred for 18 hr. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% -30% ethyl acetate / hexane) to give the title compound (7.70 g, yield 37%) as a yellow oil.
MS m / z 233 (MH ⁺ ).
Reference Example 14 Ethyl 5- (3-methoxyphenyl) pentanoate

In the same manner as in Reference Example 10, the title compound was obtained as a colorless oil from ethyl (2E, 4E) -5- (3-methoxyphenyl) penta-2,4-dienoate. Yield 77%.
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.2Hz), 1.60-1.72 (4H, m), 2.32 (2H, t, J = 7.0Hz), 2.61 (2H, t, J = 7.0Hz), 3.80 (3H, s), 4.12 (2H, q, J = 7.2Hz), 6.72-6.78 (3H, m), 7.16-7.22 (1H, m).
Reference Example 15 5- (3-methoxyphenyl) pentanoic acid

To a mixed solution of ethyl 5- (3-methoxyphenyl) pentanoate (6.01 g, 25.4 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added 2 M aqueous sodium hydroxide solution (25 mL), and the mixture was stirred at room temperature for 3 hours. Stir. Water was added to the reaction mixture, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (5.28 g, yield 99%) as a red-brown oil.
¹ H NMR (CDCl ₃ ) δ: 1.66-1.70 (4H, m), 2.36-2.41 (2H, m), 2.59-2.64 (2H, m), 3.80 (3H, s), 6.72-6.78 (3H, m ), 7.17-7.22 (1H, m).

酸化リン(V)(10 g) とメタンスルホン酸 (70 mL) の混合物を 100 ℃ で 1 時間攪拌し、得られた溶液と5-(3-メトキシフェニル)ペンタン酸 (5.28 g、25.4 mmol) を混合して 1 時間攪拌した。反応液を氷水に注ぎ、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜30% 酢酸エチル／ヘキサン) で精製し、表題化合物 (4.02 g、83%) を赤茶色油状物として得た。
MS m/z 191 (MH⁺)。
参考例１７ 2-(ベンジルオキシ)-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-オ
ン

参考例８と同様にして、2-メトキシ-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-オンから表題化合物を無色プリズム晶として得た。収率 91% (酢酸エチル−ヘキサンか
ら再結晶)。
MS m/z 267 (MH⁺)。
参考例１８ (2-ヒドロキシ-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-イル)酢
酸エチル

参考例９および参考例１０と同様にして、2-(ベンジルオキシ)-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-オンから表題化合物を無色油状物として得た。収率89%。
MS m/z 249 (MH⁺)。 Reference Example 16 2-Methoxy-6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-one

A mixture of phosphorus (V) oxide (10 g) and methanesulfonic acid (70 mL) was stirred at 100 ° C for 1 hour, and the resulting solution and 5- (3-methoxyphenyl) pentanoic acid (5.28 g, 25.4 mmol) Were mixed and stirred for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-30% ethyl acetate / hexane) to give the title compound (4.02 g, 83%) as a red-brown oil.
MS m / z 191 (MH ⁺ ).
Reference Example 17 2- (Benzyloxy) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-one

In the same manner as in Reference Example 8, the title compound was obtained as colorless prism crystals from 2-methoxy-6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-one. Yield 91% (recrystallized from ethyl acetate-hexane).
MS m / z 267 (MH ⁺ ).
Reference Example 18 (2-hydroxy-6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-yl) ethyl acetate

In the same manner as in Reference Example 9 and Reference Example 10, the title compound was obtained as a colorless oil from 2- (benzyloxy) -6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-one. . Yield 89%.
MS m / z 249 (MH ⁺ ).

氷冷下、4-クロロアセト酢酸エチル (14.0 g、85.0mmol) を濃硫酸 (30 mL) に溶解し
、レゾルシノール (8.81 g、80.0 mmol) を少しずつ加えた後、室温で 2 時間攪拌した。反応液を氷水に注ぎ、生じた固体を濾取し、水で洗浄後、風乾して表題化合物(14.1 g、84%) を得た。
MS m/z 211 (MH⁺)。
参考例２０ (6-ヒドロキシ-1-ベンゾフラン-3-イル)酢酸メチル

［工程１］4-(クロロメチル)-7-ヒドロキシ-2H-クロメン-2-オン(10.9 g、51.8 mmol) と
1 M 水酸化ナトリウム水溶液 (500 mL) の混合液を 2 時間加熱還流した。反応液を放冷し、濃硫酸で酸性にした後酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮して(6-ヒドロキシ-1-ベンゾフラン-3-イル)酢酸 (8.27 g、83%) を茶色結晶として得た。
［工程２］本品 (9.85 g、51.3 mmol) をメタノール(45 mL) に懸濁させ、濃硫酸 (5 mL)
を加えて 4 時間加熱還流した。反応液を減圧濃縮し、水を加えてジエチルエーテルで抽出した。抽出液を飽和重曹水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (10%〜50% 酢酸エチル／
ヘキサン) で精製し、得られた固体を酢酸エチル−ヘキサンから再結晶して、表題化合物(7.38 g、収率 70%) を淡黄色プリズム晶として得た。
MS m/z 207 (MH⁺)。
参考例２１ (6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル

(6-ヒドロキシ-1-ベンゾフラン-3-イル)酢酸メチル(11.4 g、55.3 mmol) のメタノール
(100 mL) 溶液に 10% パラジウム−炭素(50% 含水品、2 g) を加え、水素雰囲気下 (風
船圧)、 室温で 18 時間攪拌した。触媒を濾別し、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (20%〜50% 酢酸エチル／ヘキサン) で精製し、得られた固
体を酢酸エチル−ヘキサンから再結晶して、表題化合物(8.74 g、収率 76%) を無色プリ
ズム晶として得た。
MS m/z 209 (MH⁺)。 Reference Example 19 4- (Chloromethyl) -7-hydroxy-2H-chromen-2-one

Under ice-cooling, ethyl 4-chloroacetoacetate (14.0 g, 85.0 mmol) was dissolved in concentrated sulfuric acid (30 mL), resorcinol (8.81 g, 80.0 mmol) was added little by little, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and the resulting solid was collected by filtration, washed with water, and then air-dried to obtain the title compound (14.1 g, 84%).
MS m / z 211 (MH ⁺ ).
Reference Example 20 Methyl (6-hydroxy-1-benzofuran-3-yl) acetate

[Step 1] 4- (Chloromethyl) -7-hydroxy-2H-chromen-2-one (10.9 g, 51.8 mmol) and
A mixture of 1 M aqueous sodium hydroxide (500 mL) was heated to reflux for 2 hours. The reaction mixture was allowed to cool, acidified with concentrated sulfuric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (6-hydroxy-1-benzofuran-3-yl) acetic acid (8.27 g, 83%) as brown crystals.
[Step 2] This product (9.85 g, 51.3 mmol) is suspended in methanol (45 mL) and concentrated sulfuric acid (5 mL).
And heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% -50% ethyl acetate /
The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (7.38 g, yield 70%) as pale yellow prisms.
MS m / z 207 (MH ^<+> ).
Reference Example 21 Methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate

Methyl (6-hydroxy-1-benzofuran-3-yl) acetate (11.4 g, 55.3 mmol) in methanol
(100 mL) To the solution was added 10% palladium-carbon (50% water-containing product, 2 g), and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere (balloon pressure). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% -50% ethyl acetate / hexane), and the resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (8.74 g, yield 76%) as a colorless prism. Obtained as crystals.
MS m / z 209 (MH ⁺ ).

(2,4-ジメチルフェニル)ボロン酸 (3.0 g, 20.0mmol)、3-ブロモ安息香酸エチル (4.3 g, 18.8 mmol)、炭酸セシウム (9.8 g, 30.0 mmol) をエタノール (20 mL) およびトルエン(80 mL) の混合溶液に加え、アルゴン置換した後、テトラキス(トリフェニルホスフィ
ン)パラジウム(0)(0.30 g、0.26 mmol) を加えた。反応液をアルゴン雰囲気下、70 ℃ で
18 時間攪拌した。反応液を冷却後、不溶物をセライトで濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン=1:10) に付し、表題化合物 (5.0 g、収率 100％) を無色油状物として得た。
¹H NMR (CDCl₃) δ： 1.39(3H, t, J=7.0Hz), 2.23(3H, s), 2.37(3H, s), 4.38(2H, q, J=7.0Hz), 7.02-7.54(5H, m), 8.00-8.05(2H,m)。
参考例２３ (2',4'-ジメチルビフェニル-3-イル)メタノール

2', 4'-ジメチルビフェニル-3-カルボン酸エチル(5.0 g, 19.7 mmol) の無水テトラヒ
ドロフラン溶液 (50 mL) に氷冷下、水素化リチウムアルミニウム (0.91 g, 24.0mmol)
を加え、室温で 3 時間攪拌した。反応溶液を氷冷した後、硫酸ナトリウム 十水和物 (8.0 g, 24.8 mmol) を加え、室温で 1 時間攪拌した。析出した不溶物をセライトで濾過し
、濾液を減圧濃縮し、表題化合物を無色油状物として得た。収率96%。
¹H NMR (CDCl₃) δ： 2.24(3H, s), 2.36(3H, s), 4.73(2H, d, J=6.0Hz), 7.00-7.45(7H, m)。
参考例２４ 2',4',6’-トリメチルビフェニル-3-カルバルデヒド

参考例２２と同様にして、3-ブロモベンズアルデヒドおよび(2,4,6-トリメチルフェニ
ル)ボロン酸から表題化合物を無色油状物として得た。収率 76%。
MS m/z 225 (MH⁺)。 Reference Example 22 Ethyl 2 ', 4'-dimethylbiphenyl-3-carboxylate

(2,4-Dimethylphenyl) boronic acid (3.0 g, 20.0 mmol), ethyl 3-bromobenzoate (4.3 g, 18.8 mmol), cesium carbonate (9.8 g, 30.0 mmol) in ethanol (20 mL) and toluene ( 80 mL), and after purging with argon, tetrakis (triphenylphosphine) palladium (0) (0.30 g, 0.26 mmol) was added. Reaction mixture at 70 ° C under argon atmosphere
Stir for 18 hours. After cooling the reaction solution, the insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give the title compound (5.0 g, yield 100%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.0Hz), 2.23 (3H, s), 2.37 (3H, s), 4.38 (2H, q, J = 7.0Hz), 7.02-7.54 (5H, m), 8.00-8.05 (2H, m).
Reference Example 23 (2 ', 4'-dimethylbiphenyl-3-yl) methanol

Lithium aluminum hydride (0.91 g, 24.0 mmol) in an anhydrous tetrahydrofuran solution (50 mL) of ethyl 2 ', 4'-dimethylbiphenyl-3-carboxylate (5.0 g, 19.7 mmol) under ice-cooling
And stirred at room temperature for 3 hours. The reaction solution was ice-cooled, sodium sulfate decahydrate (8.0 g, 24.8 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil. Yield 96%.
¹ H NMR (CDCl ₃ ) δ: 2.24 (3H, s), 2.36 (3H, s), 4.73 (2H, d, J = 6.0 Hz), 7.00-7.45 (7H, m).
Reference Example 24 2 ', 4', 6'-trimethylbiphenyl-3-carbaldehyde

In the same manner as in Reference Example 22, the title compound was obtained as a colorless oil from 3-bromobenzaldehyde and (2,4,6-trimethylphenyl) boronic acid. Yield 76%.
MS m / z 225 (MH ⁺ ).

2',4',6’-トリメチルビフェニル-3-カルバルデヒド(2.36 g, 10.5 mmol) をエタノー
ル (20 mL) に溶解し、この溶液に水素化ホウ素ナトリウム (0.40 g, 10.6 mmol) を加えた。氷冷下で3 時間攪拌した後、反応溶液にクエン酸水溶液を加え、酢酸エチルで抽出し、塩化ナトリウム水溶液で洗浄後、硫酸マグネシウムで乾燥、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン=1:5〜1:2) に付し、表題化合物 (1.66 g、収率 70%)を無色油状物として得た。
¹H NMR (CDCl₃) δ： 2.00(6H, s), 2.33(3H, s), 4.73(2H, d, J=6.2Hz), 6.94(2H, s),
7.00-7.42(4H, m)。
参考例２６ (2',6'-ジメチル-6-メトキシビフェニル-3-イル)メタノール

参考例２２及び参考例２５と同様にして、1-ブロモ-2,6-ジメチルベンゼンおよび(2-メトキシ-5-ホルミルフェニル)ボロン酸から表題化合物を無色油状物として得た。収率 76％。
¹H NMR (CDCl₃) δ： 2.01(6H, s), 3.74(3H, s), 4.65(2H, d, J=5.2Hz), 6.97(1H, d, J=8.4Hz), 7.03(1H, d, J=2.2Hz), 7.06-7.24(3H, m), 7.35(1H, dd, J=8.4, 2.6Hz)。
参考例２７ 3-(1-ベンゾチエン-5-イル)ベンズアルデヒド

参考例２２と同様にして、5-ブロモ-1-ベンゾチオフェンおよび(3-ホルミルフェニル)
ボロン酸から表題化合物を淡黄色油状物として得た。収率 70%。
MS m/z 239 (MH⁺)。 Reference Example 25 (2 ', 4', 6'-trimethylbiphenyl-3-yl) methanol

2 ', 4', 6'-Trimethylbiphenyl-3-carbaldehyde (2.36 g, 10.5 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (0.40 g, 10.6 mmol) was added to this solution. . After stirring for 3 hours under ice cooling, an aqueous citric acid solution was added to the reaction solution, extracted with ethyl acetate, washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 5 to 1: 2) to give the title compound (1.66 g, yield 70%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 2.00 (6H, s), 2.33 (3H, s), 4.73 (2H, d, J = 6.2Hz), 6.94 (2H, s),
7.00-7.42 (4H, m).
Reference Example 26 (2 ', 6'-dimethyl-6-methoxybiphenyl-3-yl) methanol

In the same manner as in Reference Example 22 and Reference Example 25, the title compound was obtained as a colorless oil from 1-bromo-2,6-dimethylbenzene and (2-methoxy-5-formylphenyl) boronic acid. Yield 76%.
¹ H NMR (CDCl ₃ ) δ: 2.01 (6H, s), 3.74 (3H, s), 4.65 (2H, d, J = 5.2Hz), 6.97 (1H, d, J = 8.4Hz), 7.03 (1H , d, J = 2.2 Hz), 7.06-7.24 (3H, m), 7.35 (1H, dd, J = 8.4, 2.6 Hz).
Reference Example 27 3- (1-Benzothien-5-yl) benzaldehyde

In the same manner as in Reference Example 22, 5-bromo-1-benzothiophene and (3-formylphenyl)
The title compound was obtained as a pale yellow oil from boronic acid. Yield 70%.
MS m / z 239 (MH ⁺ ).

3-(1-ベンゾチエン-5-イル)ベンズアルデヒド (3.9g, 16.4 mmol) をエタノール (80 mL) およびテトラヒドロフラン (20 mL) に溶解し、氷冷した。この溶液に水素化ホウ素ナトリウム(0.62 g, 16.4 mmol) を加えた。氷冷下で 3 時間攪拌した後、反応溶液にクエ
ン酸水溶液を加え、酢酸エチルで抽出し、塩化ナトリウム水溶液で洗浄後、硫酸マグネシウムで乾燥、減圧濃縮した。得られた油状物を酢酸エチル−ヘキサンから結晶化し、表題化合物 (3.9 g、収率 99%) を無色プリズム晶として得た。
¹H NMR (CDCl₃) δ： 1.73(1H, t, J=6.0Hz), 4.79(2H, d, J=6.0Hz), 7.35-7.63(6H, m), 7.68(1H, s), 7.94(1H, d, J=8.1 Hz), 8.04(1H, d, J=1.8Hz)。
参考例２９ 3-(1-ベンゾチエン-3-イル)ベンズアルデヒド

(3-ホルミルフェニル)ボロン酸 (1.7 g, 11.3mmol)、3-ブロモ-1-ベンゾチオフェン(2.0 g, 9.39 mmol)、炭酸セシウム (4.6 g, 14.1 mmol) をエタノール (10mL) およびトル
エン (50 mL) の混合溶液に加え、アルゴン置換した後、テトラキス(トリフェニルホスフィン)パラジウム(0)(0.20 g、0.17 mmol) を加えた。反応液をアルゴン雰囲気下、70 ℃ で 18 時間攪拌した。反応液を冷却後、不溶物をセライトで濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン=1:10〜1:5) に付し、表題化合物 (2.1 g、収率 94％) を淡黄色油状物として得た。
MS m/z 239(MH⁺)。
参考例３０ [3-(1-ベンゾチエン-3-イル)フェニル]メタノール

3-(1-ベンゾチエン-3-イル)ベンズアルデヒド (2.1g, 8.81 mmol) の無水テトラヒドロフラン溶液 (30 mL) に氷冷下、水素化リチウムアルミニウム (0.37 g, 9.75 mmol) を加え、室温で2 時間攪拌した。反応溶液を氷冷した後、硫酸ナトリウム 十水和物 (3.0 g, 5.74 mmol) を加え、室温で 1 時間攪拌した。析出した不溶物をセライトで濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:5〜1:3) に付し、表題化合物 (2.0 g、収率95％) を無色油状物として得た。
¹H NMR (CDCl₃) δ： 1.72(1H, t, J=5.8Hz), 4.80(2H, d, J=5.8Hz), 7.35-7.64(7H, m), 7.88-7.98(2H, m)。 Reference Example 28 [3- (1-Benzothien-5-yl) phenyl] methanol

3- (1-Benzothien-5-yl) benzaldehyde (3.9 g, 16.4 mmol) was dissolved in ethanol (80 mL) and tetrahydrofuran (20 mL) and cooled on ice. To this solution was added sodium borohydride (0.62 g, 16.4 mmol). After stirring for 3 hours under ice cooling, an aqueous citric acid solution was added to the reaction solution, extracted with ethyl acetate, washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (3.9 g, yield 99%) as colorless prism crystals.
¹ H NMR (CDCl ₃ ) δ: 1.73 (1H, t, J = 6.0 Hz), 4.79 (2H, d, J = 6.0 Hz), 7.35-7.63 (6H, m), 7.68 (1H, s), 7.94 (1H, d, J = 8.1 Hz), 8.04 (1H, d, J = 1.8 Hz).
Reference Example 29 3- (1-Benzothien-3-yl) benzaldehyde

(3-Formylphenyl) boronic acid (1.7 g, 11.3 mmol), 3-bromo-1-benzothiophene (2.0 g, 9.39 mmol), cesium carbonate (4.6 g, 14.1 mmol) in ethanol (10 mL) and toluene (50 mL), and after purging with argon, tetrakis (triphenylphosphine) palladium (0) (0.20 g, 0.17 mmol) was added. The reaction solution was stirred at 70 ° C. for 18 hours under an argon atmosphere. After cooling the reaction solution, the insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 5) to give the title compound (2.1 g, yield 94%) as a pale-yellow oil.
MS m / z 239 (MH ^<+> ).
Reference Example 30 [3- (1-benzothien-3-yl) phenyl] methanol

Lithium aluminum hydride (0.37 g, 9.75 mmol) was added to an anhydrous tetrahydrofuran solution (30 mL) of 3- (1-benzothien-3-yl) benzaldehyde (2.1 g, 8.81 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Stir. The reaction solution was ice-cooled, sodium sulfate decahydrate (3.0 g, 5.74 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 5 to 1: 3) to give the title compound (2.0 g, yield 95%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 1.72 (1H, t, J = 5.8Hz), 4.80 (2H, d, J = 5.8Hz), 7.35-7.64 (7H, m), 7.88-7.98 (2H, m) .

参考例５と同様にして、1-ブロモ-2-メチルナフタレンおよび(3-ホルミルフェニル)ボ
ロン酸から表題化合物を淡黄色油状物として得た。収率 65%。
MSm/z 247 (MH⁺)。
参考例３２ [3-(2-メチル-1-ナフチル)フェニル]メタノール

3-(2-メチル-1-ナフチル)ベンズアルデヒド(2.39 g、9.70 mmol) を1,2-ジメトキシエ
タン (10 mL) およびテトラヒドロフラン (10 mL) の混液に溶解させ、氷冷下で水素化ホウ素ナトリウム (0.189 g、5.00 mmol) を加えた後、同温で 3 時間撹拌した。反応液に
希塩酸を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（5%〜30%酢
酸エチル／ヘキサン）で精製し、表題化合物 (1.96 g、収率 81%) を無色粘稠性油状物として得た。
¹H NMR (CDCl₃) δ： 1.66(1H, t, J=5.9Hz), 2.03(6H, s), 4.74(2H, d, J=5.9Hz), 7.07-7.19(5H, m), 7.35(1H, d, J=7.5Hz), 7.43(1H, t, J=7.5Hz)。
参考例３３ 4'-ヒドロキシ-2',6'-ジメチル-3-ビフェニルカルバルデヒド

参考例５と同様にして、4-ブロモ-3,5-ジメチルフェノールおよび (3-ホルミルフェニ
ル)ボロン酸から表題化合物を淡黄色結晶として得た。収率83%。
MSm/z 227 (MH⁺)。 Reference Example 31 3- (2-Methyl-1-naphthyl) benzaldehyde

In the same manner as in Reference Example 5, the title compound was obtained as a pale yellow oil from 1-bromo-2-methylnaphthalene and (3-formylphenyl) boronic acid. Yield 65%.
MSm / z 247 (MH ⁺ ).
Reference Example 32 [3- (2-Methyl-1-naphthyl) phenyl] methanol

3- (2-Methyl-1-naphthyl) benzaldehyde (2.39 g, 9.70 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (10 mL) and tetrahydrofuran (10 mL), and sodium borohydride was cooled with ice. (0.189 g, 5.00 mmol) was added, followed by stirring at the same temperature for 3 hours. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% -30% ethyl acetate / hexane) to give the title compound (1.96 g, yield 81%) as a colorless viscous oil.
¹ H NMR (CDCl ₃ ) δ: 1.66 (1H, t, J = 5.9 Hz), 2.03 (6H, s), 4.74 (2H, d, J = 5.9 Hz), 7.07-7.19 (5H, m), 7.35 (1H, d, J = 7.5Hz), 7.43 (1H, t, J = 7.5Hz).
Reference Example 33 4'-hydroxy-2 ', 6'-dimethyl-3-biphenylcarbaldehyde

In the same manner as in Reference Example 5, the title compound was obtained as pale yellow crystals from 4-bromo-3,5-dimethylphenol and (3-formylphenyl) boronic acid. Yield 83%.
MS m / z 227 (MH ⁺ ).

4-ブロモ-3-メチルフェノール (4.72 g、25.2mmol)、3,4-ジヒドロ-2H-ピラン (3.18 g、37.8 mmol) および p-トルエンスルホン酸ピリジニウム (0.628 g、2.50mmol) のジク
ロロメタン (100 mL) 溶液を、室温で 24 時間攪拌した。反応液を水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去して、表題化合物 (7.11 g、未反応の3,4-ジヒドロ-2H-ピランを含む) を黄色油状物として得た。
¹H NMR (CDCl₃) δ： 1.58-2.06(6H, m), 2.35(3H, s), 3.56-3.63(1H, m), 3.83-3.91(1H, m), 5.37(1H, t, J=3.1Hz), 6.77(1H, dd, J=8.8, 3.0Hz), 6.95(1H, d, J=3.0Hz), 7.39(1H, d, J=8.8Hz)。
参考例３５ 2'-メチル-4'-(テトラヒドロ-2H-ピラン-2-イルオキシ)ビフェニル-3-カル
バルデヒド

参考例５と同様にして、2-(4-ブロモ-3-メチルフェノキシ)テトラヒドロ-2H-ピランお
よび(3-ホルミルフェニル)ボロン酸から表題化合物を淡黄色油状物として得た。収率 82%
(2 工程)。
¹H NMR (CDCl₃) δ： 1.53-1.77(3H, m), 1.86-1.91(2H, m), 1.98-2.09(1H, m), 2.25(3H, s), 3.61-3.68(1H, m), 3.91-3.99(1H, m), 5.48(1H, t, J=3.2Hz), 6.95-7.00(2H, m), 7.15(1H, d, J=8.3Hz), 7.53-7.60(2H, m), 7.82-7.86(2H, m), 10.06(1H, s)。
参考例３６ [2'-メチル-4'-(テトラヒドロ-2H-ピラン-2-イルオキシ)ビフェニル-3-イル]メタノール

参考例６と同様にして、2'-メチル-4'-(テトラヒドロ-2H-ピラン-2-イルオキシ)ビフェニル-3-カルバルデヒドから表題化合物を無色油状物として得た。収率 89%。
¹H NMR (CDCl₃) δ1.59-1.76(4H, m), 1.85-1.90(2H, m), 1.97-2.11(1H, m), 2.25(3H, s), 3.60-3.67(1H, m), 3.91-3.99(1H, m), 4.73(2H, d, J=5.8Hz), 5.46(1H, t, J=3.1Hz), 6.92-6.97(2H, m), 7.14(1H, d, J=8.1Hz), 7.22-7.41(4H, m)。 Reference Example 34 2- (4-Bromo-3-methylphenoxy) tetrahydro-2H-pyran

4-Bromo-3-methylphenol (4.72 g, 25.2 mmol), 3,4-dihydro-2H-pyran (3.18 g, 37.8 mmol) and pyridinium p-toluenesulfonate (0.628 g, 2.50 mmol) in dichloromethane (100 mL) The solution was stirred at room temperature for 24 hours. The reaction mixture was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.11 g, containing unreacted 3,4-dihydro-2H-pyran) as a yellow oil Got as.
¹ H NMR (CDCl ₃ ) δ: 1.58-2.06 (6H, m), 2.35 (3H, s), 3.56-3.63 (1H, m), 3.83-3.91 (1H, m), 5.37 (1H, t, J = 3.1Hz), 6.77 (1H, dd, J = 8.8, 3.0Hz), 6.95 (1H, d, J = 3.0Hz), 7.39 (1H, d, J = 8.8Hz).
Reference Example 35 2'-Methyl-4 '-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-carbaldehyde

In the same manner as in Reference Example 5, the title compound was obtained as a pale yellow oil from 2- (4-bromo-3-methylphenoxy) tetrahydro-2H-pyran and (3-formylphenyl) boronic acid. Yield 82%
(2 steps).
¹ H NMR (CDCl ₃ ) δ: 1.53-1.77 (3H, m), 1.86-1.91 (2H, m), 1.98-2.09 (1H, m), 2.25 (3H, s), 3.61-3.68 (1H, m ), 3.91-3.99 (1H, m), 5.48 (1H, t, J = 3.2Hz), 6.95-7.00 (2H, m), 7.15 (1H, d, J = 8.3Hz), 7.53-7.60 (2H, m), 7.82-7.86 (2H, m), 10.06 (1H, s).
Reference Example 36 [2'-Methyl-4 '-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methanol

In the same manner as in Reference Example 6, the title compound was obtained as a colorless oil from 2'-methyl-4 '-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-carbaldehyde. Yield 89%.
¹ H NMR (CDCl ₃ ) δ1.59-1.76 (4H, m), 1.85-1.90 (2H, m), 1.97-2.11 (1H, m), 2.25 (3H, s), 3.60-3.67 (1H, m ), 3.91-3.99 (1H, m), 4.73 (2H, d, J = 5.8Hz), 5.46 (1H, t, J = 3.1Hz), 6.92-6.97 (2H, m), 7.14 (1H, d, J = 8.1Hz), 7.22-7.41 (4H, m).

(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル (2.71 g、13.0 mmol) および 1-ブロモ-3-クロロプロパン (2.46 g、15.6 mmol)を N,N-ジメチルホルムアミ
ド (15 mL) に溶解し、炭酸カリウム (1.98 g、14.3 mmol) を加えて、窒素雰囲気下、室温で 24 時間攪拌した。反応液を減圧濃縮し、水を加えて、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (5%〜30% 酢酸エチル／ヘキサン)で精製し、表題化合物 (2.95 g、収率 80%) を無色油状物として得た。
MS m/z 285 (MH⁺)。
参考例３８ 4-{[(2-フェニルエチル)(4-フェニル-1,3-チアゾール-2-イル)アミノ]メチ
ル}安息香酸メチル

4-フェニル-N-(2-フェニルエチル)-1,3-チアゾール-2-アミン (4.63 g、16.5 mmol) の
N,N-ジメチルホルムアミド (50 mL) 溶液に水素化ナトリウム (60% 油性、990mg、24.8 mmol) を加えて 30 分間撹拌した後、4-(ブロモメチル)安息香酸メチル (4.54 g、19.8 mmol) を加えた。混合物を室温で2 時間撹拌した後、反応液に水を加え、酢酸エチルで抽
出した。抽出液を水洗した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 (3.39g、収率 48%) を黄色油状物として得た。
¹H NMR (CDCl₃) δ： 3.00(2H, t, J=7.8Hz), 3.69(2H, t, J=7.8Hz), 3.90(3H, s), 4.71(2H, s), 6.76(1H, s), 7.18-7.41(10H, m), 7.86-7.88(2H, m), 7.98-8.00(2H, m)。
参考例３９ (4-{[(2-フェニルエチル)(4-フェニル-1,3-チアゾール-2-イル)アミノ]メチル}フェニル)メタノール

参考例４１と同様にして、4-{[(2-フェニルエチル)(4-フェニル-1,3-チアゾール-2-イ
ル)アミノ]メチル}安息香酸メチルから表題化合物を無色油状物として得た。収率81%。
¹H NMR (CDCl₃) δ： 2.99(2H, t, J=8.1Hz), 3.68(2H, t, J=8.1Hz),4.65-4.69(4H, m),
6.74(1H, s), 7.19-7.41(12H, m), 7.87-7.90(2H, m)。 Reference Example 37 Methyl [6- (3-chloropropoxy) -2,3-dihydro-1-benzofuran-3-yl] acetate

Methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate (2.71 g, 13.0 mmol) and 1-bromo-3-chloropropane (2.46 g, 15.6 mmol) in N, N-dimethylformamide (15 mL), potassium carbonate (1.98 g, 14.3 mmol) was added, and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% -30% ethyl acetate / hexane) to give the title compound (2.95 g, yield 80%) as a colorless oil.
MS m / z 285 (MH ⁺ ).
Reference Example 38 4-{[(2-Phenylethyl) (4-phenyl-1,3-thiazol-2-yl) amino] methyl} methyl benzoate

4-phenyl-N- (2-phenylethyl) -1,3-thiazol-2-amine (4.63 g, 16.5 mmol)
To a solution of N, N-dimethylformamide (50 mL) was added sodium hydride (60% oily, 990 mg, 24.8 mmol), and the mixture was stirred for 30 min, and then methyl 4- (bromomethyl) benzoate (4.54 g, 19.8 mmol) was added. added. The mixture was stirred at room temperature for 2 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.39 g, yield 48%) as a yellow oil.
¹ H NMR (CDCl ₃ ) δ: 3.00 (2H, t, J = 7.8Hz), 3.69 (2H, t, J = 7.8Hz), 3.90 (3H, s), 4.71 (2H, s), 6.76 (1H , s), 7.18-7.41 (10H, m), 7.86-7.88 (2H, m), 7.98-8.00 (2H, m).
Reference Example 39 (4-{[(2-phenylethyl) (4-phenyl-1,3-thiazol-2-yl) amino] methyl} phenyl) methanol

In the same manner as in Reference Example 41, the title compound was obtained as a colorless oil from methyl 4-{[(2-phenylethyl) (4-phenyl-1,3-thiazol-2-yl) amino] methyl} benzoate. . Yield 81%.
¹ H NMR (CDCl ₃ ) δ: 2.99 (2H, t, J = 8.1 Hz), 3.68 (2H, t, J = 8.1 Hz), 4.65-4.69 (4H, m),
6.74 (1H, s), 7.19-7.41 (12H, m), 7.87-7.90 (2H, m).

2-フェニルインドール (4.2 g、21.7 mmol) および水素化ナトリウム(60%、油性、0.96
g、24 mmol) のテトラヒドロフラン (90 mL) および N,N-ジメチルホルムアミド (10 mL) 溶液を氷冷下20分間攪拌した。反応液に4-(ブロモメチル)安息香酸メチル (5.0 g、21.8 mmol) を加え、室温で 18 時間攪拌した。反応液にクエン酸水溶液を加え、酢酸エチルで抽出した。抽出液を塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー (酢酸エチル:ヘキサン=1:10〜1:5〜1:2) に付し、表題化合物 (2.8 g、収率 38%) を淡黄色油状物として得た。
MS m/z 242 (MH⁺)。
参考例４１ {4-[(2-フェニル-1H-インドール-1-イル)メチル]フェニル}メタノール

4-[(2-フェニル-1H-インドール-1-イル)メチル]安息香酸メチル(2.8 g、8.20 mmol) を無水テトラヒドロフラン (100 mL) に溶解し、氷冷した。この溶液に 1.5 mol/L 水素化
ジイソブチルアルミニウムのトルエン溶液(13.5 mL、20.3 mmol) を滴下した。この溶液
を氷冷下で 4 時間攪拌した後、反応液にクエン酸水溶液を加え、酢酸エチルで抽出し、
塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー (酢酸エチル:ヘキサン=1:4〜1:2) に付し、表題化合物 (2.25 g、収率 88%) を無色油状物として得た。
MS m/z 314 (MH⁺)。
参考例４２ {4-[(2-メチル-1H-インドール-1-イル)メチル]フェニル}メタノール

参考例４０および参考例４１と同様にして、2-メチルインドールおよび4-(ブロモメチ
ル)安息香酸メチルから表題化合物を淡黄色結晶 (収率 14%) として得た。
MS m/z 252 (MH⁺)。 Reference Example 40 methyl 4-[(2-phenyl-1H-indol-1-yl) methyl] benzoate

2-Phenylindole (4.2 g, 21.7 mmol) and sodium hydride (60%, oily, 0.96
g, 24 mmol) in tetrahydrofuran (90 mL) and N, N-dimethylformamide (10 mL) were stirred under ice-cooling for 20 minutes. To the reaction solution was added methyl 4- (bromomethyl) benzoate (5.0 g, 21.8 mmol), and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate: hexane = 1: 10-1: 5-1: 2) to give the title compound (2.8 g, yield 38%) as a pale-yellow oil.
MS m / z 242 (MH ⁺ ).
Reference Example 41 {4-[(2-Phenyl-1H-indol-1-yl) methyl] phenyl} methanol

Methyl 4-[(2-phenyl-1H-indol-1-yl) methyl] benzoate (2.8 g, 8.20 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled on ice. To this solution was added dropwise a 1.5 mol / L diisobutylaluminum hydride toluene solution (13.5 mL, 20.3 mmol). This solution was stirred for 4 hours under ice-cooling, then an aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
The extract was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate: hexane = 1: 4 to 1: 2) to give the title compound (2.25 g, yield 88%) as a colorless oil.
MS m / z 314 (MH ⁺ ).
Reference Example 42 {4-[(2-Methyl-1H-indol-1-yl) methyl] phenyl} methanol

In the same manner as in Reference Example 40 and Reference Example 41, the title compound was obtained as pale yellow crystals (yield 14%) from 2-methylindole and methyl 4- (bromomethyl) benzoate.
MS m / z 252 (MH ⁺ ).

4'-ヒドロキシ-2',6'-ジメチル-3-ビフェニルカルバルデヒド(2.26 g、10.0 mmol) お
よびベンジルブロミド (3.42 g、20.0 mmol) の N,N-ジメチルホルムアミド (10 mL) 溶
液に炭酸カリウム(2.76 g、20.0 mmol) を加え、70 ℃ で 2 時間撹拌した。反応液に水
を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン〜10% 酢
酸エチル／ヘキサン) で精製し、表題化合物 (2.90 g、収率 92%)を無色油状物として得
た。
MS m/z 317 (MH⁺)。
参考例４４ [4'-(ベンジルオキシ)-2',6'-ジメチルビフェニル-3-イル]メタノール

参考例６と同様にして、4'-(ベンジルオキシ)-2',6'-ジメチル-3-ビフェニルカルバル
デヒドから表題化合物を無色油状物として得た。収率95%。
¹H NMR (CDCl₃) δ： 1.65(1H, t, J=5.9Hz), 2.01(6H, s), 4.73(2H, d, J=5.9Hz), 5.07(2H, s), 6.75(2H, s), 7.07(1H, d, J=7.3Hz), 7.13(1H,s), 7.30-7.48(7H, m)。
参考例４５ 4'-(2-エトキシエトキシ)-2',6'-ジメチル-3-ビフェニルカルバルデヒド

4'-ヒドロキシ-2',6'-ジメチル-3-ビフェニルカルバルデヒド(8.52 g、37.7 mmol) お
よび 2-クロロエチル エチル エーテル (6.15 g、56.6 mmol) の N,N-ジメチルホルムア
ミド(40 mL) 溶液に炭酸カリウム (6.25 g、45.2 mmol) およびヨウ化カリウム (1.25 g
、7.54 mmol) を加え、80 ℃ で18 時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%〜25% 酢酸エチル／ヘキサン) で精製し、
表題化合物 (10.0 g、収率 89%)を無色油状物として得た。
MS m/z 299 (MH⁺)。 Reference Example 43 4 '-(Benzyloxy) -2', 6'-dimethyl-3-biphenylcarbaldehyde

4'-Hydroxy-2 ', 6'-dimethyl-3-biphenylcarbaldehyde (2.26 g, 10.0 mmol) and benzyl bromide (3.42 g, 20.0 mmol) in N, N-dimethylformamide (10 mL) in potassium carbonate (2.76 g, 20.0 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-10% ethyl acetate / hexane) to give the title compound (2.90 g, yield 92%) as a colorless oil.
MS m / z 317 (MH ⁺ ).
Reference Example 44 [4 '-(benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methanol

In the same manner as in Reference Example 6, the title compound was obtained as a colorless oil from 4 ′-(benzyloxy) -2 ′, 6′-dimethyl-3-biphenylcarbaldehyde. Yield 95%.
¹ H NMR (CDCl ₃ ) δ: 1.65 (1H, t, J = 5.9Hz), 2.01 (6H, s), 4.73 (2H, d, J = 5.9Hz), 5.07 (2H, s), 6.75 (2H , s), 7.07 (1H, d, J = 7.3 Hz), 7.13 (1H, s), 7.30-7.48 (7H, m).
Reference Example 45 4 '-(2-Ethoxyethoxy) -2', 6'-dimethyl-3-biphenylcarbaldehyde

4'-hydroxy-2 ', 6'-dimethyl-3-biphenylcarbaldehyde (8.52 g, 37.7 mmol) and 2-chloroethyl ethyl ether (6.15 g, 56.6 mmol) in N, N-dimethylformamide (40 mL) Potassium carbonate (6.25 g, 45.2 mmol) and potassium iodide (1.25 g
7.54 mmol), and the mixture was stirred at 80 ° C. for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% -25% ethyl acetate / hexane)
The title compound (10.0 g, yield 89%) was obtained as a colorless oil.
MS m / z 299 (MH ⁺ ).

4'-(2-エトキシエトキシ)-2',6'-ジメチル-3-ビフェニルカルバルデヒド (2.39 g、9.70 mmol) を1,2-ジメトキシエタン(20 mL) およびテトラヒドロフラン (20 mL) の混液に
溶解させ、氷冷下で水素化ホウ素ナトリウム(0.227 g、6.00 mmol) を加えた後、同温で 3 時間撹拌した。反応液に塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（20%〜50%酢酸エチル／ヘキサン）で精製し、表題化合物
(3.55 g、収率 98%) を無色結晶として得た。
MSm/z 301 (MH⁺)。
参考例４７ (6-ベンジルオキシ-2’,6’-ジメチルビフェニル-3-イル)メタノール

参考例２２および参考例２３と同様にして、4-ベンジルオキシ-3-ブロモ安息香酸メチ
ルおよび(2,6-ジメチルフェニル)ボロン酸から表題化合物を無色油状物として得た。収率
37％。
¹H NMR (CDCl₃) δ： 1.56(1H, t, J=5.6Hz), 2.04(6H, s),4.65(2H, d, J=5.6Hz), 5.03(2H, s), 6.96-7.44(11H, m)。
参考例４８ 5-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-1H-インドール

(2',6'-ジメチルビフェニル-3-イル)メタノール (1.0g、4.71 mmol)、5-ヒドロキシイ
ンドール (0.63 g、4.73 mmol) およびトリブチルホスフィン (1.5 mL、6.02 mmol) のテトラヒドロフラン(30 mL) 溶液を攪拌し、1,1'-(アゾジカルボニル)ジピペリジン (1.6 g、6.34 mmol) を少量ずつ加え、室温で 18 時間撹拌した。反応液にジエチルエーテル(30
mL) を加え、析出した不溶物を濾別して、濾液を減圧濃縮した。残渣をシリカゲルカラ
ムクロマトグラフィー (酢酸エチル:ヘキサン=1:10〜1:5) で精製して、表題化合物(0.95
g、収率 62%) を淡茶色油状物として得た。
MS m/z 328 (MH⁺)。 Reference Example 46 [4 '-(2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methanol

4 '-(2-Ethoxyethoxy) -2', 6'-dimethyl-3-biphenylcarbaldehyde (2.39 g, 9.70 mmol) was mixed with 1,2-dimethoxyethane (20 mL) and tetrahydrofuran (20 mL). After dissolution, sodium borohydride (0.227 g, 6.00 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 3 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% -50% ethyl acetate / hexane) to give the title compound
(3.55 g, yield 98%) was obtained as colorless crystals.
MS m / z 301 (MH ⁺ ).
Reference Example 47 (6-Benzyloxy-2 ′, 6′-dimethylbiphenyl-3-yl) methanol

In the same manner as in Reference Example 22 and Reference Example 23, the title compound was obtained as a colorless oil from methyl 4-benzyloxy-3-bromobenzoate and (2,6-dimethylphenyl) boronic acid. yield
37%.
¹ H NMR (CDCl ₃ ) δ: 1.56 (1H, t, J = 5.6 Hz), 2.04 (6H, s), 4.65 (2H, d, J = 5.6 Hz), 5.03 (2H, s), 6.96-7.44 (11H, m).
Reference Example 48 5-[(2 ′, 6′-Dimethylbiphenyl-3-yl) methoxy] -1H-indole

(2 ', 6'-dimethylbiphenyl-3-yl) methanol (1.0 g, 4.71 mmol), 5-hydroxyindole (0.63 g, 4.73 mmol) and tributylphosphine (1.5 mL, 6.02 mmol) in tetrahydrofuran (30 mL) The solution was stirred and 1,1 ′-(azodicarbonyl) dipiperidine (1.6 g, 6.34 mmol) was added in small portions and stirred at room temperature for 18 hours. Diethyl ether (30
mL) was added, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 5) to give the title compound (0.95
g, yield 62%) was obtained as a light brown oil.
MS m / z 328 (MH ⁺ ).

2-クロロ-3-ヒドロキシシクロヘキサ-2-エン-1-オン(4.4 g、30 mmol)、チオ尿素 (2.66 g、35 mmol)、およびエタノール (15 mL) の混合物を 1 時間加熱環流した。反応混合
物をジイソプロピルエーテル(50 mL) で希釈し、析出した固体を濾取、ジイソプロピルエーテルで洗浄後、風乾して、表題化合物 (3.90 g、収率 52%) を無色結晶として得た。
¹H NMR (DMSO-d₆) δ： 2.0-2.2(2H, m), 2.44(2H, t, J=6.2Hz), 2.77(2H, t, J=6.2Hz), 9.38(3H, br s)。
参考例５０ 2-クロロ-5,6-ジヒドロ-1,3-ベンゾチアゾール-7(4H)-オン

2-アミノ-5,6-ジヒドロ-1,3-ベンゾチアゾール-7(4H)-オン臭化水素酸塩 (3.75 g、15 mmol)、無水塩化第二銅 (2.01 g、15 mmol)、トリエチルアミン (1.5 g、15 mmol)、およびアセトニトリル(50 mL) の混合物に氷冷下、亜硝酸 t-ブチル (1.70 g、16.5 mmol) を滴下し、氷冷下 1 時間攪拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。有機
層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(AcOEt:hexane=1:19〜1:1) で精製して
、表題化合物 (2.3 g、収率82%) を淡黄色油状物として得た。
¹H NMR (CDCl₃) δ： 2.15-2.30(2H, m), 2.63(2H, t, J=6.1Hz), 3.02(2H, t, J=6.1Hz)。
参考例５１ 2-[(3-フェノキシベンジル)チオ]-5,6-ジヒドロ-1,3-ベンゾチアゾール-7(4H)-オン

3-フェノキシベンジルクロリド (2.84 g、13.0mmol)、チオ尿素 (1.22 g、16 mmol)、
エタノール (30 mL) の混合物を 1 時間加熱環流した。反応混合物に 1 M 水酸化ナトリ
ウム水溶液(20 mL) を加え、さらに 1 時間加熱環流した。反応混合物を冷却して、2-ク
ロロ-5,6-ジヒドロ-1,3-ベンゾチアゾール-7(4H)-オン(1.55 g, 7.99 mmol) を加え、室
温で 3 時間攪拌した。反応混合物を 1 M 塩酸で中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、濃縮して残留物をシリカゲルカラムクロマトグラフィー(AcOEt:hexane=1:19〜1:1) で精製して、表題化合物 (2.67 g、収率91%) を淡黄色油状物として得た。
¹H NMR (CDCl₃) δ： 2.12-2.23(2H, m), 2.55-2.62(2H, m), 2.96(2H, t, J=6.2Hz), 4.44(2H, s), 6.90-6.96(1H, m), 6.97-7.04(2H, m), 7.04-7.17(3H, m), 7.27-7.39(3H, m)。 Reference Example 49 2-Amino-5,6-dihydro-1,3-benzothiazol-7 (4H) -one hydrobromide

A mixture of 2-chloro-3-hydroxycyclohex-2-en-1-one (4.4 g, 30 mmol), thiourea (2.66 g, 35 mmol), and ethanol (15 mL) was heated to reflux for 1 hour. The reaction mixture was diluted with diisopropyl ether (50 mL), and the precipitated solid was collected by filtration, washed with diisopropyl ether, and then air-dried to obtain the title compound (3.90 g, yield 52%) as colorless crystals.
¹ H NMR (DMSO-d ₆ ) δ: 2.0-2.2 (2H, m), 2.44 (2H, t, J = 6.2Hz), 2.77 (2H, t, J = 6.2Hz), 9.38 (3H, br s ).
Reference Example 50 2-Chloro-5,6-dihydro-1,3-benzothiazol-7 (4H) -one

2-Amino-5,6-dihydro-1,3-benzothiazol-7 (4H) -one hydrobromide (3.75 g, 15 mmol), anhydrous cupric chloride (2.01 g, 15 mmol), triethylamine To a mixture of (1.5 g, 15 mmol) and acetonitrile (50 mL), t-butyl nitrite (1.70 g, 16.5 mmol) was added dropwise under ice cooling, followed by stirring for 1 hour under ice cooling. 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, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (AcOEt: hexane = 1: 19-1: 1) to give the title compound (2.3 g, yield 82%) as a pale yellow oil.
¹ H NMR (CDCl ₃ ) δ: 2.15-2.30 (2H, m), 2.63 (2H, t, J = 6.1 Hz), 3.02 (2H, t, J = 6.1 Hz).
Reference Example 51 2-[(3-phenoxybenzyl) thio] -5,6-dihydro-1,3-benzothiazol-7 (4H) -one

3-phenoxybenzyl chloride (2.84 g, 13.0 mmol), thiourea (1.22 g, 16 mmol),
A mixture of ethanol (30 mL) was heated to reflux for 1 hour. To the reaction mixture was added 1 M aqueous sodium hydroxide solution (20 mL), and the mixture was further refluxed with heating for 1 hour. The reaction mixture was cooled, 2-chloro-5,6-dihydro-1,3-benzothiazol-7 (4H) -one (1.55 g, 7.99 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the residue is purified by silica gel column chromatography (AcOEt: hexane = 1: 19-1: 1) to give the title compound (2.67 g, 91% yield) was obtained as a pale yellow oil.
¹ H NMR (CDCl ₃ ) δ: 2.12-2.23 (2H, m), 2.55-2.62 (2H, m), 2.96 (2H, t, J = 6.2Hz), 4.44 (2H, s), 6.90-6.96 ( 1H, m), 6.97-7.04 (2H, m), 7.04-7.17 (3H, m), 7.27-7.39 (3H, m).

2- [(3-フェノキシベンジル)チオ]-5,6-ジヒドロ-1,3-ベンゾチアゾール-7(4H)-オン(2.50 g、6.80 mmol) のテトラヒドロフラン (50 mL) 溶液に、氷冷下、水素化リチウムア
ルミニウム (280 mg) を少量づつ加え、同温で1 時間攪拌した。反応混合物に硫酸ナトリウム 十水和物 (1.5 g) を加え、室温で 1 時間攪拌後、不溶物を濾別した。濾液を減圧
濃縮して、表題化合物(2.20 g、収率87%) を無色油状物として得た。
¹H NMR (CDCl₃) δ： 1.77-2.11(5H, m), 2.59-2.85(2H, m), 4.35(2H, s), 4.85-4.92(1H, m), 6.87-6.93(1H, m), 6.96-7.04(3H, m), 7.07-7.15(2H, m), 7.23-7.37(3H, m)。
参考例５３ {2-[(3-フェノキシベンジル)チオ]-4,5,6,7-テトラヒドロ-1,3-ベンゾチア
ゾール-7-イル}マロン酸ジエチル

2-[(3-フェノキシベンジル)チオ]-4,5,6,7-テトラヒドロ-1,3-ベンゾチアゾール-7-オ
ール(2.00 g、5.41 mmol)、塩化チオニル (0.723 mL)およびトルエン (10 mL) の混合物
を室温で 3 時間攪拌した。反応混合物を濃縮し、残留物をテトラヒドロフラン(10 mL)
に溶解し、マロン酸ジエチル (1.60 g、10 mmol)、水素化ナトリウム (60% 油性、400 mg)およびテトラヒドロフラン(20 mL) の混合物に室温で加え、同温で 3 時間攪拌した。反応混合物を 1 M 塩酸で中和し、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次
洗浄し、無水硫酸マグネシウムで乾燥後、濃縮して残留物をシリカゲルカラムクロマトグラフィー(AcOEt:hexane=1:19〜2:1) で精製して、表題化合物 (2.73 g、定量的) を淡黄
色油状物として得た。
¹H NMR (CDCl₃) δ： 1.19-1.33(6H, m), 1.69-1.95(4H, m), 2.73(2H, t, J=4.9Hz), 3.52(1H, d, J=9.0Hz), 3.63-3.75(1H, m), 4.06-4.27(4H, m), 4.31(2H, s), 6.85-7.15(6H, m), 7.21-7.37(3H, m)。 Reference Example 52 2-[(3-phenoxybenzyl) thio] -4,5,6,7-tetrahydro-1,3-benzothiazol-7-ol

To a solution of 2-[(3-phenoxybenzyl) thio] -5,6-dihydro-1,3-benzothiazol-7 (4H) -one (2.50 g, 6.80 mmol) in tetrahydrofuran (50 mL) under ice-cooling Lithium aluminum hydride (280 mg) was added in small portions and stirred at the same temperature for 1 hour. Sodium sulfate decahydrate (1.5 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr, and insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (2.20 g, yield 87%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ: 1.77-2.11 (5H, m), 2.59-2.85 (2H, m), 4.35 (2H, s), 4.85-4.92 (1H, m), 6.87-6.93 (1H, m ), 6.96-7.04 (3H, m), 7.07-7.15 (2H, m), 7.23-7.37 (3H, m).
Reference Example 53 {2-[(3-phenoxybenzyl) thio] -4,5,6,7-tetrahydro-1,3-benzothiazol-7-yl} diethyl malonate

2-[(3-phenoxybenzyl) thio] -4,5,6,7-tetrahydro-1,3-benzothiazol-7-ol (2.00 g, 5.41 mmol), thionyl chloride (0.723 mL) and toluene (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was tetrahydrofuran (10 mL)
The mixture was added to a mixture of diethyl malonate (1.60 g, 10 mmol), sodium hydride (60% oily, 400 mg) and tetrahydrofuran (20 mL) at room temperature, and stirred at the same temperature for 3 hours. The reaction mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the residue is purified by silica gel column chromatography (AcOEt: hexane = 1: 19-2: 1) to give the title compound (2.73 g, quantitative) was obtained as a pale yellow oil.
¹ H NMR (CDCl ₃ ) δ: 1.19-1.33 (6H, m), 1.69-1.95 (4H, m), 2.73 (2H, t, J = 4.9Hz), 3.52 (1H, d, J = 9.0Hz) , 3.63-3.75 (1H, m), 4.06-4.27 (4H, m), 4.31 (2H, s), 6.85-7.15 (6H, m), 7.21-7.37 (3H, m).

［工程１］氷冷したホスホノ酢酸トリエチル (20.2 g、90.0 mmol) のトルエン (100 mL)
溶液に水素化ナトリウム (60% 油性、3.60 g、90.0mmol) を少しずつ加えた後、窒素雰
囲気下で 50 ℃ まで昇温して 1.5 時間撹拌した。反応液を氷冷し、6-メトキシ-1-テト
ラロン (10.6 g、60.0 mmol) のトルエン(100 mL) 溶液を滴下して 10 時間加熱還流した。室温まで冷却した後、水を加えて酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%〜50% 酢酸エチル／ヘキサン) で精製して、(6-メトキシ-3,4-ジヒドロナフタレン-1-イル)酢酸エチルおよび (2E)-(6-メトキシ-3,4-ジヒドロナフタレン-1(2H)-イリデン)酢酸エチルの混合物(11.0 g) を淡黄色油状物として得た。
［工程２］本品をジクロロメタン (300 mL) に溶解し、窒素雰囲気下 -78 ℃ で 1 M 三
臭化ホウ素ジクロロメタン (135 mL、135 mmol) 溶液を滴下後、同温で4 時間、室温まで昇温してさらに 1 時間攪拌した。反応液を氷冷した飽和炭酸水素ナトリウム水溶液に加
え、室温で 12 時間攪拌した。有機相を分離し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(15%〜50% 酢酸エチル／ヘキサン) で精製し、(6-ヒドロキシ-3,4-ジヒドロナフタレン-1-イル)酢酸エチルおよび (2E)-(6-ヒドロキシ-3,4-ジヒドロナフタレン-1(2H)-イリデン)酢酸エチルの混合物(5.5 g) を淡茶色油状物として得た。
［工程３］本品をトルエン (25 mL) に溶解し、3-フェノキシベンジルアルコール (2.40 g、12.0 mmol) およびトリブチルホスフィン (2.99 mL、12.0 mmol) を加えて氷冷後、1,
1'-(アゾジカルボニル)ジピペリジン(3.03 g、12.0 mmol) およびテトラヒドロフラン (150 mL) を加え、窒素雰囲気下、室温で 8 時間攪拌した。反応混合物を減圧濃縮し、残渣にトルエン／ヘキサン(2:1) 混合溶液を加えることにより生じる不溶物を濾別した。濾液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー (5%〜10% 酢酸エチル／ヘキサン)で精製して、無色油状の表題化合物 (2.33 g、収率 70%) を主生成物とし
て得た。
MS m/z 415 (MH⁺)。 Example 1 Ethyl {6-[(3-phenoxybenzyl) oxy] -3,4-dihydronaphthalen-1-yl} acetate

[Step 1] Ice-cooled triethyl phosphonoacetate (20.2 g, 90.0 mmol) in toluene (100 mL)
To the solution was added sodium hydride (60% oily, 3.60 g, 90.0 mmol) little by little, and then the mixture was heated to 50 ° C. under a nitrogen atmosphere and stirred for 1.5 hr. The reaction mixture was ice-cooled, and a solution of 6-methoxy-1-tetralone (10.6 g, 60.0 mmol) in toluene (100 mL) was added dropwise and heated to reflux for 10 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% -50% ethyl acetate / hexane) to give ethyl (6-methoxy-3,4-dihydronaphthalen-1-yl) acetate and (2E)-(6-methoxy- A mixture (11.0 g) of ethyl 3,4-dihydronaphthalene-1 (2H) -ylidene) acetate was obtained as a pale yellow oil.
[Step 2] Dissolve this product in dichloromethane (300 mL) and add 1 M boron tribromide dichloromethane (135 mL, 135 mmol) dropwise at -78 ° C under a nitrogen atmosphere, then at the same temperature for 4 hours until room temperature The temperature was raised and the mixture was further stirred for 1 hour. The reaction solution was added to ice-cooled saturated aqueous sodium hydrogen carbonate solution and stirred at room temperature for 12 hours. The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% -50% ethyl acetate / hexane) and ethyl (6-hydroxy-3,4-dihydronaphthalen-1-yl) acetate and (2E)-(6-hydroxy-3 , 4-Dihydronaphthalene-1 (2H) -ylidene) ethyl acetate mixture (5.5 g) was obtained as a light brown oil.
[Step 3] Dissolve this product in toluene (25 mL), add 3-phenoxybenzyl alcohol (2.40 g, 12.0 mmol) and tributylphosphine (2.99 mL, 12.0 mmol), cool with ice,
1 '-(Azodicarbonyl) dipiperidine (3.03 g, 12.0 mmol) and tetrahydrofuran (150 mL) were added, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the insoluble matter produced by adding a toluene / hexane (2: 1) mixed solution to the residue was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (5% -10% ethyl acetate / hexane) to give the title compound (2.33 g, yield 70%) as a main product as a colorless oil. Obtained.
MS m / z 415 (MH ⁺ ).

{6-[(3-フェノキシベンジル)オキシ]-3,4-ジヒドロナフタレン-1-イル}酢酸エチル (0.622 g、1.50 mmol) のエタノール (3 mL) およびテトラヒドロフラン (3 mL) 混合溶液に2 M 水酸化ナトリウム水溶液 (3 mL) を加え、室温で 1 時間さらに 70 ℃ で 5 時間撹
拌した。反応液に水を加え、1 M 塩酸で酸性にして、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (20%〜80% 酢酸エチル／ヘキサン)で精製し、酢酸エチル−ヘキサンから再結晶して、表題化合物 (0.198 g、収率 34%) を無色針状晶として得た。
MS m/z 387 (MH⁺)。
実施例３ (2E)-[6-[(3-フェノキシベンジル)オキシ]-3,4-ジヒドロナフタレン-1(2H)-イリデン]酢酸エチル

無色油状の表題化合物 (0.42 g、13%) を実施例１の副生成物として得た。
¹HNMR (CDCl₃) δ： 1.31(3H, t, J=7.2Hz), 1.79-1.88(2H, m), 2.76(2H, t, J=6.1Hz),
3.15-3.20(2H, m), 4.19(2H, q, J=7.2Hz), 5.04(2H, s), 6.23(1H, s), 6.71(1H, d, J=2.5Hz), 6.79(1H, dd, J=8.9, 2.5Hz), 6.96(1H, dd, J=8.1, 1.9Hz), 7.01(2H, dd, J=8.6, 1.0Hz), 7.08-7.17(3H, m), 7.31-7.37(3H, m), 7.61(1H, d, J=8.9Hz)。
実施例４ (2E)-[6-[(3-フェノキシベンジル)オキシ]-3,4-ジヒドロナフタレン-1(2H)-イリデン]酢酸

実施例２と同様にして、(2E)-[6-[(3-フェノキシベンジル)オキシ]-3,4-ジヒドロナフ
タレン-1(2H)-イリデン]酢酸エチルから表題化合物を無色針状晶として得た。収率 41% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 387 (MH⁺)。 Example 2 {6-[(3-phenoxybenzyl) oxy] -3,4-dihydronaphthalen-1-yl} acetic acid

Add 2 M to a mixed solution of {6-[(3-phenoxybenzyl) oxy] -3,4-dihydronaphthalen-1-yl} ethyl acetate (0.622 g, 1.50 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL). Aqueous sodium hydroxide (3 mL) was added, and the mixture was stirred at room temperature for 1 hr and further at 70 ° C. for 5 hr. Water was added to the reaction mixture, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% -80% ethyl acetate / hexane) and recrystallized from ethyl acetate-hexane to give the title compound (0.198 g, yield 34%) as colorless needle crystals. .
MS m / z 387 (MH ⁺ ).
Example 3 (2E)-[6-[(3-phenoxybenzyl) oxy] -3,4-dihydronaphthalene-1 (2H) -ylidene] ethyl acetate

The title compound (0.42 g, 13%) as a colorless oil was obtained as a byproduct of Example 1.
¹ HNMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.2 Hz), 1.79-1.88 (2H, m), 2.76 (2H, t, J = 6.1 Hz),
3.15-3.20 (2H, m), 4.19 (2H, q, J = 7.2Hz), 5.04 (2H, s), 6.23 (1H, s), 6.71 (1H, d, J = 2.5Hz), 6.79 (1H , dd, J = 8.9, 2.5Hz), 6.96 (1H, dd, J = 8.1, 1.9Hz), 7.01 (2H, dd, J = 8.6, 1.0Hz), 7.08-7.17 (3H, m), 7.31- 7.37 (3H, m), 7.61 (1H, d, J = 8.9Hz).
Example 4 (2E)-[6-[(3-phenoxybenzyl) oxy] -3,4-dihydronaphthalene-1 (2H) -ylidene] acetic acid

In the same manner as in Example 2, the title compound was obtained as colorless needles from (2E)-[6-[(3-phenoxybenzyl) oxy] -3,4-dihydronaphthalene-1 (2H) -ylidene] ethyl acetate. Obtained. Yield 41% (recrystallized from hexane-ethyl acetate).
MS m / z 387 (MH ⁺ ).

(6-((3-フェノキシベンジル)オキシ)-3,4-ジヒドロ-1-ナフタレニル)酢酸エチル(1.04 g、2.51 mmol) および 2,2'-ビピリジル (0.197 g、1.26 mmol) の1,4-ジオキサン (10 mL) 溶液に10% パラジウム−炭素 (50%、含水品、0.2 g) を加え、水素雰囲気下 (風船圧)、 室温で 24 時間攪拌した。触媒を濾別し、濾液を減圧濃縮した。残渣をシリカゲルカ
ラムクロマトグラフィー (ヘキサン〜30% 酢酸エチル／ヘキサン) で精製して、表題化合物 (0.481g、収率 46%) を無色油状物として得た。
MS m/z 417 (MH⁺)。
実施例６ (6-((3-フェノキシベンジル)オキシ)-1,2,3,4-テトラヒドロ-1-ナフタレニル)酢酸

(6- ((3-フェノキシベンジル)オキシ)-1,2,3,4-テトラヒドロ-1-ナフタレニル)酢酸エ
チル (0.481 g、1.15 mmol) のエタノール(4 mL) およびテトラヒドロフラン (4 mL) 混
合溶液に 2 M 水酸化ナトリウム水溶液 (2 mL) を加え、室温で 9 時間撹拌した。反応液に水を加え、10%クエン酸水溶液で中和して、酢酸エチルで抽出した。抽出液を飽和食塩
水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣を酢酸エチル−ヘキサンから再結晶して、表題化合物 (0.360 g、収率 81%) を無色針状晶として得た。
¹HNMR (CDCl₃) δ： 1.68-2.00(4H, m), 2.56(1H, dd, J=15.5, 9.9Hz), 2.65-2.81(3H, m), 3.27-3.35(1H, m), 4.99(2H, s), 6.67(1H, d, J=2.6Hz), 6.76(1H, dd, J=8.4, 2.6Hz), 6.92-6.96(1H, m), 6.99-7.03(2H, m),7.08-7.17(4H, m), 7.31-7.37(3H, m)。
実施例７ {6-[(3-フェノキシベンジル)オキシ]-1H-インデン-3-イル}酢酸

実施例１および実施例２と同様にして、5-メトキシ-1-インダノンおよび 3-フェノキシベンジルアルコールから表題化合物を淡茶色粘稠性油状物として得た。収率 4%。
MS m/z 373 (MH⁺)。 Example 5 Ethyl (6-((3-phenoxybenzyl) oxy) -1,2,3,4-tetrahydro-1-naphthalenyl) acetate

(6-((3-phenoxybenzyl) oxy) -3,4-dihydro-1-naphthalenyl) ethyl acetate (1.04 g, 2.51 mmol) and 2,2'-bipyridyl (0.197 g, 1.26 mmol) of 1,4 -To a dioxane (10 mL) solution was added 10% palladium-carbon (50%, water-containing product, 0.2 g), and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere (balloon pressure). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-30% ethyl acetate / hexane) to give the title compound (0.481 g, yield 46%) as a colorless oil.
MS m / z 417 (MH ⁺ ).
Example 6 (6-((3-phenoxybenzyl) oxy) -1,2,3,4-tetrahydro-1-naphthalenyl) acetic acid

(6-((3-phenoxybenzyl) oxy) -1,2,3,4-tetrahydro-1-naphthalenyl) ethyl acetate (0.481 g, 1.15 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) To the mixture was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 9 hr. Water was added to the reaction solution, neutralized with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.360 g, yield 81%) as colorless needle crystals.
¹ HNMR (CDCl ₃ ) δ: 1.68-2.00 (4H, m), 2.56 (1H, dd, J = 15.5, 9.9Hz), 2.65-2.81 (3H, m), 3.27-3.35 (1H, m), 4.99 (2H, s), 6.67 (1H, d, J = 2.6Hz), 6.76 (1H, dd, J = 8.4, 2.6Hz), 6.92-6.96 (1H, m), 6.99-7.03 (2H, m), 7.08-7.17 (4H, m), 7.31-7.37 (3H, m).
Example 7 {6-[(3-phenoxybenzyl) oxy] -1H-inden-3-yl} acetic acid

In the same manner as in Example 1 and Example 2, the title compound was obtained as a light brown viscous oil from 5-methoxy-1-indanone and 3-phenoxybenzyl alcohol. Yield 4%.
MS m / z 373 (MH ⁺ ).

8-ヒドロキシ-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-カルボン酸エチル(0.189 g、0.800 mmol)、3-フェノキシベンジルアルコール (0.240 g、1.20 mmol) およびトリブチルホスフィン (0.299 mL、1.20 mmol) のトルエン (8 mL) 溶液を氷冷下攪拌し、1,1'-(アゾジカルボニル)ジピペリジン(0.279 g、1.20 mmol) を少量ずつ加え、窒素雰囲気下
、室温で 8 時間撹拌した。反応液にヘキサン (4 mL) を加え、析出した不溶物を濾別し
て、濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%〜20% 酢酸エ
チル／ヘキサン) で精製して、表題化合物 (0.20 g、収率 60%) を無色油状物として得た。
MS m/z 419 (MH⁺)。
実施例９ 8-[(3-フェノキシベンジル)オキシ]-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-カルボン酸

実施例６と同様にして、8-[(3-フェノキシベンジル)オキシ]-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-カルボン酸エチルから表題化合物を無色プリズム晶として得た。収
率 87%。
MS m/z 391 (MH⁺)。
実施例１０ {6-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-1,2,3,4-テトラヒドロ
ナフタレン-1-イル}酢酸エチル

実施例８と同様にして、(6-ヒドロキシ-1,2,3,4-テトラヒドロナフタレン-1-イル)酢酸エチルおよび (2',6'-ジメチルビフェニル-3-イル)メタノールから表題化合物を無色油状物として得た。収率 23%。
MS m/z 429 (MH⁺)。 Example 8 Ethyl 8-[(3-phenoxybenzyl) oxy] -2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate

8-Hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate (0.189 g, 0.800 mmol), 3-phenoxybenzyl alcohol (0.240 g, 1.20 mmol) and tributylphosphine (0.299 mL, 1.20 mmol) in toluene (8 mL) was stirred under ice-cooling, 1,1 '-(azodicarbonyl) dipiperidine (0.279 g, 1.20 mmol) was added in small portions, and the mixture was stirred at room temperature for 8 hours under a nitrogen atmosphere. . Hexane (4 mL) was added to the reaction solution, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% -20% ethyl acetate / hexane) to give the title compound (0.20 g, yield 60%) as a colorless oil.
MS m / z 419 (MH ⁺ ).
Example 9 8-[(3-phenoxybenzyl) oxy] -2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylic acid

In the same manner as in Example 6, the title compound was obtained as colorless prism crystals from ethyl 8-[(3-phenoxybenzyl) oxy] -2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate. Yield 87%.
MS m / z 391 (MH ⁺ ).
Example 10 {6-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1,2,3,4-tetrahydronaphthalen-1-yl} ethyl acetate

In the same manner as in Example 8, the title compound was obtained from (6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) ethyl acetate and (2 ′, 6′-dimethylbiphenyl-3-yl) methanol. Obtained as a colorless oil. Yield 23%.
MS m / z 429 (MH ⁺ ).

{6-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-1,2,3,4-テトラヒドロナフタレン-1-イル}酢酸エチル (0.15 g、0.35 mmol) のエタノール (1 mL) およびテトラヒドロフラン (1 mL) 混合溶液に2 M 水酸化ナトリウム水溶液 (0.5 mL) を加え、室温で 18 時間撹拌した。反応液に水を加え、1 M 塩酸で酸性にして、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣を酢酸エチル−ヘキサンから再結晶して、表題化合物 (0.08 g、収率 57%) を無色プリズム晶として得た。
¹HNMR (CDCl₃) δ： 1.67-1.98(4H, m), 2.01(6H, s), 2.55(1H, dd, J=15.5, 9.9Hz), 2.70-2.77(3H, m), 3.26-3.34(1H, m), 5.08(2H, s), 6.68(1H, d, J=2.6Hz), 6.78(1H, dd, J=8.5, 2.6Hz), 7.07-7.19(6H, m), 7.37-7.46(2H, m)。
実施例１２ 8-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-カルボン酸エチル

実施例８と同様にして、8-ヒドロキシ-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-
カルボン酸エチルおよび(2',6'-ジメチルビフェニル-3-イル)メタノールから表題化合物
を無色油状物として得た。収率 33%。
MS m/z 431 (MH⁺)。
実施例１３ 8-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3,4,5-テトラヒドロ-1
-ベンゾオキセピン-4-カルボン酸

実施例６と同様にして、8-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-カルボン酸エチルから表題化合物を無色プリズム晶として得た。収率 87%。
MS m/z 403 (MH⁺)。 Example 11 {6-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1,2,3,4-tetrahydronaphthalen-1-yl} acetic acid

{6-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1,2,3,4-tetrahydronaphthalen-1-yl} ethyl acetate (0.15 g, 0.35 mmol) in ethanol (1 mL ) And tetrahydrofuran (1 mL) mixed solution was added 2 M aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.08 g, yield 57%) as colorless prism crystals.
¹ HNMR (CDCl ₃ ) δ: 1.67-1.98 (4H, m), 2.01 (6H, s), 2.55 (1H, dd, J = 15.5, 9.9Hz), 2.70-2.77 (3H, m), 3.26-3.34 (1H, m), 5.08 (2H, s), 6.68 (1H, d, J = 2.6Hz), 6.78 (1H, dd, J = 8.5, 2.6Hz), 7.07-7.19 (6H, m), 7.37- 7.46 (2H, m).
Example 12 Ethyl 8-[(2 ′, 6′-dimethylbiphenyl-3-yl) methoxy] -2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate

In the same manner as in Example 8, 8-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-4-
The title compound was obtained as a colorless oil from ethyl carboxylate and (2 ′, 6′-dimethylbiphenyl-3-yl) methanol. Yield 33%.
MS m / z 431 (MH ⁺ ).
Example 13 8-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -2,3,4,5-tetrahydro-1
-Benzoxepin-4-carboxylic acid

In the same manner as in Example 6, the title compound was obtained from ethyl 8-[(2 ′, 6′-dimethylbiphenyl-3-yl) methoxy] -2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate. Was obtained as colorless prism crystals. Yield 87%.
MS m / z 403 (MH ⁺ ).

実施例８と同様にして、(5-ヒドロキシ-2,3-ジヒドロ-1H-インデン-1-イル)酢酸エチルおよび 3-フェノキシベンジルアルコールから表題化合物を無色油状物として得た。収率 83%。
MS m/z 403 (MH⁺)。
実施例１５ {5-[(3-フェノキシベンジル)オキシ]-2,3-ジヒドロ-1H-インデン-1-イル}酢酸

実施例１１と同様にして、{5-[(3-フェノキシベンジル)オキシ]-2,3-ジヒドロ-1H-インデン-1-イル}酢酸エチルから表題化合物を無色プリズム晶として得た。収率 79% (ヘキサン−酢酸エチルから再結晶)。
¹HNMR (CDCl₃) δ： 1.72-1.84(1H, m), 2.37-2.52(2H,m), 2.76-2.97(3H, m), 3.49-3.59(1H, m), 5.01(2H, s), 6.77(1H, dd, J=8.3, 2.5Hz), 6.83(1H, s), 6.94(1H, dd, J=8.0, 1.6Hz), 6.99-7.04(2H, m), 7.08-7.17(4H, m), 7.31-7.37(3H, m)。
実施例１６ {5-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1H-イン
デン-1-イル}酢酸エチル

実施例８と同様にして、(5-ヒドロキシ-2,3-ジヒドロ-1H-インデン-1-イル)酢酸エチルおよび (2',6'-ジメチルビフェニル-3-イル)メタノールから表題化合物を無色油状物として得た。収率 24%。
MS m/z 415 (MH⁺)。 Example 14 {5-[(3-phenoxybenzyl) oxy] -2,3-dihydro-1H-inden-1-yl} ethyl acetate

In the same manner as in Example 8, the title compound was obtained as a colorless oil from ethyl (5-hydroxy-2,3-dihydro-1H-inden-1-yl) acetate and 3-phenoxybenzyl alcohol. Yield 83%.
MS m / z 403 (MH ⁺ ).
Example 15 {5-[(3-phenoxybenzyl) oxy] -2,3-dihydro-1H-inden-1-yl} acetic acid

In the same manner as in Example 11, the title compound was obtained as colorless prism crystals from {5-[(3-phenoxybenzyl) oxy] -2,3-dihydro-1H-inden-1-yl} ethyl acetate. Yield 79% (recrystallized from hexane-ethyl acetate).
¹ HNMR (CDCl ₃ ) δ: 1.72-1.84 (1H, m), 2.37-2.52 (2H, m), 2.76-2.97 (3H, m), 3.49-3.59 (1H, m), 5.01 (2H, s) , 6.77 (1H, dd, J = 8.3, 2.5Hz), 6.83 (1H, s), 6.94 (1H, dd, J = 8.0, 1.6Hz), 6.99-7.04 (2H, m), 7.08-7.17 (4H , m), 7.31-7.37 (3H, m).
Example 16 {5-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1H-inden-1-yl} ethyl acetate

In the same manner as in Example 8, the title compound was colorless from ethyl (5-hydroxy-2,3-dihydro-1H-inden-1-yl) acetate and (2 ′, 6′-dimethylbiphenyl-3-yl) methanol. Obtained as an oil. Yield 24%.
MS m / z 415 (MH ⁺ ).

実施例１１と同様にして、{5-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3-ジ
ヒドロ-1H-インデン-1-イル}酢酸エチルから表題化合物を無色プリズム晶として得た。収率 53% (ヘキサン−酢酸エチルから再結晶)。
¹HNMR (CDCl₃) δ： 1.71-1.83(1H, m), 2.01(6H, s), 2.36-2.51(2H, m), 2.76-2.96(3H, m), 3.49-3.58(1H, m), 5.09(2H, s), 6.79(1H, dd, J=8.3, 2.5Hz), 6.85(1H, s), 7.08-7.17(5H, m), 7.20(1H, s), 7.38-7.47(2H, m)。
実施例１８ {6-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}
ベンジル)オキシ]-1,2,3,4-テトラヒドロナフタレン-1-イル}酢酸エチル

実施例８と同様にして、(6-ヒドロキシ-1,2,3,4-テトラヒドロナフタレン-1-イル)酢酸エチルおよび (4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}フェニル)メタノールから表題化合物を淡黄色油状物として得た。収率 64%。
MS m/z 555 (MH⁺)。
実施例１９ {6-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}
ベンジル)オキシ]-1,2,3,4-テトラヒドロナフタレン-1-イル}酢酸

実施例６と同様にして、{6-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)ア
ミノ]メチル}ベンジル)オキシ]-1,2,3,4-テトラヒドロナフタレン-1-イル}酢酸エチルか
ら表題化合物を淡黄色粘稠性油状物として得た。収率 99%。
MS m/z 527 (MH⁺)。 Example 17 {5-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1H-inden-1-yl} acetic acid

In the same manner as in Example 11, the title compound was purified from ethyl {5-[(2 ′, 6′-dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1H-inden-1-yl} acetate. Obtained as prismatic crystals. Yield 53% (recrystallized from hexane-ethyl acetate).
¹ HNMR (CDCl ₃ ) δ: 1.71-1.83 (1H, m), 2.01 (6H, s), 2.36-2.51 (2H, m), 2.76-2.96 (3H, m), 3.49-3.58 (1H, m) , 5.09 (2H, s), 6.79 (1H, dd, J = 8.3, 2.5Hz), 6.85 (1H, s), 7.08-7.17 (5H, m), 7.20 (1H, s), 7.38-7.47 (2H , m).
Example 18 {6-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl}
Benzyl) oxy] -1,2,3,4-tetrahydronaphthalen-1-yl} ethyl acetate

Analogously to Example 8, (6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) ethyl acetate and (4-{[(4-phenyl-1,3-thiazol-2-yl) ) (Propyl) amino] methyl} phenyl) methanol gave the title compound as a pale yellow oil. Yield 64%.
MS m / z 555 (MH ⁺ ).
Example 19 {6-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl}
Benzyl) oxy] -1,2,3,4-tetrahydronaphthalen-1-yl} acetic acid

In the same manner as in Example 6, {6-[(4-{[(4-phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} benzyl) oxy] -1,2,3, The title compound was obtained as a pale yellow viscous oil from ethyl 4-tetrahydronaphthalen-1-yl} acetate. Yield 99%.
MS m / z 527 (MH ⁺ ).

実施例８と同様にして、8-ヒドロキシ-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-
カルボン酸エチルおよび (4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]
メチル}フェニル)メタノールから表題化合物を淡黄色油状物として得た。収率 76%。
MS m/z 557 (MH⁺)。
実施例２１ 8-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}ベンジル)オキシ]-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-カルボン酸

実施例６と同様にして、8-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}ベンジル)オキシ]-2,3,4,5-テトラヒドロ-1-ベンゾオキセピン-4-カルボン酸
エチルから表題化合物を無色プリズム晶として得た。収率 72% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 529 (MH⁺)。
実施例２２ {2-[(3-フェノキシベンジル)オキシ]-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]
アンヌレン-5-イル}酢酸エチル

実施例８と同様にして、(2-ヒドロキシ-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレ
ン-5-イル)酢酸エチルおよび 3-フェノキシベンジルアルコールから表題化合物を無色油
状物として得た。収率 73%。
MS m/z 431 (MH⁺)。 Example 20 8-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} benzyl) oxy] -2,3,4,5-tetrahydro-1- Benzooxepin-4-carboxylate

In the same manner as in Example 8, 8-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-4-
Ethyl carboxylate and (4-{[(4-phenyl-1,3-thiazol-2-yl) (propyl) amino]
The title compound was obtained as a pale yellow oil from (methyl} phenyl) methanol. Yield 76%.
MS m / z 557 (MH ⁺ ).
Example 21 8-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} benzyl) oxy] -2,3,4,5-tetrahydro-1- Benzooxepin-4-carboxylic acid

In the same manner as in Example 6, 8-[(4-{[(4-phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} benzyl) oxy] -2,3,4,5 The title compound was obtained as colorless prism crystals from ethyl -tetrahydro-1-benzoxepin-4-carboxylate. Yield 72% (recrystallized from hexane-ethyl acetate).
MS m / z 529 (MH ⁺ ).
Example 22 {2-[(3-phenoxybenzyl) oxy] -6,7,8,9-tetrahydro-5H-benzo [7]
Annulen-5-yl} ethyl acetate

In the same manner as in Example 8, the title compound was obtained as a colorless oil from (2-hydroxy-6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-yl) ethyl acetate and 3-phenoxybenzyl alcohol. Got as. Yield 73%.
MS m / z 431 (MH ⁺ ).

実施例１１と同様にして、{2-[(3-フェノキシベンジル)オキシ]-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-イル}酢酸エチルから表題化合物を無色針状晶として得た。
収率 67% (ヘキサン−酢酸エチルから再結晶)。
¹HNMR (CDCl₃) δ： 1.46-1.91(6H, m), 2.68-2.89(4H, m), 3.37-3.44(1H, m), 4.99(2H, s), 6.69(1H, dd, J=8.4, 2.7Hz), 6.74(1H, d, J=2.7Hz), 6.94(1H, dd, J=8.1, 1.9Hz), 6.99-7.03(3H, m), 7.08-7.17(3H, m), 7.31-7.36(3H,m)。
実施例２４ {2-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-イル}酢酸エチル

実施例８と同様にして、(2-ヒドロキシ-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレ
ン-5-イル)酢酸エチルおよび (2',6'-ジメチルビフェニル-3-イル)メタノールから表題化合物を無色油状物として得た。収率 72%。
MS m/z 443 (MH⁺)。
実施例２５ {2-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-イル}酢酸

実施例１１と同様にして、{2-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-イル}酢酸エチルから表題化合物を無色結晶性粉末として得た。収率 60% (ヘキサン−酢酸エチルから再結晶)。
¹HNMR (CDCl₃) δ： 1.44-1.92(6H, m), 2.01(6H, s), 2.68-2.89(4H, m), 3.36-3.44(1H, m), 5.08(2H, s), 6.70-6.75(2H, m), 7.00(1H, d, J=8.3Hz), 7.06-7.19(5H, m), 7.37-7.46(2H, m)。 Example 23 {2-[(3-phenoxybenzyl) oxy] -6,7,8,9-tetrahydro-5H-benzo [7]
Annulen-5-yl} acetic acid

In the same manner as in Example 11, the title compound was colorless from {2-[(3-phenoxybenzyl) oxy] -6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-yl} ethyl acetate. Obtained as needles.
Yield 67% (recrystallized from hexane-ethyl acetate).
¹ HNMR (CDCl ₃ ) δ: 1.46-1.91 (6H, m), 2.68-2.89 (4H, m), 3.37-3.44 (1H, m), 4.99 (2H, s), 6.69 (1H, dd, J = 8.4, 2.7Hz), 6.74 (1H, d, J = 2.7Hz), 6.94 (1H, dd, J = 8.1, 1.9Hz), 6.99-7.03 (3H, m), 7.08-7.17 (3H, m), 7.31-7.36 (3H, m).
Example 24 {2-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-yl} ethyl acetate

Analogously to Example 8, ethyl (2-hydroxy-6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-yl) acetate and (2 ′, 6′-dimethylbiphenyl-3- Yl) The title compound was obtained as a colorless oil from methanol. Yield 72%.
MS m / z 443 (MH ⁺ ).
Example 25 {2-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-yl} acetic acid

In the same manner as in Example 11, {2-[(2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -6,7,8,9-tetrahydro-5H-benzo [7] annulen-5-yl } The title compound was obtained as a colorless crystalline powder from ethyl acetate. Yield 60% (recrystallized from hexane-ethyl acetate).
¹ HNMR (CDCl ₃ ) δ: 1.44-1.92 (6H, m), 2.01 (6H, s), 2.68-2.89 (4H, m), 3.36-3.44 (1H, m), 5.08 (2H, s), 6.70 -6.75 (2H, m), 7.00 (1H, d, J = 8.3Hz), 7.06-7.19 (5H, m), 7.37-7.46 (2H, m).

実施例８と同様にして、(6-ヒドロキシ-1-ベンゾフラン-3-イル)酢酸メチルおよび 3-
フェノキシベンジルアルコールから表題化合物を無色油状物として得た。収率 91%。
MS m/z 389 (MH⁺)。
実施例２７ {6-[(3-フェノキシベンジル)オキシ]-1-ベンゾフラン-3-イル}酢酸

実施例１１と同様にして、{6-[(3-フェノキシベンジル)オキシ]-1-ベンゾフラン-3-イ
ル}酢酸メチルから表題化合物を無色板状晶として得た。収率 77% (ヘキサン−酢酸エチ
ルから再結晶)。
MS m/z 375 (MH⁺)。
実施例２８ {6-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-1-ベンゾフラン-3-イル}酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-1-ベンゾフラン-3-イル)酢酸メチルおよび (2',6'-ジメチルビフェニル-3-イル)メタノールから表題化合物を無色油状物として得た。収率 96%。
MS m/z 401 (MH⁺)。 Example 26 Methyl {6-[(3-phenoxybenzyl) oxy] -1-benzofuran-3-yl} acetate

Analogously to Example 8, methyl (6-hydroxy-1-benzofuran-3-yl) acetate and 3-
The title compound was obtained as a colorless oil from phenoxybenzyl alcohol. Yield 91%.
MS m / z 389 (MH ⁺ ).
Example 27 {6-[(3-phenoxybenzyl) oxy] -1-benzofuran-3-yl} acetic acid

In the same manner as in Example 11, the title compound was obtained as colorless plate crystals from methyl {6-[(3-phenoxybenzyl) oxy] -1-benzofuran-3-yl} acetate. Yield 77% (recrystallized from hexane-ethyl acetate).
MS m / z 375 (MH ⁺ ).
Example 28 {6-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1-benzofuran-3-yl} methyl acetate

In the same manner as in Example 8, the title compound was obtained as a colorless oil from methyl (6-hydroxy-1-benzofuran-3-yl) acetate and (2 ′, 6′-dimethylbiphenyl-3-yl) methanol. Yield 96%.
MS m / z 401 (MH ⁺ ).

実施例１１と同様にして、{6-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-1-ベン
ゾフラン-3-イル}酢酸メチルから表題化合物を無色板状晶として得た。収率 80% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 387 (MH⁺)。
実施例３０ {6-[(3-フェノキシベンジル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび 3-フェノキシベンジルアルコールから表題化合物を無色油状物として得た。
収率 77%。
MS m/z 391 (MH⁺)。
実施例３１ {6-[(3-フェノキシベンジル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

実施例１１と同様にして、{6-[(3-フェノキシベンジル)オキシ]-2,3-ジヒドロ-1-ベン
ゾフラン-3-イル}酢酸メチルから表題化合物を無色針状晶として得た。収率 78% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 377 (MH⁺)。 Example 29 {6-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1-benzofuran-3-yl} acetic acid

In the same manner as in Example 11, the title compound was obtained as colorless plate crystals from methyl {6-[(2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -1-benzofuran-3-yl} acetate. . Yield 80% (recrystallized from hexane-ethyl acetate).
MS m / z 387 (MH ⁺ ).
Example 30 {6-[(3-phenoxybenzyl) oxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

In the same manner as in Example 8, the title compound was obtained as a colorless oil from methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and 3-phenoxybenzyl alcohol.
Yield 77%.
MS m / z 391 (MH ⁺ ).
Example 31 {6-[(3-phenoxybenzyl) oxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

In the same manner as in Example 11, the title compound was obtained as colorless needle crystals from methyl {6-[(3-phenoxybenzyl) oxy] -2,3-dihydro-1-benzofuran-3-yl} acetate. Yield 78% (recrystallized from hexane-ethyl acetate).
MS m / z 377 (MH ⁺ ).

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび (2',6'-ジメチルビフェニル-3-イル)メタノールから表題化合物を無色油状物として得た。収率 72%。
MS m/z 403 (MH⁺)。
実施例３３ {6-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

実施例１１と同様にして、{6-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3-ジ
ヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を無色針状晶として得た。収
率 73% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 389 (MH⁺)。
実施例３４ {6-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}
ベンジル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび (4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}フェニル)メタノールから表題化合物を無色油状物として得た。収率 73%。
MS m/z 529 (MH⁺)。 Example 32 {6-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

In the same manner as in Example 8, colorless the title compound from methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and (2 ′, 6′-dimethylbiphenyl-3-yl) methanol. Obtained as an oil. Yield 72%.
MS m / z 403 (MH ⁺ ).
Example 33 {6-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

In the same manner as in Example 11, the title compound was purified from methyl {6-[(2 ′, 6′-dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetate. Obtained as needles. Yield 73% (recrystallized from hexane-ethyl acetate).
MS m / z 389 (MH ⁺ ).
Example 34 {6-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl}
Benzyl) oxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

Analogously to Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and (4-{[(4-phenyl-1,3-thiazol-2-yl) The title compound was obtained as a colorless oil from (propyl) amino] methyl} phenyl) methanol. Yield 73%.
MS m / z 529 (MH ⁺ ).

実施例６と同様にして、{6-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)ア
ミノ]メチル}ベンジル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を淡緑色結晶性粉末として得た。収率 65% (ヘキサン−酢酸エチルから再結晶)
。
MS m/z 515 (MH⁺)。
実施例３６ {6-[(2',4'-ジメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび (2',4'-ジメチルビフェニル-3-イル)メタノールから表題化合物を無色油状物として得た。収率 67%。
MS m/z 403 (MH⁺)。
実施例３７ {6-[(2',4'-ジメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

実施例１１と同様にして、(6-((2',4'-ジメチル-1,1'-ビフェニル-3-イル)メトキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色プリズム晶として得た。収率 92% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 389 (MH⁺)。 Example 35 {6-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl}
Benzyl) oxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

In the same manner as in Example 6, {6-[(4-{[(4-phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} benzyl) oxy] -2,3-dihydro- The title compound was obtained as a light green crystalline powder from methyl 1-benzofuran-3-yl} acetate. Yield 65% (recrystallized from hexane-ethyl acetate)
.
MS m / z 515 (MH ⁺ ).
Example 36 {6-[(2 ', 4'-Dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

In the same manner as in Example 8, colorless the title compound from methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and (2 ′, 4′-dimethylbiphenyl-3-yl) methanol. Obtained as an oil. Yield 67%.
MS m / z 403 (MH ⁺ ).
Example 37 {6-[(2 ', 4'-Dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

In the same manner as in Example 11, (6-((2 ′, 4′-dimethyl-1,1′-biphenyl-3-yl) methoxy) -2,3-dihydro-1-benzofuran-3-yl) acetic acid The title compound was obtained as colorless prism crystals from methyl. Yield 92% (recrystallized from hexane-ethyl acetate).
MS m / z 389 (MH ⁺ ).

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび (2',4',6'-トリメチルビフェニル-3-イル)メタノールから表題化合物を無色
油状物として得た。収率 78%。
MS m/z 417 (MH⁺)。
実施例３９ {6-[(2',4',6'-トリメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-
ベンゾフラン-3-イル}酢酸

実施例１１と同様にして、{6-[(2',4',6'-トリメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を無色板状晶として得た
。収率 75% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 403 (MH⁺)。
実施例４０ {6-[(6-メトキシ-2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび (6-メトキシ-2',6'-ジメチルビフェニル-3-イル)メタノールから表題化合物
を無色油状物として得た。収率 73%。
¹HNMR (CDCl₃) δ： 2.00(6H, s), 2.55(1H, dd,J=16.4, 9.2Hz), 2.74(1H, dd, J=16.4,
5.4Hz), 3.71(3H, s), 3.74(3H, s), 3.77-3.85(1H,m), 4.25(1H, dd, J=9.2, 6.0Hz), 4.74(1H, t, J=9.2Hz), 4.97(2H, s), 6.45-6.49(2H,m), 6.97-7.03(2H, m), 7.07-7.18(4H, m), 7.39(1H, dd, J=8.4, 2.2Hz)。 Example 38 {6-[(2 ', 4', 6'-trimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-
Benzofuran-3-yl} methyl acetate

As in Example 8, from (methyl 6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and (2 ′, 4 ′, 6′-trimethylbiphenyl-3-yl) methanol The compound was obtained as a colorless oil. Yield 78%.
MS m / z 417 (MH ⁺ ).
Example 39 {6-[(2 ', 4', 6'-trimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-
Benzofuran-3-yl} acetic acid

In the same manner as in Example 11, the title was obtained from methyl {6-[(2 ′, 4 ′, 6′-trimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetate. The compound was obtained as colorless plate crystals. Yield 75% (recrystallized from hexane-ethyl acetate).
MS m / z 403 (MH ⁺ ).
Example 40 {6-[(6-Methoxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

Analogously to Example 8, from methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and (6-methoxy-2 ′, 6′-dimethylbiphenyl-3-yl) methanol The title compound was obtained as a colorless oil. Yield 73%.
¹ HNMR (CDCl ₃ ) δ: 2.00 (6H, s), 2.55 (1H, dd, J = 16.4, 9.2 Hz), 2.74 (1H, dd, J = 16.4,
5.4Hz), 3.71 (3H, s), 3.74 (3H, s), 3.77-3.85 (1H, m), 4.25 (1H, dd, J = 9.2, 6.0Hz), 4.74 (1H, t, J = 9.2 Hz), 4.97 (2H, s), 6.45-6.49 (2H, m), 6.97-7.03 (2H, m), 7.07-7.18 (4H, m), 7.39 (1H, dd, J = 8.4, 2.2Hz) .

実施例１１と同様にして、{6-[(6-メトキシ-2',6'-ジメチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を無色プリズム晶
として得た。収率 58% (ヘキサン−酢酸エチルから再結晶)。
¹HNMR (CDCl₃) δ： 2.00(6H, s), 2.61(1H, dd,J=16.8, 9.2Hz), 2.80(1H, dd, J=16.8,
5.4Hz), 3.74(3H, s), 3.77 -3.85(1H, m),4.28(1H, dd, J=9.2, 6.0Hz), 4.75(1H, t, J=9.2Hz), 4.98(2H, s), 6.45-6.50(2H, m),6.97-7.19(6H, m), 7.39(1H, dd, J=8.5, 2.3Hz)。
実施例４２ (6-((3-(1-ベンゾチエン-5-イル)ベンジル)オキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび [3-(1-ベンゾチエン-5-イル)フェニル]メタノールから表題化合物を無色油状物として得た。収率 74%。
MS m/z 431 (MH⁺)。
実施例４３ (6-{[3-(1-ベンゾチエン-5-イル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

実施例１１と同様にして、(6-{[3-(1-ベンゾチエン-5-イル)ベンジル]オキシ}-2,3-ジ
ヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色板状晶として得た。収
率 84% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 417 (MH⁺)。 Example 41 {6-[(6-Methoxy-2 ', 6'-dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

In the same manner as in Example 11, from methyl {6-[(6-methoxy-2 ′, 6′-dimethylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetate The title compound was obtained as colorless prism crystals. Yield 58% (recrystallized from hexane-ethyl acetate).
¹ HNMR (CDCl ₃ ) δ: 2.00 (6H, s), 2.61 (1H, dd, J = 16.8, 9.2 Hz), 2.80 (1H, dd, J = 16.8,
5.4Hz), 3.74 (3H, s), 3.77 -3.85 (1H, m), 4.28 (1H, dd, J = 9.2, 6.0Hz), 4.75 (1H, t, J = 9.2Hz), 4.98 (2H, s), 6.45-6.50 (2H, m), 6.97-7.19 (6H, m), 7.39 (1H, dd, J = 8.5, 2.3 Hz).
Example 42 Methyl (6-((3- (1-benzothien-5-yl) benzyl) oxy) -2,3-dihydro-1-benzofuran-3-yl) acetate

In the same manner as in Example 8, colorless the title compound from methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and [3- (1-benzothien-5-yl) phenyl] methanol. Obtained as an oil. Yield 74%.
MS m / z 431 (MH ⁺ ).
Example 43 (6-{[3- (1-Benzothien-5-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

In the same manner as in Example 11, the title compound was purified from methyl (6-{[3- (1-benzothien-5-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetate. Obtained as plate crystals. Yield 84% (recrystallized from hexane-ethyl acetate).
MS m / z 417 (MH ⁺ ).

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび [3-(1-ベンゾチエン-3-イル)フェニル]メタノールから表題化合物を無色油状物として得た。収率 72%。
MS m/z 431 (MH⁺)。
実施例４５ (6-{[3-(1-ベンゾチエン-3-イル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

実施例１１と同様にして、(6-{[3-(1-ベンゾチエン-3-イル)ベンジル]オキシ}-2,3-ジ
ヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色針状晶として得た。収
率 69% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 417 (MH⁺)。
実施例４６ (6-{[3-(2-メチル-1-ナフチル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび [3-(2-メチル-1-ナフチル)フェニル]メタノールから表題化合物を無色油状物として得た。収率91%。
MS m/z 439 (MH⁺)。 Example 44 Methyl (6-{[3- (1-benzothien-3-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetate

In the same manner as in Example 8, colorless the title compound from methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and [3- (1-benzothien-3-yl) phenyl] methanol. Obtained as an oil. Yield 72%.
MS m / z 431 (MH ⁺ ).
Example 45 (6-{[3- (1-Benzothien-3-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

In the same manner as in Example 11, the title compound was purified from methyl (6-{[3- (1-benzothien-3-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetate. Obtained as needles. Yield 69% (recrystallized from hexane-ethyl acetate).
MS m / z 417 (MH ⁺ ).
Example 46 Methyl (6-{[3- (2-methyl-1-naphthyl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetate

In the same manner as in Example 8, colorless the title compound from methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and [3- (2-methyl-1-naphthyl) phenyl] methanol. Obtained as an oil. Yield 91%.
MS m / z 439 (MH ⁺ ).

(6-{[3-(2-メチル-1-ナフチル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イ
ル)酢酸メチル (0.801 g、1.90 mmol) のメタノール (6 mL) およびテトラヒドロフラン(6 mL) 混合溶液に 2 M 水酸化ナトリウム水溶液 (3 mL) を加え、室温で 20 時間撹拌し
た。反応液に水を加え、1 M 塩酸で酸性にして、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (30% 酢酸エチル／ヘキサン〜酢酸エチル) で精製し、酢酸エチル−ヘキサンから再結晶して、表題化合物 (0.444 g、収率 55%)を無色針状晶として得た。
MS m/z 425 (MH⁺)。
実施例４８ {5-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}
ベンジル)オキシ]-2,3-ジヒドロ-1H-インデン-1-イル}酢酸エチル

実施例８と同様にして、(5-ヒドロキシ-2,3-ジヒドロ-1H-インデン-1-イル)酢酸エチルおよび (4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}フェニル)
メタノールから表題化合物を無色油状物として得た。収率70%。
MS m/z 541 (MH⁺)。
実施例４９ {5-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}
ベンジル)オキシ]-2,3-ジヒドロ-1H-インデン-1-イル}酢酸

{5-[(4-{[(4-フェニル-1,3-チアゾール-2-イル)(プロピル)アミノ]メチル}ベンジル)オキシ]-2,3-ジヒドロ-1H-インデン-1-イル}酢酸エチル (0.684 g、1.17 mmol) のエタノール (6 mL) およびテトラヒドロフラン (6 mL) 混合溶液に2 M 水酸化ナトリウム水溶液 (2 mL) を加え、室温で 24 時間撹拌した。反応液に水を加え、10% クエン酸水溶液で中和して、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (30%〜80% 酢酸エチ
ル／ヘキサン) で精製し、酢酸エチル−ヘキサンから再結晶して、表題化合物 (0.393 g
、収率 66%) を無色プリズム晶として得た。
MS m/z 513 (MH⁺)。 Example 47 (6-{[3- (2-Methyl-1-naphthyl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

(6-{[3- (2-Methyl-1-naphthyl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) methyl acetate (0.801 g, 1.90 mmol) in methanol (6 mL) To the mixed solution of tetrahydrofuran and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (0.444 g, yield 55%) as colorless needle crystals. .
MS m / z 425 (MH ⁺ ).
Example 48 {5-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl}
Benzyl) oxy] -2,3-dihydro-1H-inden-1-yl} ethyl acetate

Analogously to Example 8, ethyl (5-hydroxy-2,3-dihydro-1H-inden-1-yl) acetate and (4-{[(4-phenyl-1,3-thiazol-2-yl) (Propyl) amino] methyl} phenyl)
The title compound was obtained as a colorless oil from methanol. Yield 70%.
MS m / z 541 (MH ^<+> ).
Example 49 {5-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl}
Benzyl) oxy] -2,3-dihydro-1H-inden-1-yl} acetic acid

{5-[(4-{[(4-Phenyl-1,3-thiazol-2-yl) (propyl) amino] methyl} benzyl) oxy] -2,3-dihydro-1H-inden-1-yl} To a mixed solution of ethyl acetate (0.684 g, 1.17 mmol) in ethanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction solution, neutralized with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% -80% ethyl acetate / hexane) and recrystallized from ethyl acetate-hexane to give the title compound (0.393 g
Yield 66%) as colorless prism crystals.
MS m / z 513 (MH ⁺ ).

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび [2'-メチル-4'-(テトラヒドロ-2H-ピラン-2-イルオキシ)ビフェニル-3-イル]メタノールから表題化合物を無色油状物として得た。収率84%。
MS m/z 489 (MH⁺)。
実施例５１ {6-[(4'-ヒドロキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチル

(6-{[2'-メチル-4'-(テトラヒドロ-2H-ピラン-2-イルオキシ)ビフェニル-3-イル]メト
キシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル (4.49 g、9.19 mmol) および p-トルエンスルホン酸 一水和物 (0.175 g、0.919 mmol) のメタノール(50 mL) 溶液を室
温で 30 時間攪拌した。反応溶媒を減圧留去した後、残渣を酢酸エチルで希釈し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー (20%〜60% 酢酸エチル／ヘキサン) で精製して、表題化合物 (3.21 g
、収率86%) を無色粘稠性油状物として得た。
MS m/z 405 (MH⁺)。
実施例５２ {6-[(4'-ヒドロキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

実施例１１と同様にして、{6-[(4'-ヒドロキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を無色プリズム晶と
して得た。収率 45% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 391 (MH⁺)。 Example 50 (6-{[2'-Methyl-4 '-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) Methyl acetate

Analogously to Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and [2′-methyl-4 ′-(tetrahydro-2H-pyran-2-yloxy) The title compound was obtained as a colorless oil from biphenyl-3-yl] methanol. Yield 84%.
MS m / z 489 (MH ⁺ ).
Example 51 {6-[(4'-Hydroxy-2'-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

(6-{[2'-Methyl-4 '-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) methyl acetate ( A solution of 4.49 g, 9.19 mmol) and p-toluenesulfonic acid monohydrate (0.175 g, 0.919 mmol) in methanol (50 mL) was stirred at room temperature for 30 hours. After evaporating the reaction solvent under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% -60% ethyl acetate / hexane) to give the title compound (3.21 g
Yield 86%) as a colorless viscous oil.
MS m / z 405 (MH ⁺ ).
Example 52 {6-[(4'-Hydroxy-2'-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

The title compound was obtained from methyl {6-[(4′-hydroxy-2′-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetate as in Example 11. Was obtained as colorless prism crystals. Yield 45% (recrystallized from hexane-ethyl acetate).
MS m / z 391 (MH ⁺ ).

実施例８と同様にして、{6-[(4'-ヒドロキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルおよびメタノールから表題化合物を無
色油状物として得た。収率 97%。
MS m/z 419 (MH⁺)。
実施例５４ {6-[(4'-メトキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

実施例６と同様にして、{6-[(4'-メトキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を無色プリズム晶として
得た。収率 82% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 405 (MH⁺)。
実施例５５ (6-{[4'-(シクロプロピルメトキシ)-2'-メチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル

実施例８と同様にして、{6-[(4'-ヒドロキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルおよびシクロプロピルメタノールから
表題化合物を無色油状物として得た。収率 81%。
MS m/z 459 (MH⁺)。 Example 53 {6-[(4'-Methoxy-2'-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

Analogously to Example 8, from {6-[(4′-hydroxy-2′-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate and methanol The title compound was obtained as a colorless oil. Yield 97%.
MS m / z 419 (MH ⁺ ).
Example 54 {6-[(4'-Methoxy-2'-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

In the same manner as in Example 6, from the methyl {6-[(4'-methoxy-2'-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetate Was obtained as colorless prism crystals. Yield 82% (recrystallized from hexane-ethyl acetate).
MS m / z 405 (MH ⁺ ).
Example 55 (6-{[4 '-(Cyclopropylmethoxy) -2'-methylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) methyl acetate

Analogously to Example 8, {6-[(4'-hydroxy-2'-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate and cyclopropyl The title compound was obtained as a colorless oil from methanol. Yield 81%.
MS m / z 459 (MH ⁺ ).

実施例６と同様にして、(6-{[4'-(シクロプロピルメトキシ)-2'-メチルビフェニル-3-
イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色プリズム晶として得た。収率 63% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 445 (MH⁺)。
実施例５７ (6-{[4'-(2-ブトキシエトキシ)-2'-メチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル

実施例８と同様にして、{6-[(4'-ヒドロキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルおよび 2-ブトキシエタノールから表題化合物を無色油状物として得た。収率 72%。
MS m/z 505 (MH⁺)。
実施例５８ (6-{[4'-(2-ブトキシエトキシ)-2'-メチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

実施例４９と同様にして、(6-{[4'-(2-ブトキシエトキシ)-2'-メチルビフェニル-3-イ
ル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色結晶として得た。収率 83% (ヘプタンから再結晶)。
MS m/z 491 (MH⁺)。 Example 56 (6-{[4 '-(Cyclopropylmethoxy) -2'-methylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

In the same manner as in Example 6, (6-{[4 ′-(cyclopropylmethoxy) -2′-methylbiphenyl-3-
[Il] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid methyl ester gave the title compound as colorless prism crystals. Yield 63% (recrystallized from hexane-ethyl acetate).
MS m / z 445 (MH ⁺ ).
Example 57 (6-{[4 '-(2-Butoxyethoxy) -2'-methylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) methyl acetate

Analogously to Example 8, {6-[(4′-hydroxy-2′-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate and 2- The title compound was obtained as a colorless oil from butoxyethanol. Yield 72%.
MS m / z 505 (MH ⁺ ).
Example 58 (6-{[4 '-(2-Butoxyethoxy) -2'-methylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Analogously to Example 49, (6-{[4 ′-(2-butoxyethoxy) -2′-methylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) The title compound was obtained as colorless crystals from methyl acetate. Yield 83% (recrystallized from heptane).
MS m / z 491 (MH ⁺ ).

実施例８と同様にして、{6-[(4'-ヒドロキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルおよび 4-ヘプタノールから表題化合物を無色油状物として得た。収率 63%。
MS m/z 503 (MH⁺)。
実施例６０ (6-{[2'-メチル-4'-(1-プロピルブトキシ)ビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

実施例４９と同様にして、(6-{[2'-メチル-4'-(1-プロピルブトキシ)ビフェニル-3-イ
ル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色針状晶として得た。収率 82% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 489 (MH⁺)。
実施例６１ (6-{[4'-(2-エチルブトキシ)-2'-メチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル

実施例８と同様にして、{6-[(4'-ヒドロキシ-2'-メチルビフェニル-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルおよび 2-エチル-1-ブタノールから表
題化合物を無色油状物として得た。収率 37%。
MS m/z 489 (MH⁺)。 Example 59 (6-{[2'-Methyl-4 '-(1-propylbutoxy) biphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) methyl acetate

Analogously to Example 8, {6-[(4′-hydroxy-2′-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate and 4- The title compound was obtained as a colorless oil from heptanol. Yield 63%.
MS m / z 503 (MH ⁺ ).
Example 60 (6-{[2'-Methyl-4 '-(1-propylbutoxy) biphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Analogously to Example 49, (6-{[2'-methyl-4 '-(1-propylbutoxy) biphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) The title compound was obtained as colorless needles from methyl acetate. Yield 82% (recrystallized from hexane-ethyl acetate).
MS m / z 489 (MH ⁺ ).
Example 61 (6-{[4 '-(2-Ethylbutoxy) -2'-methylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) methyl acetate

Analogously to Example 8, {6-[(4′-hydroxy-2′-methylbiphenyl-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate and 2- The title compound was obtained as a colorless oil from ethyl-1-butanol. Yield 37%.
MS m / z 489 (MH ⁺ ).

実施例６と同様にして、(6-{[4'-(2-エチルブトキシ)-2'-メチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色プリズ
ム晶として得た。収率 93% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 475 (MH⁺)。
実施例６３ {6-[(4-{[(2-フェニルエチル)(4-フェニル-1,3-チアゾール-2-イル)アミノ]メチル}ベンジル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび (4-{[(2-フェニルエチル)(4-フェニル-1,3-チアゾール-2-イル)アミノ]メチ
ル}フェニル)メタノールから表題化合物を黄色油状物として得た。収率 89%。
MS m/z 591 (MH⁺)。
実施例６４ {6-[(4-{[(2-フェニルエチル)(4-フェニル-1,3-チアゾール-2-イル)アミノ]メチル}ベンジル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

実施例４９と同様にして、{6-[(4-{[(2-フェニルエチル)(4-フェニル-1,3-チアゾール-2-イル)アミノ]メチル}ベンジル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メ
チルから表題化合物を黄色粘稠性油状物として得た。収率 97%。
MS m/z 577 (MH⁺)。 Example 62 (6-{[4 '-(2-Ethylbutoxy) -2'-methylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

In the same manner as in Example 6, (6-{[4 '-(2-ethylbutoxy) -2'-methylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) The title compound was obtained as colorless prism crystals from methyl acetate. Yield 93% (recrystallized from hexane-ethyl acetate).
MS m / z 475 (MH ⁺ ).
Example 63 {6-[(4-{[(2-Phenylethyl) (4-phenyl-1,3-thiazol-2-yl) amino] methyl} benzyl) oxy] -2,3-dihydro-1- Benzofuran-3-yl} methyl acetate

Analogously to Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and (4-{[(2-phenylethyl) (4-phenyl-1,3- The title compound was obtained as a yellow oil from thiazol-2-yl) amino] methyl} phenyl) methanol. Yield 89%.
MS m / z 591 (MH ⁺ ).
Example 64 {6-[(4-{[(2-Phenylethyl) (4-phenyl-1,3-thiazol-2-yl) amino] methyl} benzyl) oxy] -2,3-dihydro-1- Benzofuran-3-yl} acetic acid

Analogously to Example 49, {6-[(4-{[(2-phenylethyl) (4-phenyl-1,3-thiazol-2-yl) amino] methyl} benzyl) oxy] -2,3 -Dihydro-1-benzofuran-3-yl} methyl acetate gave the title compound as a yellow viscous oil. Yield 97%.
MS m / z 577 (MH ⁺ ).

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび {4-[(2-フェニル-1H-インドール-1-イル)メチル]フェニル}メタノールから表題化合物を淡黄色油状物として得た。収率 88%。
MS m/z 504 (MH⁺)。
実施例６６ [6-({4-[(2-フェニル-1H-インドール-1-イル)メチル]ベンジル}オキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸

実施例６と同様にして、[6-({4-[(2-フェニル-1H-インドール-1-イル)メチル]ベンジル}オキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸メチルから表題化合物を淡黄色プリズム晶として得た。収率 81% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 490 (MH⁺)。
実施例６７ [6-({4-[(2-メチル-1H-インドール-1-イル)メチル]ベンジル}オキシ)-2,3-
ジヒドロ-1-ベンゾフラン-3-イル]酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび {4-[(2-メチル-1H-インドール-1-イル)メチル]フェニル}メタノールから表題化合物を淡黄色油状物として得た。収率 95%。
MS m/z 442 (MH⁺)。 Example 65 [6-({4-[(2-Phenyl-1H-indol-1-yl) methyl] benzyl} oxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid methyl

Analogously to Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and {4-[(2-phenyl-1H-indol-1-yl) methyl] phenyl } The title compound was obtained as a pale yellow oil from methanol. Yield 88%.
MS m / z 504 (MH ⁺ ).
Example 66 [6-({4-[(2-Phenyl-1H-indol-1-yl) methyl] benzyl} oxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

In the same manner as in Example 6, [6-({4-[(2-phenyl-1H-indol-1-yl) methyl] benzyl} oxy) -2,3-dihydro-1-benzofuran-3-yl] The title compound was obtained as pale yellow prisms from methyl acetate. Yield 81% (recrystallized from hexane-ethyl acetate).
MS m / z 490 (MH ⁺ ).
Example 67 [6-({4-[(2-Methyl-1H-indol-1-yl) methyl] benzyl} oxy) -2,3-
Dihydro-1-benzofuran-3-yl] methyl acetate

Analogously to Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and {4-[(2-methyl-1H-indol-1-yl) methyl] phenyl } The title compound was obtained as a pale yellow oil from methanol. Yield 95%.
MS m / z 442 (MH ⁺ ).

実施例６と同様にして、[6-({4-[(2-メチル-1H-インドール-1-イル)メチル]ベンジル}
オキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸メチルから表題化合物を淡赤色結晶
性粉末として得た。収率 84% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 428 (MH⁺)。
実施例６９ (6-{[4'-(ベンジルオキシ)-2',6'-ジメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび [4'-(ベンジルオキシ)-2',6'-ジメチルビフェニル-3-イル]メタノールから表題化合物を無色油状物として得た。収率 93%。
MS m/z 509 (MH⁺)。
実施例７０ (6-{[4'-(ベンジルオキシ)-2',6'-ジメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

実施例６と同様にして、(6-{[4'-(ベンジルオキシ)-2',6'-ジメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色プリズム晶として得た。収率 91% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 495 (MH⁺)。 Example 68 [6-({4-[(2-Methyl-1H-indol-1-yl) methyl] benzyl} oxy) -2,3-
Dihydro-1-benzofuran-3-yl] acetic acid

In the same manner as in Example 6, [6-({4-[(2-methyl-1H-indol-1-yl) methyl] benzyl}
The title compound was obtained as a pale red crystalline powder from methyl (oxy) -2,3-dihydro-1-benzofuran-3-yl] acetate. Yield 84% (recrystallized from hexane-ethyl acetate).
MS m / z 428 (MH ⁺ ).
Example 69 Methyl (6-{[4 '-(Benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetate

Analogously to Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and [4 ′-(benzyloxy) -2 ′, 6′-dimethylbiphenyl-3- The title compound was obtained from [yl] methanol as a colorless oil. Yield 93%.
MS m / z 509 (MH ⁺ ).
Example 70 (6-{[4 '-(Benzyloxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

In the same manner as in Example 6, (6-{[4 ′-(benzyloxy) -2 ′, 6′-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl ) The title compound was obtained as colorless prism crystals from methyl acetate. Yield 91% (recrystallized from hexane-ethyl acetate).
MS m / z 495 (MH ⁺ ).

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび [4'-(2-エトキシエトキシ)-2',6'-ジメチルビフェニル-3-イル]メタノールから表題化合物を無色油状物として得た。収率 89%。
MS m/z 491 (MH⁺)。
実施例７２ (6-{[4'-(2-エトキシエトキシ)-2',6'-ジメチルビフェニル-3-イル]メトキ
シ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

実施例４９と同様にして、(6-{[4'-(2-エトキシエトキシ)-2',6'-ジメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色プリズム晶として得た。収率 68% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 477 (MH⁺)。
実施例７３ (6-{[4'-(2-エトキシエトキシ)-2',6'-ジメチルビフェニル-3-イル]メトキ
シ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸カルシウム

{6-[(4-{[(2-フェニルエチル)(4-フェニル-1,3-チアゾール-2-イル)アミノ]メチル}ベ
ンジル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸 (0.541 g、0.938mmol) のメタノール (5 mL) 溶液に 2 M水酸化ナトリウム水溶液 (1 mL) を加えて、減圧濃縮した。得られた残渣に水 (50 mL) およびメタノール(20 mL) を加え、そこに塩化カルシウム (0.111 g、1.00 mmol) の水 (5 mL) 溶液を加えた。本混合液を減圧濃縮して析出した固体
を濾取し、水で洗浄して、表題化合物 (0.454 g、収率 81%) を淡黄色アモルファスとし
て得た。
¹H NMR (DMSO-d₆) δ： 2.16(1H,dd, J=15.5, 9.3Hz), 2.43(1H, dd, J=15.5, 5.6Hz), 2.90-3.00(2H, m), 3.58-3.73(3H,m), 4.10-4.19(1H, m), 4.62-4.73(3H, m), 4.97(2H, s), 6.36-6.42(2H, m), 7.09(1H,d, J=8.7Hz), 7.17-7.42(13H, m), 7.87(1H, d, J=7.3Hz)。 Example 71 Methyl (6-{[4 '-(2-ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetate

In the same manner as in Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and [4 ′-(2-ethoxyethoxy) -2 ′, 6′-dimethylbiphenyl- The title compound was obtained as a colorless oil from 3-yl] methanol. Yield 89%.
MS m / z 491 (MH ⁺ ).
Example 72 (6-{[4 '-(2-Ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Analogously to Example 49, (6-{[4 ′-(2-ethoxyethoxy) -2 ′, 6′-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3 -Yl) The title compound was obtained as colorless prism crystals from methyl acetate. Yield 68% (recrystallized from hexane-ethyl acetate).
MS m / z 477 (MH ⁺ ).
Example 73 (6-{[4 '-(2-Ethoxyethoxy) -2', 6'-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) calcium acetate

{6-[(4-{[(2-Phenylethyl) (4-phenyl-1,3-thiazol-2-yl) amino] methyl} benzyl) oxy] -2,3-dihydro-1-benzofuran-3 To a solution of -yl} acetic acid (0.541 g, 0.938 mmol) in methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was concentrated under reduced pressure. Water (50 mL) and methanol (20 mL) were added to the obtained residue, and a solution of calcium chloride (0.111 g, 1.00 mmol) in water (5 mL) was added thereto. The mixture was concentrated under reduced pressure and the precipitated solid was collected by filtration and washed with water to give the title compound (0.454 g, yield 81%) as a pale yellow amorphous product.
¹ H NMR (DMSO-d ₆ ) δ: 2.16 (1H, dd, J = 15.5, 9.3 Hz), 2.43 (1H, dd, J = 15.5, 5.6 Hz), 2.90-3.00 (2H, m), 3.58- 3.73 (3H, m), 4.10-4.19 (1H, m), 4.62-4.73 (3H, m), 4.97 (2H, s), 6.36-6.42 (2H, m), 7.09 (1H, d, J = 8.7 Hz), 7.17-7.42 (13H, m), 7.87 (1H, d, J = 7.3 Hz).

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび [6-(ベンジルオキシ)-2',6'-ジメチル-3-ビフェニリル]メタノールから表題
化合物を無色油状物として得た。収率50%。
MS m/z 509 (MH⁺)。
実施例７５ (6-{[6-(ベンジルオキシ)-2',6'-ジメチルビフェニル-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

実施例４９と同様にして、(6-{[6-(ベンジルオキシ)-2',6'-ジメチルビフェニル-3-イ
ル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチルから表題化合物を無色プリズム晶として得た。収率 76% (ヘプタン−酢酸エチルから再結晶)。
MS m/z 495 (MH⁺)。
実施例７６ {5-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-1H-インドール-1-イル}酢酸エチル

5-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-1H-インドール(0.95g、2.90 mmol)
をテトラヒドロフラン (30 mL) および N,N-ジメチルホルムアミド (4 mL) の混合溶液に溶解させた。その溶液を氷冷し、水素化ナトリウム(60% 油性、0.12 g、3.0 mmol) を加
え、同温度で 20 分間攪拌した。次いで、その溶液にブロモ酢酸エチル (0.36 mL、3.25mmol) を加え、室温まで昇温し、2 日間攪拌した。反応溶液を酢酸エチルで希釈し、クエ
ン酸水溶液、水、食塩水で順次洗浄後、硫酸マグネシウムで乾燥、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:10〜1:5) で精製して、表題化合物 (1.0 g、収率 83%) を淡黄色油状物として得た。
MS m/z 414 (MH⁺)。 Example 74 Methyl (6-{[6- (benzyloxy) -2 ', 6'-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetate

Analogously to Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and [6- (benzyloxy) -2 ′, 6′-dimethyl-3-biphenylyl] The title compound was obtained as a colorless oil from methanol. Yield 50%.
MS m / z 509 (MH ⁺ ).
Example 75 (6-{[6- (Benzyloxy) -2 ', 6'-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Analogously to Example 49, (6-{[6- (benzyloxy) -2 ′, 6′-dimethylbiphenyl-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) The title compound was obtained as colorless prism crystals from methyl acetate. Yield 76% (recrystallized from heptane-ethyl acetate).
MS m / z 495 (MH ⁺ ).
Example 76 {5-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1H-indol-1-yl} ethyl acetate

5-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1H-indole (0.95 g, 2.90 mmol)
Was dissolved in a mixed solution of tetrahydrofuran (30 mL) and N, N-dimethylformamide (4 mL). The solution was ice-cooled, sodium hydride (60% oily, 0.12 g, 3.0 mmol) was added, and the mixture was stirred at the same temperature for 20 min. Next, ethyl bromoacetate (0.36 mL, 3.25 mmol) was added to the solution, and the mixture was warmed to room temperature and stirred for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 5) to give the title compound (1.0 g, yield 83%) as a pale yellow oil.
MS m / z 414 (MH ⁺ ).

{5-[(2',6'-ジメチルビフェニル-3-イル)メトキシ]-1H-インドール-1-イル}酢酸エチル(0.27g、0.65 mmol) のメタノール (10 mL) およびテトラヒドロフラン (10 mL) 混合溶
液に85% 水酸化カリウム (0.13 g、1.97mmol) の水溶液 (5 mL) を加え、室温で 18 時間撹拌した。反応液に水を加え、10% クエン酸水溶液で弱酸性にして、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣を
シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:2〜2:1) で精製して、表
題化合物 (0.19 g、収率 76%) を淡黄色アモルファスとして得た。
MS m/z 386 (MH⁺)。
実施例７８ {2-[(3-フェノキシベンジル)チオ]-4,5,6,7-テトラヒドロ-1,3-ベンゾチア
ゾール-7-イル}酢酸

{2-[(3-フェノキシベンジル)チオ]-4,5,6,7-テトラヒドロ-1,3-ベンゾチアゾール-7-イル}マロン酸ジエチル(1.21 g、2.36 mmol)、37% 塩酸 (10 mL)、酢酸 (10 mL) の混合物
を 120 ℃ に加熱して 12 時間攪拌した。反応混合物を濃縮し、酢酸エチルで希釈し、10%炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後
、減圧濃縮して、表題化合物 (890 mg、92%) を淡黄色油状物として得た。
¹H NMR (CDCl₃) δ： 1.53-2.13(6H, m),2.47-2.77(2H, m), 3.33-3.42(1H, m), 4.31(2H, s), 6.90(1H, dd, J=7.7, 2.1Hz),6.96-7.02(3H, m), 7.06-7.14(2H, m), 7.21-7.37(3H, m)。
実施例７９ [6-({2-メチル-5-[4-(トリフルオロメチル)フェニル]-3-フリル}メトキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸メチル

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび {2-メチル-5-[4-(トリフルオロメチル)フェニル]-3-フリル}メタノールから
表題化合物を無色プリズム晶として得た。収率84% (ヘキサン−酢酸エチルから再結晶)。融点 131-132 ℃。 Example 77 {5-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1H-indol-1-yl} acetic acid

{5-[(2 ', 6'-Dimethylbiphenyl-3-yl) methoxy] -1H-indol-1-yl} ethyl acetate (0.27 g, 0.65 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) To the mixed solution was added an aqueous solution (5 mL) of 85% potassium hydroxide (0.13 g, 1.97 mmol), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2 to 2: 1) to give the title compound (0.19 g, yield 76%) as a pale yellow amorphous product.
MS m / z 386 (MH ⁺ ).
Example 78 {2-[(3-phenoxybenzyl) thio] -4,5,6,7-tetrahydro-1,3-benzothiazol-7-yl} acetic acid

{2-[(3-phenoxybenzyl) thio] -4,5,6,7-tetrahydro-1,3-benzothiazol-7-yl} diethyl malonate (1.21 g, 2.36 mmol), 37% hydrochloric acid (10 mL) and acetic acid (10 mL) were heated to 120 ° C. and stirred for 12 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (890 mg, 92%) Obtained as a yellow oil.
¹ H NMR (CDCl ₃ ) δ: 1.53-2.13 (6H, m), 2.47-2.77 (2H, m), 3.33-3.42 (1H, m), 4.31 (2H, s), 6.90 (1H, dd, J = 7.7, 2.1 Hz), 6.96-7.02 (3H, m), 7.06-7.14 (2H, m), 7.21-7.37 (3H, m).
Example 79 [6-({2-Methyl-5- [4- (trifluoromethyl) phenyl] -3-furyl} methoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid methyl ester

Analogously to Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and {2-methyl-5- [4- (trifluoromethyl) phenyl] -3- The title compound was obtained as colorless prism crystals from furyl} methanol. Yield 84% (recrystallized from hexane-ethyl acetate). Melting point 131-132 ° C.

実施例６と同様にして、[6-({2-メチル-5-[4-(トリフルオロメチル)フェニル]-3-フリ
ル}メトキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸メチルから表題化合物を無色プリズム晶として得た。収率 95% (ヘキサン−酢酸エチルから再結晶)。
融点 180-181 ℃。
実施例８１ {6-[(2-フェニル-1,3-チアゾール-4-イル)メトキシ]-2,3-ジヒドロ-1-ベン
ゾフラン-3-イル}酢酸メチル

(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル (200 mg、0.961 mmol) および 4-(クロロメチル)-2-フェニル-1,3-チアゾール (240 mg、1.14 mmol) を N,N-ジメチルホルムアミド(5 mL) に溶解し、炭酸カリウム (160 mg、1.16 mmol)を加えて、60〜70 ℃で 3 時間攪拌した。反応液に水を加えて 2 M 塩酸で中和し、析出した結晶を酢酸エチル−ジイソプロピルエーテルから再結晶して、表題化合物 (270 mg、収率 74%) を無色プリズム晶として得た。
融点 116-117 ℃。
実施例８２ {6-[(2-フェニル-1,3-チアゾール-4-イル)メトキシ]-2,3-ジヒドロ-1-ベン
ゾフラン-3-イル}酢酸メチル

実施例６と同様にして、{6-[(2-フェニル-1,3-チアゾール-4-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を無色針状晶として得た。収率 98% (酢酸エチル−メタノールから再結晶)。
融点 169-170 ℃。 Example 80 [6-({2-Methyl-5- [4- (trifluoromethyl) phenyl] -3-furyl} methoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

In the same manner as in Example 6, [6-({2-methyl-5- [4- (trifluoromethyl) phenyl] -3-furyl} methoxy) -2,3-dihydro-1-benzofuran-3-yl The title compound was obtained as colorless prism crystals from methyl acetate. Yield 95% (recrystallized from hexane-ethyl acetate).
Melting point 180-181 ° C.
Example 81 {6-[(2-Phenyl-1,3-thiazol-4-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid methyl ester

Methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate (200 mg, 0.961 mmol) and 4- (chloromethyl) -2-phenyl-1,3-thiazole (240 mg, 1.14 mmol) was dissolved in N, N-dimethylformamide (5 mL), potassium carbonate (160 mg, 1.16 mmol) was added, and the mixture was stirred at 60 to 70 ° C. for 3 hr. Water was added to the reaction mixture and neutralized with 2 M hydrochloric acid, and the precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (270 mg, yield 74%) as colorless prism crystals.
Melting point 116-117 ° C.
Example 82 {6-[(2-Phenyl-1,3-thiazol-4-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid methyl ester

In the same manner as in Example 6, the title compound was obtained from methyl {6-[(2-phenyl-1,3-thiazol-4-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetate. Obtained as colorless needles. Yield 98% (recrystallized from ethyl acetate-methanol).
Melting point 169-170 ° C.

実施例８と同様にして、(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メ
チルおよび (2-ピラジン-2-イル-1,3-チアゾール-4-イル)メタノールから表題化合物を無色結晶として得た。収率 35%。
MS m/z 384 (MH⁺)。
実施例８４ {6-[(2-ピラジン-2-イル-1,3-チアゾール-4-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

実施例６と同様にして、{6-[(2-ピラジン-2-イル-1,3-チアゾール-4-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を無色針状晶として得た。収率 87% (酢酸エチルから再結晶)。
MS m/z 370 (MH⁺)。
実施例８５ {6-[3-(2-フェニル-1H-インドール-1-イル)プロポキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチル

2-フェニル-1H-インドール (0.425 g、2.20mmol) の N,N-ジメチルホルムアミド (2 mL) 溶液に水素化ナトリウム (60% 油性、88 mg、2.20 mmol) を加え、室温で 30 分間攪拌した。反応液にヨウ化ナトリウム(0.330 g、2.20 mmol) および [6-(3-クロロプロポキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸メチル (0.589 g、2.07mmol) の N,N-ジメ
チルホルムアミド (3 mL) 溶液を加え、室温で 18 時間攪拌した。反応液に水および飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%〜40% 酢酸エチル／ヘキサン) で精製して、表題化合物 (0.160 g、収率 18%)
を無色油状物として得た。
MS m/z 442 (MH⁺)。 Example 83 {6-[(2-Pyrazin-2-yl-1,3-thiazol-4-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

In the same manner as in Example 8, methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate and (2-pyrazin-2-yl-1,3-thiazol-4-yl) methanol Gave the title compound as colorless crystals. Yield 35%.
MS m / z 384 (MH ⁺ ).
Example 84 {6-[(2-Pyrazin-2-yl-1,3-thiazol-4-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

In the same manner as in Example 6, methyl {6-[(2-pyrazin-2-yl-1,3-thiazol-4-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetate To give the title compound as colorless needles. Yield 87% (recrystallized from ethyl acetate).
MS m / z 370 (MH ⁺ ).
Example 85 {6- [3- (2-Phenyl-1H-indol-1-yl) propoxy] -2,3-dihydro-1-benzofuran-3-yl} methyl acetate

Sodium hydride (60% oily, 88 mg, 2.20 mmol) was added to a solution of 2-phenyl-1H-indole (0.425 g, 2.20 mmol) in N, N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 30 min. . To the reaction mixture was added sodium iodide (0.330 g, 2.20 mmol) and methyl [6- (3-chloropropoxy) -2,3-dihydro-1-benzofuran-3-yl] acetate (0.589 g, 2.07 mmol), N, N-dimethylformamide (3 mL) solution was added and stirred at room temperature for 18 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% -40% ethyl acetate / hexane) to give the title compound (0.160 g, yield 18%)
Was obtained as a colorless oil.
MS m / z 442 (MH ⁺ ).

実施例６と同様にして、{6-[3-(2-フェニル-1H-インドール-1-イル)プロポキシ]-2,3-
ジヒドロ-1-ベンゾフラン-3-イル}酢酸メチルから表題化合物を無色プリズム晶として得
た。収率 83% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 428 (MH⁺)。 Example 86 {6- [3- (2-Phenyl-1H-indol-1-yl) propoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

In the same manner as in Example 6, {6- [3- (2-phenyl-1H-indol-1-yl) propoxy] -2,3-
The title compound was obtained as colorless prism crystals from methyl dihydro-1-benzofuran-3-yl} acetate. Yield 83% (recrystallized from hexane-ethyl acetate).
MS m / z 428 (MH ⁺ ).

収率 43%。MS (ESI+, m/e) 490 (M+1)。
実施例８８ (6-{2-[シクロヘキシル(2-ニトロベンジル)アミノ]エトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸トリフルオロ酢酸塩

収率 24%。MS (ESI+, m/e) 455 (M+1)。
実施例８９ {6-[4-(イミダゾ[1,2-a]ピリジン-8-イルオキシ)ブトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸トリフルオロ酢酸塩

収率 2%。MS (ESI+, m/e) 383 (M+1)。
実施例９０ (6-{[3-ベンジル-2-(2-チエニル)-3H-チエノ[2,3-d]イミダゾール-5-イル]
メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 16%。MS (ESI+, m/e) 503 (M+1)。
実施例９１ (6-{[1-ベンジル-2-フェニル-4-(フェニルチオ)-1H-イミダゾール-5-イル]
メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 29%。MS (ESI+,m/e) 549 (M+1)。 The compounds described in Examples 87-95 and Examples 97-118 were synthesized in the same manner as Example 96.
Example 87 (6-{[4- (2-Benzoyl-4-chlorophenyl) -4H-1,2,4-triazol-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl Acetic acid

Yield 43%. MS (ESI +, m / e) 490 (M + 1).
Example 88 (6- {2- [Cyclohexyl (2-nitrobenzyl) amino] ethoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid trifluoroacetate

Yield 24%. MS (ESI +, m / e) 455 (M + 1).
Example 89 {6- [4- (imidazo [1,2-a] pyridin-8-yloxy) butoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid trifluoroacetate salt

Yield 2%. MS (ESI +, m / e) 383 (M + 1).
Example 90 (6-{[3-benzyl-2- (2-thienyl) -3H-thieno [2,3-d] imidazol-5-yl]
Methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 16%. MS (ESI +, m / e) 503 (M + 1).
Example 91 (6-{[1-benzyl-2-phenyl-4- (phenylthio) -1H-imidazol-5-yl]
Methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 29%. MS (ESI +, m / e) 549 (M + 1).

収率 67%。MS (ESI+,m/e) 356 (M+1)。
実施例９３ (6-{[2-(3-フリル)-1,3-オキサゾール-4-イル]メトキシ}-2,3-ジヒドロ-1-
ベンゾフラン-3-イル)酢酸

収率 55%。MS (ESI+,m/e) 342 (M+1)。
実施例９４ (6-{[3-(2-チエニル)-1,2,4-オキサジアゾール-5-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 48%。MS (ESI+,m/e) 359 (M+1)。
実施例９５ {6-[(5-オキソ-2-フェニル-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-7-イ
ル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 3%。MS (ESI+,m/e) 418 (M+1)。 Example 92 (6-{[2- (5-Methyl-2-furyl) -1,3-oxazol-4-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 67%. MS (ESI +, m / e) 356 (M + 1).
Example 93 (6-{[2- (3-furyl) -1,3-oxazol-4-yl] methoxy} -2,3-dihydro-1-
Benzofuran-3-yl) acetic acid

Yield 55%. MS (ESI +, m / e) 342 (M + 1).
Example 94 (6-{[3- (2-thienyl) -1,2,4-oxadiazol-5-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 48%. MS (ESI +, m / e) 359 (M + 1).
Example 95 {6-[(5-oxo-2-phenyl-4,5-dihydropyrazolo [1,5-a] pyrimidin-7-yl) methoxy] -2,3-dihydro-1-benzofuran-3 -Il} Acetic acid

Yield 3%. MS (ESI +, m / e) 418 (M + 1).

［工程１］(6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸メチル(30mg、0.14
mmol) のDMF(1 mL) 溶液に N,N-ジベンジル-4-(クロロメチル)ベンズアミド (63 mg、0.18 mmol) のDMF(0.5 mL) 溶液および炭酸カリウム (29 mg、0.21 mmol) を加えて 70 ℃ で 20 時間攪拌した。反応液に水 (2 mL) を加え、ジクロロメタン(2 mL) で抽出した。
有機層をGeneVac遠心濃縮装置で減圧濃縮した。
［工程２］得られた生成物をメタノール (2 mL) に溶解し、1M 水酸化ナトリウム水溶液 (0.25 mL、0.25 mmol) を加え、室温で 18 時間攪拌した。反応液に 1 M 塩酸を加えて酸性とした後、ジクロロメタン(2 mL) で抽出した。有機層をGeneVac遠心濃縮装置で減圧濃縮した。残留物を分取HPLCで精製することにより表題化合物 (48.8 mg、収率 68%)を得た。
¹H NMR (DMSO-d₆) δ： 2.46(1H, dd, J=9.0, 16.5Hz), 2.68(1H, dd, J=5.4, 16.5Hz),3.62-3.72(1H, m), 4.18(1H, dd, J=6.9, 9.0Hz), 4.41(2H, br), 4.58(2H, br),4.68(1H,
t, J=9.0Hz), 5.06(2H, s), 6.44-6.48(2H, m), 7.10(1H, d, J=7.5Hz),7.16-7.36(10H,
m), 7.48(4H, s)。
実施例９７ [6-({4-[(4-フェニル-1-ピペラジニル)カルボニル]ベンジル}オキシ)-2,3-
ジヒドロ-1-ベンゾフラン-3-イル]酢酸トリフルオロ酢酸塩

収率 30%。MS (ESI+,m/e) 473 (M+1)。 Example 96 [6-({4-[(Dibenzylamino) carbonyl] benzyl} oxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

[Step 1] Methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl) acetate (30 mg, 0.14
mmol) in DMF (1 mL), N, N-dibenzyl-4- (chloromethyl) benzamide (63 mg, 0.18 mmol) in DMF (0.5 mL) and potassium carbonate (29 mg, 0.21 mmol) were added. The mixture was stirred at 70 ° C. for 20 hours. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 mL).
The organic layer was concentrated under reduced pressure using a GeneVac centrifugal concentrator.
[Step 2] The obtained product was dissolved in methanol (2 mL), 1M aqueous sodium hydroxide solution (0.25 mL, 0.25 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was acidified with 1 M hydrochloric acid, and extracted with dichloromethane (2 mL). The organic layer was concentrated under reduced pressure using a GeneVac centrifugal concentrator. The residue was purified by preparative HPLC to give the title compound (48.8 mg, yield 68%).
¹ H NMR (DMSO-d ₆ ) δ: 2.46 (1H, dd, J = 9.0, 16.5Hz), 2.68 (1H, dd, J = 5.4, 16.5Hz), 3.62-3.72 (1H, m), 4.18 ( 1H, dd, J = 6.9, 9.0Hz), 4.41 (2H, br), 4.58 (2H, br), 4.68 (1H,
t, J = 9.0Hz), 5.06 (2H, s), 6.44-6.48 (2H, m), 7.10 (1H, d, J = 7.5Hz), 7.16-7.36 (10H,
m), 7.48 (4H, s).
Example 97 [6-({4-[(4-phenyl-1-piperazinyl) carbonyl] benzyl} oxy) -2,3-
Dihydro-1-benzofuran-3-yl] acetic acid trifluoroacetate

Yield 30%. MS (ESI +, m / e) 473 (M + 1).

収率 79%。MS (ESI+,m/e) 473 (M+1)。
実施例９９ {6-[(3'-フルオロ-4-ビフェニリル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラ
ン-3-イル}酢酸

収率 48%。MS (ESI+,m/e) 379 (M+1)。
実施例１００ (6-{[8-(ベンジルオキシ)イミダゾ[1,2-a]ピリジン-2-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸トリフルオロ酢酸塩

収率 23%。MS (ESI+,m/e) 431 (MH⁺)。
実施例１０１ (6-{3-[(4'-シアノ-4-ビフェニリル)オキシ]プロポキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 37%。MS (ESI+,m/e) 430 (M+1)。
実施例１０２ 4-[4-(3-{[3-(カルボキシメチル)-2,3-ジヒドロ-1-ベンゾフラン-6-イル]オキシ}プロポキシ)フェノキシ]安息香酸

収率 9%。MS (ESI+,m/e) 465 (M+1)。 Example 98 (6- {2- [4- (Diphenylmethyl) -1-piperazinyl] ethoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid 2 trifluoroacetate

Yield 79%. MS (ESI +, m / e) 473 (M + 1).
Example 99 {6-[(3'-Fluoro-4-biphenylyl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 48%. MS (ESI +, m / e) 379 (M + 1).
Example 100 (6-{[8- (Benzyloxy) imidazo [1,2-a] pyridin-2-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid trifluoroacetate

Yield 23%. MS (ESI +, m / e) 431 (MH ^<+> ).
Example 101 (6- {3-[(4'-Cyano-4-biphenylyl) oxy] propoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 37%. MS (ESI +, m / e) 430 (M + 1).
Example 102 4- [4- (3-{[3- (carboxymethyl) -2,3-dihydro-1-benzofuran-6-yl] oxy} propoxy) phenoxy] benzoic acid

Yield 9%. MS (ESI +, m / e) 465 (M + 1).

収率 48%。MS (ESI+,m/e) 454 (M+1)。
実施例１０４ (6-{[4-(1H-ピラゾール-1-イル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベン
ゾフラン-3-イル)酢酸

収率 60%。MS (ESI+,m/e) 351 (M+1)。
実施例１０５ (6-{[4-(1H-イミダゾール-1-イル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベ
ンゾフラン-3-イル)酢酸トリフルオロ酢酸塩

収率 12%。MS (ESI+,m/e) 351 (M+1)。
実施例１０６ (6-{[4-(1,3-オキサゾール-5-イル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 10%。MS (ESI+,m/e) 352 (M+1)。
実施例１０７ (6-{[4-(1H-1,2,4-トリアゾール-1-イル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 13%。MS (ESI+,m/e) 352 (M+1)。 Example 103 [6- (3- {4-[(7-oxo-3-azepanyl) methyl] phenoxy} propoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

Yield 48%. MS (ESI +, m / e) 454 (M + 1).
Example 104 (6-{[4- (1H-pyrazol-1-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 60%. MS (ESI +, m / e) 351 (M + 1).
Example 105 (6-{[4- (1H-imidazol-1-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid trifluoroacetate

Yield 12%. MS (ESI +, m / e) 351 (M + 1).
Example 106 (6-{[4- (1,3-oxazol-5-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 10%. MS (ESI +, m / e) 352 (M + 1).
Example 107 (6-{[4- (1H-1,2,4-triazol-1-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 13%. MS (ESI +, m / e) 352 (M + 1).

収率 59%。MS (ESI+,m/e) 532 (M+1)。
実施例１０９ {6-[(5-フェニルペンチル)オキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 65%。MS (ESI+,m/e) 341 (M+1)。
実施例１１０ (6-{3-[4-(3-クロロフェニル)-1-ピペラジニル]プロポキシ}-2,3-ジヒド
ロ-1-ベンゾフラン-3-イル)酢酸2トリフルオロ酢酸塩

収率 30%。MS (ESI+,m/e) 431 (M+1)。
実施例１１１ {6-[(1-ベンジル-1H-イミダゾール-2-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 25%。MS (ESI+,m/e) 365 (M+1)。
実施例１１２ (6-{[5-(2-メトキシフェニル)-1,2,4-オキサジアゾール-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 69%。MS (ESI+,m/e) 383 (M+1)。 Example 108 [6-({3,5-dimethoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl) methoxy] benzyl} oxy) -2,3-dihydro-1 -Benzofuran-3-yl] acetic acid

Yield 59%. MS (ESI +, m / e) 532 (M + 1).
Example 109 {6-[(5-Phenylpentyl) oxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 65%. MS (ESI +, m / e) 341 (M + 1).
Example 110 (6- {3- [4- (3-Chlorophenyl) -1-piperazinyl] propoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid 2 trifluoroacetate salt

Yield 30%. MS (ESI +, m / e) 431 (M + 1).
Example 111 {6-[(1-Benzyl-1H-imidazol-2-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 25%. MS (ESI +, m / e) 365 (M + 1).
Example 112 (6-{[5- (2-methoxyphenyl) -1,2,4-oxadiazol-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 69%. MS (ESI +, m / e) 383 (M + 1).

収率 50%。MS (ESI+,m/e) 383 (M+1)。
実施例１１４ {6-[(5-フェニル-1,2,4-オキサジアゾール-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 67%。MS (ESI+,m/e) 353 (M+1)。
実施例１１５ [6-(3-フェノキシプロポキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢
酸

収率 23%。MS (ESI+,m/e) 329 (M+1)。
実施例１１６ (6-{[2-(4-クロロフェニル)-1,3-チアゾール-4-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 50%。MS (ESI+,m/e) 402 (M+1)。
実施例１１７ [6-(4-フェノキシブトキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸

収率 37%。MS (ESI+,m/e) 343 (M+1)。
実施例１１８ (6-{2-オキソ-2-[4-(1-ピロリジニル)フェニル]エトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸トリフルオロ酢酸塩

収率 36%。MS (ESI+,m/e) 382 (M+1)。 Example 113 (6-{[5- (4-Methoxyphenyl) -1,2,4-oxadiazol-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 50%. MS (ESI +, m / e) 383 (M + 1).
Example 114 {6-[(5-Phenyl-1,2,4-oxadiazol-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 67%. MS (ESI +, m / e) 353 (M + 1).
Example 115 [6- (3-phenoxypropoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

Yield 23%. MS (ESI +, m / e) 329 (M + 1).
Example 116 (6-{[2- (4-Chlorophenyl) -1,3-thiazol-4-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 50%. MS (ESI +, m / e) 402 (M + 1).
Example 117 [6- (4-Phenoxybutoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

Yield 37%. MS (ESI +, m / e) 343 (M + 1).
Example 118 (6- {2-oxo-2- [4- (1-pyrrolidinyl) phenyl] ethoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid trifluoroacetate

Yield 36%. MS (ESI +, m / e) 382 (M + 1).

収率 17%。MS (ESI+,m/e) 357 (M+1)。
実施例１２０ (6-{2-[[4-(メトキシカルボニル)フェニル](メチル)アミノ]エトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸トリフルオロ酢酸塩

収率 23%。MS (ESI+,m/e) 386 (M+1)。
実施例１２１ (6-{2-[(6-メトキシ-2-フェニル-4-ピリミジニル)チオ]エトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 3%。MS (ESI+,m/e) 439 (M+1)。
実施例１２２ [6-(2-{5-[(4-ピリジニルメチル)チオ]-1H-テトラゾール-1-イル}エトキ
シ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸トリフルオロ酢酸塩

収率 3%。MS (ESI+,m/e) 414 (M+1)。
実施例１２３ (6-{[3-(4-アセチルフェニル)-2-オキソ-1,3-オキサゾリジン-5-イル]メ
トキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 42%。MS (ESI+,m/e) 412 (M+1)。
実施例１２４ (6-{[3-メチル-4-(2,2,2-トリフルオロエトキシ)-2-ピリジニル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸トリフルオロ酢酸塩

収率 29%。MS (ESI+,m/e) 398 (M+1)。 The compounds described in Examples 119-140 and Examples 142-152 were synthesized in the same manner as in Example 141.
Example 119 {6-[(4-Butoxybenzyl) oxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 17%. MS (ESI +, m / e) 357 (M + 1).
Example 120 (6- {2-[[4- (Methoxycarbonyl) phenyl] (methyl) amino] ethoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid trifluoroacetate

Yield 23%. MS (ESI +, m / e) 386 (M + 1).
Example 121 (6- {2-[(6-Methoxy-2-phenyl-4-pyrimidinyl) thio] ethoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 3%. MS (ESI +, m / e) 439 (M + 1).
Example 122 [6- (2- {5-[(4-pyridinylmethyl) thio] -1H-tetrazol-1-yl} ethoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid trifluoroacetic acid salt

Yield 3%. MS (ESI +, m / e) 414 (M + 1).
Example 123 (6-{[3- (4-Acetylphenyl) -2-oxo-1,3-oxazolidine-5-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 42%. MS (ESI +, m / e) 412 (M + 1).
Example 124 (6-{[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid trifluoro Acetate

Yield 29%. MS (ESI +, m / e) 398 (M + 1).

収率 43%。MS (ESI+,m/e) 379 (M+1)。
実施例１２６ {6-[3-(4-シクロヘキシルフェノキシ)プロポキシ]-2,3-ジヒドロ-1-ベン
ゾフラン-3-イル}酢酸

収率 5%。MS (ESI+,m/e) 411 (M+1)。
実施例１２７ (6-{[4-(1H-1,2,3-トリアゾール-1-イル)ベンジル]オキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 64%。MS (ESI+,m/e) 352 (M+1)。
実施例１２８ {6-[(5-フェニル-1H-ピラゾール-3-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 7%。MS (ESI+,m/e) 351 (M+1)。
実施例１２９ (6-{[5-(4-フルオロフェニル)-1-メチル-1H-ピラゾール-3-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 43%。MS (ESI+,m/e) 383 (M+1)。
実施例１３０ (6-{[3-(4-フルオロフェニル)-1-メチル-1H-ピラゾール-5-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 13%。MS (ESI+,m/e) 383 (M+1)。 Example 125 (6-{[(2E) -3- (5,6,7,8-tetrahydro-2-naphthalenyl) -2-buten-1-yl] oxy} -2,3-dihydro-1-benzofuran -3-yl) acetic acid

Yield 43%. MS (ESI +, m / e) 379 (M + 1).
Example 126 {6- [3- (4-Cyclohexylphenoxy) propoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 5%. MS (ESI +, m / e) 411 (M + 1).
Example 127 (6-{[4- (1H-1,2,3-triazol-1-yl) benzyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 64%. MS (ESI +, m / e) 352 (M + 1).
Example 128 {6-[(5-Phenyl-1H-pyrazol-3-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 7%. MS (ESI +, m / e) 351 (M + 1).
Example 129 (6-{[5- (4-Fluorophenyl) -1-methyl-1H-pyrazol-3-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 43%. MS (ESI +, m / e) 383 (M + 1).
Example 130 (6-{[3- (4-Fluorophenyl) -1-methyl-1H-pyrazol-5-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 13%. MS (ESI +, m / e) 383 (M + 1).

収率 37%。MS (ESI+,m/e) 368 (M+1)。
実施例１３２ (6-{[2-(4-ピリジニル)-1,3-チアゾール-4-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 19%。MS (ESI+,m/e) 369 (M+1)。
実施例１３３ (6-{[2-(2-フリル)-1,3-チアゾール-4-イル]メトキシ}-2,3-ジヒドロ-1-
ベンゾフラン-3-イル)酢酸

収率 16%。MS (ESI+,m/e) 358 (M+1)。
実施例１３４ (6-{[2-(2-チエニル)-1,3-チアゾール-4-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 45%。MS (ESI+,m/e) 374 (M+1)。
実施例１３５ {6-[(4-クロロ-1-メチル-2-フェニル-1H-イミダゾール-5-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 41%。MS (ESI+,m/e) 399 (M+1)。 Example 131 {6-[(4-Phenyl-1,3-thiazol-2-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 37%. MS (ESI +, m / e) 368 (M + 1).
Example 132 (6-{[2- (4-pyridinyl) -1,3-thiazol-4-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 19%. MS (ESI +, m / e) 369 (M + 1).
Example 133 (6-{[2- (2-furyl) -1,3-thiazol-4-yl] methoxy} -2,3-dihydro-1-
Benzofuran-3-yl) acetic acid

Yield 16%. MS (ESI +, m / e) 358 (M + 1).
Example 134 (6-{[2- (2-thienyl) -1,3-thiazol-4-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 45%. MS (ESI +, m / e) 374 (M + 1).
Example 135 {6-[(4-Chloro-1-methyl-2-phenyl-1H-imidazol-5-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 41%. MS (ESI +, m / e) 399 (M + 1).

収率 40%。MS (ESI+,m/e) 400 (M+1)。
実施例１３７ {6-[2-(2-フェニル-1H-イミダゾール-4-イル)エトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 39%。MS (ESI+,m/e) 365 (M+1)。
実施例１３８ (6-{[5-(4-クロロフェニル)-1,3-オキサゾール-4-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 52%。MS (ESI+,m/e) 386 (M+1)。
実施例１３９ (6-{[5-(4-フルオロフェニル)-1,2,3-チアジアゾール-4-イル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸

収率 15%。MS (ESI+,m/e) 387 (M+1)。
実施例１４０ {6-[(1,5-ジフェニル-1H-ピラゾール-4-イル)メトキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 52%。MS (ESI+,m/e) 427 (M+1)。 Example 136 (6-{[4- (4-Chlorophenyl) -5-methyl-1,3-oxazol-2-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 40%. MS (ESI +, m / e) 400 (M + 1).
Example 137 {6- [2- (2-Phenyl-1H-imidazol-4-yl) ethoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 39%. MS (ESI +, m / e) 365 (M + 1).
Example 138 (6-{[5- (4-Chlorophenyl) -1,3-oxazol-4-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 52%. MS (ESI +, m / e) 386 (M + 1).
Example 139 (6-{[5- (4-Fluorophenyl) -1,2,3-thiadiazol-4-yl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid

Yield 15%. MS (ESI +, m / e) 387 (M + 1).
Example 140 {6-[(1,5-Diphenyl-1H-pyrazol-4-yl) methoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

Yield 52%. MS (ESI +, m / e) 427 (M + 1).

［工程１］PS-トリフェニルホスフィン樹脂 (アルゴノート社製、2.12mmol/g) (200 mg、
0.42 mmol) のTHF (1.5 mL) 懸濁液に (6-ヒドロキシ-2,3-ジヒドロ-1-ベンゾフラン-3-
イル)酢酸メチル(30 mg、0.14 mmol) のTHF (0.5 mL) 溶液を加えて室温で 15 分間振と
うした。ジアゾジカルボン酸ジ-tert-ブチル (60 mg、0.34mmol) を加えて室温でさらに 20 分間振とうした。3-(1-ブチル-1H-インドール-3-イル)プロパン-1-オール (42 mg、0.18 mmol)のTHF (0.5 mL) 溶液を加えて室温で 18 時間振とうした。反応液にジクロロメ
タン (1.5 mL) を加えて不溶物をろ去した。ろ液をGeneVac遠心濃縮装置で減圧濃縮した
。
［工程２］得られた生成物をメタノール (2 mL) に溶解し、1M 水酸化ナトリウム水溶液 (0.25 mL、0.25 mmol) を加え、室温で 18 時間攪拌した。反応液に 1 M 塩酸を加えて酸性とした後、ジクロロメタン(2 mL) で抽出した。有機層をGeneVac遠心濃縮装置で減圧濃縮した。残留物を分取HPLCで精製することにより表題化合物 (26.9 mg、収率 47%)を得た。
¹H NMR (CDCl₃) δ： 0.91(3H, t, J=7.4Hz), 1.25-1.37(2H, m),1.72-1.82(2H, m), 2.11-2.20(2H, m), 2.62(1H, dd, J=9.5, 16.7Hz), 2.82(1H, dd,J=5.1, 16.8Hz), 2.92(2H,
t, J=7.4Hz), 3.76-3.85(1H, m), 3.95(2H, t, J=6.2Hz),4.05(2H, t, J=7.4Hz), 4.28(1H, dd, J=6.0, 9.0Hz), 4.76(1H, t, J=9.0Hz),6.39-6.45(2H, m), 6.88(1H, s), 7.02-7.32(4H, m), 7.59(1H, dd, J=0.9, 7.8Hz)。
実施例１４２ [6-({6-[2-(5-メチル-2-フェニル-1,3-オキサゾール-4-イル)エトキシ]-3-ピリジニル}メトキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸

収率 37%。MS (ESI+,m/e) 487 (M+1)。
実施例１４３ [6-({2-[(5-メチル-2-フェニル-1,3-オキサゾール-4-イル)メトキシ]ベンジル}オキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸

収率 53%。MS (ESI+,m/e) 472 (M+1)。 Example 141 {6- [3- (1-Butyl-1H-indol-3-yl) propoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid

[Step 1] PS-triphenylphosphine resin (Argonaute, 2.12 mmol / g) (200 mg,
0.42-mmol) THF (1.5 mL) suspension in (6-hydroxy-2,3-dihydro-1-benzofuran-3-
Yl) A solution of methyl acetate (30 mg, 0.14 mmol) in THF (0.5 mL) was added and shaken at room temperature for 15 minutes. Di-tert-butyl diazodicarboxylate (60 mg, 0.34 mmol) was added and shaken at room temperature for an additional 20 minutes. A solution of 3- (1-butyl-1H-indol-3-yl) propan-1-ol (42 mg, 0.18 mmol) in THF (0.5 mL) was added and shaken at room temperature for 18 hours. Dichloromethane (1.5 mL) was added to the reaction solution, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure using a GeneVac centrifugal concentrator.
[Step 2] The obtained product was dissolved in methanol (2 mL), 1M aqueous sodium hydroxide solution (0.25 mL, 0.25 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was acidified with 1 M hydrochloric acid, and extracted with dichloromethane (2 mL). The organic layer was concentrated under reduced pressure using a GeneVac centrifugal concentrator. The residue was purified by preparative HPLC to give the title compound (26.9 mg, yield 47%).
¹ H NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.4Hz), 1.25-1.37 (2H, m), 1.72-1.82 (2H, m), 2.11-2.20 (2H, m), 2.62 ( 1H, dd, J = 9.5, 16.7Hz), 2.82 (1H, dd, J = 5.1, 16.8Hz), 2.92 (2H,
t, J = 7.4Hz), 3.76-3.85 (1H, m), 3.95 (2H, t, J = 6.2Hz), 4.05 (2H, t, J = 7.4Hz), 4.28 (1H, dd, J = 6.0 , 9.0Hz), 4.76 (1H, t, J = 9.0Hz), 6.39-6.45 (2H, m), 6.88 (1H, s), 7.02-7.32 (4H, m), 7.59 (1H, dd, J = 0.9, 7.8Hz).
Example 142 [6-({6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] -3-pyridinyl} methoxy) -2,3-dihydro-1- Benzofuran-3-yl] acetic acid

Yield 37%. MS (ESI +, m / e) 487 (M + 1).
Example 143 [6-({2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl) methoxy] benzyl} oxy) -2,3-dihydro-1-benzofuran-3-yl ] Acetic acid

Yield 53%. MS (ESI +, m / e) 472 (M + 1).

収率 10%。MS (ESI+,m/e) 474 (M+1)。
実施例１４５ [6-(3-{4-[(4-フェニル-1,3-チアゾール-2-イル)メトキシ]フェニル}プロポキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸

収率 11%。MS (ESI+,m/e) 502 (M+1)。
実施例１４６ [6-({4-[4-(トリフルオロメチル)フェニル]-1,3-チアゾール-2-イル}メトキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]酢酸

収率 18%。MS (ESI+,m/e) 436 (M+1)。
実施例１４７ (6-{[(2S)-2-(ジベンジルアミノ)-3-フェニルプロピル]オキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸トリフルオロ酢酸塩

収率 14%。MS (ESI+,m/e) 508 (M+1)。
実施例１４８ {6-[3-(ジベンジルアミノ)プロポキシ]-2,3-ジヒドロ-1-ベンゾフラン-3-イル}酢酸トリフルオロ酢酸塩

収率 66%。MS (ESI+,m/e) 432 (M+1)。
実施例１４９ [6-(3,3-ジフェニルプロポキシ)-2,3-ジヒドロ-1-ベンゾフラン-3-イル]
酢酸

収率 46%。MS (ESI+,m/e) 389 (M+1)。 Example 144 [6-({4-[(4-Phenyl-1,3-thiazol-2-yl) methoxy] benzyl} oxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

Yield 10%. MS (ESI +, m / e) 474 (M + 1).
Example 145 [6- (3- {4-[(4-phenyl-1,3-thiazol-2-yl) methoxy] phenyl} propoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

Yield 11%. MS (ESI +, m / e) 502 (M + 1).
Example 146 [6-({4- [4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} methoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid

Yield 18%. MS (ESI +, m / e) 436 (M + 1).
Example 147 (6-{[(2S) -2- (dibenzylamino) -3-phenylpropyl] oxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid trifluoroacetate

Yield 14%. MS (ESI +, m / e) 508 (M + 1).
Example 148 {6- [3- (Dibenzylamino) propoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid trifluoroacetate salt

Yield 66%. MS (ESI +, m / e) 432 (M + 1).
Example 149 [6- (3,3-diphenylpropoxy) -2,3-dihydro-1-benzofuran-3-yl]
Acetic acid

Yield 46%. MS (ESI +, m / e) 389 (M + 1).

収率 58%。MS (ESI+,m/e) 432 (M+1)。
実施例１５１ (6-{[(1R,2S)-2-(ベンジルアミノ)シクロヘキシル]メトキシ}-2,3-ジヒドロ-1-ベンゾフラン-3-イル)酢酸トリフルオロ酢酸塩

収率 12%。MS (ESI+,m/e) 396 (M+1)。
実施例１５２ {6-[2-(5-メチル-2-フェニル-1,3-オキサゾール-4-イル)エトキシ]-2,3-
ジヒドロ-1-ベンゾフラン-3-イル}酢酸

収率 70%。MS (ESI+,m/e) 380 (M+1)。 Example 150 {6- [2- (Dibenzylamino) ethoxy] -2,3-dihydro-1-benzofuran-3-yl} acetic acid trifluoroacetate salt

Yield 58%. MS (ESI +, m / e) 432 (M + 1).
Example 151 (6-{[(1R, 2S) -2- (Benzylamino) cyclohexyl] methoxy} -2,3-dihydro-1-benzofuran-3-yl) acetic acid trifluoroacetate salt

Yield 12%. MS (ESI +, m / e) 396 (M + 1).
Example 152 {6- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) ethoxy] -2,3-
Dihydro-1-benzofuran-3-yl} acetic acid

Yield 70%. MS (ESI +, m / e) 380 (M + 1).

実施例８１および実施例６と同様にして、[(2R)-6-ヒドロキシ-1,2,3,4-テトラヒドロ
ナフタレン-2-イル]酢酸メチルおよび4-(クロロメチル)-5-メチル-2-フェニル-1,3-オキ
サゾールから表題化合物を無色針状晶として得た。収率 62% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 378 (MH⁺)。
実施例１５４ [(2R)-6-({3-メチル-1-[5-(トリフルオロメチル)ピリジン-2-イル]-1H-ピラゾール-4-イル}メトキシ)-1,2,3,4-テトラヒドロナフタレン-2-イル]酢酸

実施例８および実施例６と同様にして、[(2R)-6-ヒドロキシ-1,2,3,4-テトラヒドロナ
フタレン-2-イル]酢酸メチルおよび{3-メチル-1-[5-(トリフルオロメチル)ピリジン-2-イル]-1H-ピラゾール-4-イル}メタノールから表題化合物を無色針状晶として得た。収率 53% (ヘキサン−酢酸エチルから再結晶)。
MS m/z 446 (MH⁺)
実施例１５５ ((2R)-6-{[4-(シクロプロピルメトキシ)ベンジル]オキシ}-1,2,3,4-テト
ラヒドロナフタレン-2-イル)酢酸

実施例８および実施例６と同様にして、[(2R)-6-ヒドロキシ-1,2,3,4-テトラヒドロナ
フタレン-2-イル]酢酸メチルおよび[4-(シクロプロピルメトキシ)フェニル]メタノールから表題化合物を無色針状晶として得た。収率 48% (ヘキサン−酢酸エチルから再結晶)。
¹H NMR (CDCl₃) δ： 0.32-0.37(2H, m), 0.61-0.68(2H, m),1.21-1.34(1H, m), 1.42-1.55(1H, m), 1.94-2.03(1H, m), 2.21-2.33(1H, m),2.41-2.50(3H, m), 2.79-2.91(3H, m), 3.80(2H, d, J=7.0Hz), 4.94(2H, s), 6.69(1H,d, J=2.5Hz), 6.74(1H, dd, J=8.3, 2.
5Hz), 6.90(2H, d, J=8.7Hz), 6.96(1H, d,J=8.3Hz), 7.33(2H, d, J=8.7Hz)。 Example 153 {(2R) -6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl) methoxy] -1,2,3,4-tetrahydronaphthalen-2-yl} acetic acid

In the same manner as in Example 81 and Example 6, methyl [(2R) -6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl] acetate and 4- (chloromethyl) -5-methyl- The title compound was obtained as colorless needles from 2-phenyl-1,3-oxazole. Yield 62% (recrystallized from hexane-ethyl acetate).
MS m / z 378 (MH ⁺ ).
Example 154 [(2R) -6-({3-methyl-1- [5- (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-4-yl} methoxy) -1,2,3, 4-Tetrahydronaphthalen-2-yl] acetic acid

In the same manner as in Example 8 and Example 6, methyl [(2R) -6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl] acetate and {3-methyl-1- [5- ( The title compound was obtained as colorless needles from (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-4-yl} methanol. Yield 53% (recrystallized from hexane-ethyl acetate).
MS m / z 446 (MH ⁺ )
Example 155 ((2R) -6-{[4- (cyclopropylmethoxy) benzyl] oxy} -1,2,3,4-tetrahydronaphthalen-2-yl) acetic acid

In the same manner as in Example 8 and Example 6, methyl [(2R) -6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl] acetate and [4- (cyclopropylmethoxy) phenyl] methanol To give the title compound as colorless needles. Yield 48% (recrystallized from hexane-ethyl acetate).
¹ H NMR (CDCl ₃ ) δ: 0.32-0.37 (2H, m), 0.61-0.68 (2H, m), 1.21-1.34 (1H, m), 1.42-1.55 (1H, m), 1.94-2.03 (1H , m), 2.21-2.33 (1H, m), 2.41-2.50 (3H, m), 2.79-2.91 (3H, m), 3.80 (2H, d, J = 7.0Hz), 4.94 (2H, s), 6.69 (1H, d, J = 2.5Hz), 6.74 (1H, dd, J = 8.3, 2.
5Hz), 6.90 (2H, d, J = 8.7Hz), 6.96 (1H, d, J = 8.3Hz), 7.33 (2H, d, J = 8.7Hz).

Formulation Example 1 (Manufacture of capsules)
1) 30 mg of the compound of Example 1
2) Fine powder cellulose 10mg
3) Lactose 19mg
4) Magnesium stearate 1mg
60mg total
Mix 1), 2), 3) and 4) above and fill into gelatin capsules.
Formulation Example 2 (Manufacture of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50g
3) Corn starch 15g
4) Carboxymethylcellulose calcium 44g
5) Magnesium stearate 1g
1000 tablets total 140g
The total amount of 1), 2) and 3) above and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

Using CHO cell lines stably expressing human-derived GPR40 in determining the decisions The EC ₅₀ values of _{The EC 50} values of example compounds on experimental example 1 human-derived GPR40. Unless otherwise specified, these CHO cell lines were cultured using α-MEM medium (Invitrogen) containing 10% fetal bovine serum (Invitrogen).
On the day before the assay, the cells cultured until they became almost confluent were rinsed with PBS (Invitrogen), then detached with 0.05% Trypsin · EDTA solution (Invitrogen), and collected by centrifugation. The number of cells obtained was measured, diluted to contain 3 × 10 ⁵ cells per mL of medium, dispensed 100 μL per well into Black welled 96-well plate (coster), and then into a CO ₂ incubator. And cultured overnight. Various test samples were added to the CHO cells prepared as described above, and the fluctuation of intracellular calcium concentration at this time was measured using FLIPR (Molecular Device). In order to measure the variation of intracellular calcium concentration by FLIPR, the following pretreatment was performed.
First, an assay buffer was prepared for adding the fluorescent dye Fluo3-AM (DOJIN) to the cells or for washing the cells immediately before performing the FLIPR assay. Probenecid (Sigma, 710 mg) was dissolved in 1N NaOH (5 mL) in a solution of 1M HEPES (pH 7.4, (DOJIN, 20 mL) added to HBSS (Invitrogen, 1000 mL) (hereinafter referred to as HBSS / HEPES solution). Thereafter, a solution (10 mL) mixed with HBSS / HEPES solution (5 mL) was further added, and this solution was used as an assay buffer, and then Fluo3-AM (50 μg) was dissolved in dimethyl sulfoxide (Wako, 21 μL). Further, an equal amount of 20% pullulonic acid (Molecular Probes) was added and mixed, and then added to assay buffer (10.6 mL) to which fetal bovine serum (105 μL) was added to prepare a fluorescent dye solution. -Well plate The CHO cell culture medium was removed, and 100 μL of the fluorescent dye solution was immediately dispensed per well, followed by culturing in a CO ₂ incubator for 1 hour, and the cells were taken up with the fluorescent dye. The test sample was diluted with DMSO in advance, dispensed 2 μl into a 96-well plate (sample plate) made of polypropylene, and frozen at −20 ° C. 198 μl of assay buffer containing 0.015% CHAPS (DOJIN) was added to the thawed sample plate at a time, and set in the FLIPR at the same time as the cell plate. Later, changes in intracellular calcium concentration were measured, and from the results, A volume response curve was prepared for each product, and an EC ₅₀ value was calculated, and the results are shown in Table 1.

  The compound of the present invention has an excellent GPR40 receptor function regulating action, and is useful as an insulin secretagogue and a preventive / therapeutic agent for diabetes.

Claims (11)

formula

[Where:
Ar represents a halogen atom; a cyano group; an optionally halogenated C _1-6 alkyl group; a C _6-14 aryl group; a hydroxy group; a C _3-8 cycloalkyl group, an optionally halogenated C _{1 1- A} C _1-10 alkoxy group optionally substituted with 1 to 3 substituents selected from ₆ alkoxy groups ; a heterocyclic oxy group; a C _7-16 aralkyloxy group; a carboxyl group; a C _1-6 alkyl-carbonyl A group; an aromatic hydrocarbon group optionally having 1 to 3 substituents selected from a C _6-14 aryl-carbonyl group ,
Ring A is a halogen atom, a C _7-16 aralkyl group, a C _6-14 aryl group, a C _1-10
An aromatic ring optionally having 1 to 3 substituents selected from an alkoxy group and a C _7-16 aralkyloxy group (provided that the ring is not thiazole, oxazole, imidazole and pyrazole),
Xa is sintered _{Gote; -O -; - S -;} - CH 2 -; - CO -; -; selected from _{C 1-6} alkyl groups and _{C 7-16} aralkyl groups on the N atom CH 2 S- —CH ₂ NH— which may have a substituent ; —OCH ₂ —; —SCH ₂ —; having a substituent selected from a C _1-6 alkyl group and a C _7-16 aralkyl group on the N atom; _Optionally substituted —NH—CH ₂ —; —CH ₂ CH ₂ O—; —CH ₂ CH ₂ S—; or a substituent selected from a C _1-6 alkyl group and a C _7-16 aralkyl group on the N atom. the _-CH 2 -NH-CO- optionally having,
Xb _{is, -CH 2 -; - CH 2} CH 2 -; - CO-CH 2 -; or _-CH 2 _CH 2 CH ₂ -, and
Xc is O ,

(Where

Indicates a bond)
Xd is the C H _2,
R ¹ represents a human Dorokishi group or a _{C 1-6} alkoxy group.
However ,
When ring A is benzene, the cyclic group represented by Ar is not a quinolinyl group. Compound monomers other salts thereof represented by. The compound according to claim 1, wherein Xa is a bond. The compound according to claim 1, wherein ring A is benzene. Xb is -CH ₂ - in which A compound according to claim 1, wherein. The compound according to claim 1, wherein R ¹ is a hydroxy group. formula

[Where:
Ar ¹ is a halogen atom, a nitro group, a carboxyl group, an optionally halogenated C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a carboxy-C _1-6 alkylcarbonylamino-C _1-6 alkyl. Each having a substituent selected from a group, an optionally halogenated C _1-6 alkoxy group, a C _6-14 aryl group, a C _6-14 aryloxy group and a C _7-16 aralkyloxy group the phenyl group or b Ndaniru group,
Xa ¹ represents a bond , —O—, —CO—, —CONH—, —N (CH ₃ ) CH ₂ —, —S—CH ₂ —, —C═C— ,
Ring A ² represents a benzene ring which may be further substituted with a C _1-6 alkyl group ,

Indicates. Ru of compound or a salt thereof represented by. formula

[Where:
Ar ² represents a thiazolyl group which may have a substituent selected from a C _6-14 aryl group and a C _1-6 alkyl group ,
Xa ² represents —N (R ⁵ ) — (CH ₂ ) m — or —S— (CH ₂ ) m — (R ⁵ represents a hydrogen atom or a C _1-6 alkyl group, and m represents an integer of 0 to 3. )
Ring A ³ is a benzene ring,

Indicates. Ru of compound or a salt thereof represented by. A pharmaceutical agent comprising a compound according to any one of claims 1-7. The medicament according to claim 8 , which is a preventive / therapeutic agent for diabetes. Insulin secretion enhancers comprising a compound according to any one of claims 1-7. A GPR40 receptor function regulator comprising the compound according to any one of claims 1 to 7.