JP2012136437A - Heterocyclic 5-membered ring compound - Google Patents

Heterocyclic 5-membered ring compound Download PDF

Info

Publication number
JP2012136437A
JP2012136437A JP2009095659A JP2009095659A JP2012136437A JP 2012136437 A JP2012136437 A JP 2012136437A JP 2009095659 A JP2009095659 A JP 2009095659A JP 2009095659 A JP2009095659 A JP 2009095659A JP 2012136437 A JP2012136437 A JP 2012136437A
Authority
JP
Japan
Prior art keywords
group
carbon atoms
compound
added
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2009095659A
Other languages
Japanese (ja)
Inventor
Minoru Taguchi
稔 田口
Takeshi Busujima
剛 毒島
Akira Suzuki
亮 鈴木
Yohei Kobashi
陽平 小橋
Tadahiro Bono
匡宏 坊野
Tetsuya Yabuuchi
哲也 薮内
Yuko Hashimoto
優子 橋本
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujifilm Corp
Taisho Pharmaceutical Co Ltd
Original Assignee
Fujifilm Corp
Taisho Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujifilm Corp, Taisho Pharmaceutical Co Ltd filed Critical Fujifilm Corp
Priority to JP2009095659A priority Critical patent/JP2012136437A/en
Priority to PCT/JP2010/056379 priority patent/WO2010117040A1/en
Publication of JP2012136437A publication Critical patent/JP2012136437A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

PROBLEM TO BE SOLVED: To provide a compound having an inhibitory effect on FATP4.SOLUTION: The heterocyclic 5-membered ring compound is represented by formula (I) (wherein A is carbonyl or methylene; X is a methylene group, oxygen atom or nitrogen atom; Y and W are the same or different and are a methine group or nitrogen atom; Z is a methylene group, oxygen atom or nitrogen atom; Ar is a substituted benzene ring, substituted pyridine ring or substituted thiophene ring; Ris -CO-NRR, -CO-R, -NHCO-Ror the like) or a pharmaceutically acceptable salt thereof.

Description

本発明は、ヘテロ５員環化合物に関する。更に詳しくは、小腸上皮細胞における脂肪酸特異的トランスポーターであるＦＡＴＰ４（Fatty acid transport protein 4）を阻害することから腸管での脂肪酸吸収阻害作用を有し、新規な高トリグリセライド血症、肥満症、糖尿病の治療薬として有用な新規ヘテロ５員環化合物に関する。   The present invention relates to a hetero 5-membered ring compound. More specifically, since it inhibits fatty acid-specific transporter FATP4 (Fatty acid transport protein 4) in small intestinal epithelial cells, it has an action to inhibit fatty acid absorption in the intestinal tract, and thus novel hypertriglyceridemia, obesity, diabetes The present invention relates to a novel hetero 5-membered ring compound useful as a therapeutic agent.

ＦＡＴＰ４を阻害する物質としては、ジヒドロピリミジン誘導体が報告されている(非特許文献１参照)。しかしながら、それら公知の化合物のＦＡＴＰ４阻害作用は充分とは言えず、それら自身がin vivoで脂肪酸吸収阻害作用を示すことはない。いずれも本発明の化合物と化学構造が異なる。   A dihydropyrimidine derivative has been reported as a substance that inhibits FATP4 (see Non-Patent Document 1). However, it cannot be said that the known compounds have sufficient FATP4 inhibitory action, and they themselves do not show fatty acid absorption inhibitory action in vivo. All have different chemical structures from the compounds of the present invention.

Blackburn C., et al., Bioorganic & Medicinal Chemistry Letters 16 (2006) 3504-3509.Blackburn C., et al., Bioorganic & Medicinal Chemistry Letters 16 (2006) 3504-3509.

本発明の目的は、優れたＦＡＴＰ４阻害作用を有する化合物を提供することである。   An object of the present invention is to provide a compound having an excellent FATP4 inhibitory action.

本発明者らは前記課題を解決するために鋭意研究を進めた結果、ある種のヘテロ５員環化合物がＦＡＴＰ４を阻害することを見出し、本発明を完成した。
かかる本発明の一実施形態は、
下記式（Ｉ）で表されるヘテロ５員環化合物又はその製薬学的に許容される塩である。
ただし、式（Ｉ）中、
Ａは−ＣＯ−又は−ＣＨ2−を示し、
Ｘは−ＣＨ2−、−Ｏ−又は−ＮＨ−を示し、
Ｙ及びＷは同一又は異なって、
又は
を示し、
Ｚは−ＣＨ2−、−Ｏ−又は−ＮＨ−を示し、
Ａｒは
又は
を示し、
Ｒ2、Ｒ3及びＲ4は同一又は異なって、水素原子、ハロゲン原子で置換されても良い炭素数１〜１２のアルキル基、ハロゲン原子で置換されても良い炭素数１〜１０のアルコキシ基、炭素数１〜６のアルキルチオ基、ハロゲン原子、ニトロ基、シアノ基、メトキシカルボニル基、メチルスルフィニル基、メチルスルホニル基、ジメチルアミノスルホニル基又はトリフルオロメチルスルホニルオキシ基を示し、
Ｒ5はハロゲン原子、ニトロ基又はシアノ基を示し、
Ｒ1は−ＣＯ−ＮＲ6Ｒ7、−ＣＯ2−Ｒ8、−ＮＨＣＯ−Ｒ9、
又は
を示し、Ｒ6は−（ＣＨ2）ｎ−Ｒ14、炭素数３〜８のシクロアルキル基、炭素数２〜１８のアルケニル基、
又は
を示し、
Ｒ7は水素原子、−（ＣＨ2）ｎ−Ｒ19又はアリル基を示し、
Ｒ8は
又は
を示し、
Ｒ9は
又は
を示し、
Ｒ10、Ｒ11及びＲ12は同一又は異なって、水素原子、塩素原子、メチル基又はメトキシ基を示し、
Ｒ13は炭素数１〜１２のアルキル基、ベンジルオキシカルボニル基、
又は
を示し、
Ｒ14は水素原子、ハロゲン原子、炭素数１〜１０のアルコキシ基、炭素数１〜６のアルキルチオ基、炭素数３〜８のシクロアルキル基、炭素数４〜８のシクロアルケニル基、メトキシカルボニル基、ベンジルオキシカルボニル基、
又は
を示し、
Ｒ15、Ｒ16及びＲ17は同一又は異なって、水素原子、ハロゲン原子、炭素数１〜１２のアルキル基、炭素数１〜１０のアルコキシ基又は炭素数１〜６のアルキルチオ基を示し、
Ｒ18はフェニル基、エトキシカルボニル基、フェネチル基、
又は
を示し、
Ｒ19は水素原子、水酸基、カルバモイル基、メチルアミノカルボニル基、シアノ基、カルボキシル基、メトキシカルボニル基又はアリル基を示し、
Ｒ20、Ｒ21及びＲ22は同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されても良い炭素数１〜１２のアルキル基、ハロゲン原子で置換されても良い炭素数１〜１０のアルコキシ基、炭素数１〜６のアルキルチオ基、フェニル基又はジメチルアミノ基を示し、
Ｒ23はハロゲン原子、炭素数１〜１２のアルキル基又は炭素数１〜６のアルキルチオ基を示し、
Ｒ24、Ｒ25及びＲ26は同一又は異なって、ハロゲン原子、炭素数１〜１２のアルキル基、炭素数１〜１０のアルコキシ基又はニトロ基を示し、
Ｒ27、Ｒ28及びＲ29は同一又は異なって、水素原子、ハロゲン原子、炭素数１〜１０のアルキル基、炭素数１〜１０のアルコキシ基又はシアノ基を示し、
ｎは１〜２０の整数を示す。 As a result of diligent research to solve the above-mentioned problems, the present inventors have found that a certain hetero 5-membered ring compound inhibits FATP4 and completed the present invention.
One embodiment of the present invention is as follows:
A hetero 5-membered ring compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
However, in formula (I),
A represents —CO— or —CH 2 —;
X represents —CH 2 —, —O— or —NH—;
Y and W are the same or different,
Or
Indicate
Z represents —CH 2 —, —O— or —NH—;
Ar is
Or
Indicate
R 2 , R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may be substituted with a halogen atom, or an alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom. , An alkylthio group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a methoxycarbonyl group, a methylsulfinyl group, a methylsulfonyl group, a dimethylaminosulfonyl group or a trifluoromethylsulfonyloxy group,
R 5 represents a halogen atom, a nitro group or a cyano group,
R 1 is —CO—NR 6 R 7 , —CO 2 —R 8 , —NHCO—R 9 ,
Or
R 6 is — (CH 2 ) n—R 14 , a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 18 carbon atoms,
Or
Indicate
R 7 represents a hydrogen atom, — (CH 2 ) n—R 19 or an allyl group,
R 8 is
Or
Indicate
R 9 is
Or
Indicate
R 10 , R 11 and R 12 are the same or different and each represents a hydrogen atom, a chlorine atom, a methyl group or a methoxy group,
R 13 represents an alkyl group having 1 to 12 carbon atoms, a benzyloxycarbonyl group,
Or
Indicate
R 14 is a hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkenyl group having 4 to 8 carbon atoms, or a methoxycarbonyl group. Benzyloxycarbonyl group,
Or
Indicate
R 15 , R 16 and R 17 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or an alkylthio group having 1 to 6 carbon atoms,
R 18 is a phenyl group, an ethoxycarbonyl group, a phenethyl group,
Or
Indicate
R 19 represents a hydrogen atom, a hydroxyl group, a carbamoyl group, a methylaminocarbonyl group, a cyano group, a carboxyl group, a methoxycarbonyl group or an allyl group,
R 20 , R 21 and R 22 are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms which may be substituted with a halogen atom, or 1 to 10 carbon atoms which may be substituted with a halogen atom. An alkoxy group, an alkylthio group having 1 to 6 carbon atoms, a phenyl group or a dimethylamino group,
R 23 represents a halogen atom, an alkyl group having 1 to 12 carbon atoms or an alkylthio group having 1 to 6 carbon atoms,
R 24 , R 25 and R 26 are the same or different and each represents a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a nitro group,
R 27 , R 28 and R 29 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a cyano group,
n shows the integer of 1-20.

本発明の他の実施形態は、下記式（II）で表されるヘテロ５員環化合物又はその製薬学的に許容される塩である。

ただし、式（II）中、Ｒ18は上記Ｒ18と同意義である。Ａｒは
を示す。ただし、Ｒ2、Ｒ3及びＲ4は上記Ｒ2、Ｒ3及びＲ4とそれぞれ同意義である。 Another embodiment of the present invention is a hetero 5-membered ring compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.

However, in formula (II), R 18 has the same meaning as R 18 described above. Ar is
Indicates. However, R 2 , R 3 and R 4 have the same meanings as R 2 , R 3 and R 4 , respectively.

更に、本発明の他の実施形態は、下記式（III）で表されるヘテロ５員環化合物又はその製薬学的に許容される塩である。

式（III）中、Ｒ13及びＡｒは上記Ｒ13及びＡｒとそれぞれ同意義である。 Furthermore, another embodiment of the present invention is a hetero 5-membered ring compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof.

In the formula (III), R 13 and Ar have the same meanings as R 13 and Ar, respectively.

本発明により、優れたＦＡＴＰ４阻害作用を有する化合物を提供することが可能となった。   According to the present invention, it has become possible to provide a compound having an excellent FATP4 inhibitory action.

以下に、本発明において使用される定義を説明する。
ハロゲン原子としては、フッ素原子、塩素原子、臭素原子又はヨウ素原子が挙げられる。
炭素原子数１〜１２のアルキル基とは、直鎖状、分岐鎖状又は環状の炭素原子数１〜１２のアルキル基を示し、例えば、メチル基、エチル基、プロピル基、ｔ−ブチル基、シクロペンチル基、シクロヘキシル基、シクロペンチルメチル基が挙げられる。
ハロゲン原子で置換されても良い炭素数１〜１２のアルキル基とは、直鎖状、分岐鎖状又は環状のハロゲン原子で置換された炭素原子数１〜１２のアルキル基を示し、例えば、トリフルオロメチル基、ペンタフルオロエチル基が挙げられる。
炭素原子数１〜１０のアルコキシ基とは、直鎖状、分岐鎖状又は環状の炭素原子数１〜１０のアルコキシ基を示し、例えば、メトキシ基、エトキシ基、プロポキシ基、ｔ−ブトキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基、シクロペンチルメチルオキシ基が挙げられる。
ハロゲン原子で置換されても良い炭素原子数１〜１０のアルコキシ基とは、直鎖状、分岐鎖状又は環状のハロゲン原子で置換された炭素原子数１〜１０のアルコキシ基を示し、例えば、トリフルオロメトキシ基、ペンタフルオロエトキシ基が挙げられる。
炭素原子数１〜６のアルキルチオ基とは、直鎖状、分岐鎖状又は環状の炭素原子数１〜6のアルキルチオ基を示し、例えば、メチルチオ基、エチルチオ基、プロピルチオ基、ｔ−ブチルチオ基、シクロペンチルチオ基、シクロヘキシルチオ基、シクロペンチルメチルチオ基が挙げられる。
炭素数３〜８のシクロアルキル基とは、例えば、シクロブチル基、シクロペンチル基、シクロヘキシル基が挙げられる。
炭素数２〜１８のアルケニル基とは直鎖状、分岐鎖状又は環状の炭素数２〜１８のアルケニル基を示し、例えば、ビニル基、ペンテニル基、シクロヘキセニル基が挙げられる。
炭素数４〜８シクロアルケニル基とは、例えば、シクロペンテニル基、シクロヘキセニル基が挙げられる。 The definitions used in the present invention are described below.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
A C1-C12 alkyl group shows a linear, branched or cyclic C1-C12 alkyl group, for example, a methyl group, an ethyl group, a propyl group, t-butyl group, Examples include a cyclopentyl group, a cyclohexyl group, and a cyclopentylmethyl group.
The alkyl group having 1 to 12 carbon atoms that may be substituted with a halogen atom refers to an alkyl group having 1 to 12 carbon atoms that is substituted with a linear, branched, or cyclic halogen atom. Examples include a fluoromethyl group and a pentafluoroethyl group.
The alkoxy group having 1 to 10 carbon atoms refers to a linear, branched or cyclic alkoxy group having 1 to 10 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, a t-butoxy group, Examples include a cyclopentyloxy group, a cyclohexyloxy group, and a cyclopentylmethyloxy group.
The alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom refers to an alkoxy group having 1 to 10 carbon atoms which is substituted with a linear, branched or cyclic halogen atom. Examples thereof include a trifluoromethoxy group and a pentafluoroethoxy group.
The alkylthio group having 1 to 6 carbon atoms refers to a linear, branched or cyclic alkylthio group having 1 to 6 carbon atoms, such as a methylthio group, an ethylthio group, a propylthio group, a t-butylthio group, Examples include a cyclopentylthio group, a cyclohexylthio group, and a cyclopentylmethylthio group.
Examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
A C2-C18 alkenyl group shows a linear, branched or cyclic C2-C18 alkenyl group, for example, a vinyl group, a pentenyl group, and a cyclohexenyl group.
Examples of the C 4-8 cycloalkenyl group include a cyclopentenyl group and a cyclohexenyl group.

本発明において医薬上許容される塩としては、酸又はアルカリ付加塩が挙げられる。酸としては、硫酸、塩酸、燐酸などの鉱酸との塩、酢酸、シュウ酸、乳酸、酒石酸、フマール酸、マレイン酸、メタンスルホン酸、ベンゼンスルホン酸などの有機酸との塩などを挙げることができ、アルカリとしては、ナトリウム、カリウムなどの金属イオン、アルキルアンモニウムなどのアンモニウムイオンを挙げることができる。
本発明の化合物は単一の化合物であっても、あるいは立体異性体の混合物であってもよく、又、これらの水和物もしくは溶媒和物であってもよい。更に、後述する実施例１２４あるいは１２５の化合物のように前記式（Ｉ）で表される化合物の２量体であってもよい。 Examples of pharmaceutically acceptable salts in the present invention include acid or alkali addition salts. Examples of acids include salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid and benzenesulfonic acid. Examples of the alkali include metal ions such as sodium and potassium, and ammonium ions such as alkylammonium.
The compound of the present invention may be a single compound, a mixture of stereoisomers, or a hydrate or solvate thereof. Further, it may be a dimer of the compound represented by the formula (I) like the compound of Example 124 or 125 described later.

前記式（Ｉ）で表される本発明の化合物の製造方法を以下に説明する。
なお、ＷＳＣ・ＨＣｌは１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩、ＤＣＣはジシクロヘキシルカルボジイミド、ＨＯＢｔは１−ヒドロキシベンゾトリアゾール、ＣＡＮは硝酸セリウム(IV)アンモニウム、ＴＢＡＢはテトラブチルアンモニウムブロマイド及びＴＭＳはトリメチルシリル基を表す。
本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは酸素原子を示し、Ｙ及びＷは
を示し、Ｚは−ＣＨ2−を示し、Ｒ1は
を示し、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である化合物群は、反応スキーム１に示した方法で合成することができる。すなわち、化合物（１）の水酸基をテトラヒドロピラニルで保護した後、ホーナーエモンズ反応により化合物（２）を得、脱保護した後に二重結合を還元、酸存在下で閉環し化合物（３）のｃｉｓ体とｔｒａｎｓ体の混合物を得ることができる。この混合物をシリカゲルクロマトグラフィーにより分離精製することで、化合物（３）のｃｉｓ体あるいはｔｒａｎｓ体を単一化合物として得ることができる。
式中、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である。 A method for producing the compound of the present invention represented by the formula (I) will be described below.
WSC · HCl is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, DCC is dicyclohexylcarbodiimide, HOBt is 1-hydroxybenzotriazole, CAN is cerium (IV) ammonium nitrate, and TBAB is tetrabutylammonium Bromide and TMS represent a trimethylsilyl group.
In the formula (I) in the present invention, A represents —CO—, X represents an oxygen atom, and Y and W represent
Z represents —CH 2 —, R 1 represents
A compound group in which Ar, R 10 , R 11 and R 12 are as defined above can be synthesized by the method shown in Reaction Scheme 1. That is, after protecting the hydroxyl group of compound (1) with tetrahydropyranyl, compound (2) is obtained by Horner-Emmons reaction, and after deprotection, the double bond is reduced and cyclized in the presence of acid to form cis of compound (3). A mixture of body and trans body can be obtained. By separating and purifying the mixture by silica gel chromatography, the cis form or the trans form of the compound (3) can be obtained as a single compound.
In the formula, Ar, R 10 , R 11 and R 12 are as defined above.

また、前記の化合物（３）は反応スキーム２に示した方法でも合成することができる。すなわち、化合物（４）をワインレブアミド化後、アリール化し化合物（５）を得、次いで酢酸を導入後、ケトンの還元、エステルの加水分解を順次行い得られた化合物（６）を、塩酸存在下、室温で閉環することにより化合物（３）のｃｉｓ体とｔｒａｎｓ体の混合物を得ることができる。
式中、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義であり、Ｒ30は塩素原子、臭素原子又はヨウ素原子を示す。
なお、ここで得られた化合物（３）のｃｉｓ体とｔｒａｎｓ体の混合物を酢酸存在下、加熱することにより異性化させ化合物（３）のｔｒａｎｓ体を単一化合物として得ることができる。 The compound (3) can also be synthesized by the method shown in Reaction Scheme 2. That is, compound (4) was subjected to wine levamidation, arylated to obtain compound (5), and then acetic acid was introduced, followed by reduction of ketone and hydrolysis of ester in the presence of hydrochloric acid. The mixture of the cis form and the trans form of Compound (3) can be obtained by ring-closing at room temperature.
In the formula, Ar, R 10 , R 11 and R 12 are as defined above, and R 30 represents a chlorine atom, a bromine atom or an iodine atom.
The mixture of the cis form and the trans form of the compound (3) obtained here is isomerized by heating in the presence of acetic acid to obtain the trans form of the compound (3) as a single compound.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘ及びＺは酸素原子を示し、Ｙ及びＷは
を示し、Ｒ1は
を示し、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である化合物群は、反応スキーム３に示したように、化合物（７）を還元後、トリホスゲンと反応させることにより化合物（９）をｃｉｓ体とｔｒａｎｓ体の混合物として得ることができる。この混合物をシリカゲルクロマトグラフィーにより分離精製することで、化合物（９）のｃｉｓ体あるいはｔｒａｎｓ体を単一化合物として得ることができる。
式中、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である。 In the formula (I) of the present invention, A represents —CO—, X and Z represent oxygen atoms, and Y and W represent
R 1 is
A compound group in which Ar, R 10 , R 11 and R 12 are as defined above is obtained by reacting compound (7) with triphosgene after reduction of compound (7) as shown in Reaction Scheme 3. ) Can be obtained as a mixture of cis and trans isomers. By separating and purifying the mixture by silica gel chromatography, the cis form or the trans form of the compound (9) can be obtained as a single compound.
In the formula, Ar, R 10 , R 11 and R 12 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘ及びＺは−ＮＨ−を示し、Ｙ及びＷは
を示し、Ｒ1は
を示し、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である化合物群は、反応スキーム４に示したように、反応スキーム３で得られた化合物（８）をメシル化後アジド化し、アジドを還元し得られたジアミン化合物を、トリホスゲンと反応させることにより、化合物（１０）をｃｉｓ体とｔｒａｎｓ体の混合物として得ることができる。この混合物をシリカゲルクロマトグラフィーにより分離精製することで、化合物（１０）のｃｉｓ体あるいはｔｒａｎｓ体を単一化合物として得ることができる。
式中、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X and Z represent —NH—, and Y and W represent
R 1 is
Wherein Ar, R 10 , R 11 and R 12 are as defined above, the compound (8) obtained in Reaction Scheme 3 was azidated after mesylation as shown in Reaction Scheme 4. By reacting the diamine compound obtained by reducing azide with triphosgene, compound (10) can be obtained as a mixture of cis and trans isomers. By separating and purifying the mixture by silica gel chromatography, the cis form or the trans form of the compound (10) can be obtained as a single compound.
In the formula, Ar, R 10 , R 11 and R 12 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは酸素原子を示し、Ｚは−ＮＨ−を示し、Ｙ及びＷは
を示し、Ｒ1は
を示し、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である化合物群は、反応スキーム５に示したように、化合物（１）をオキシム化後、オキシムを還元し得られた化合物を、トリホスゲンと反応させることにより、化合物（１１）をｃｉｓ体とｔｒａｎｓ体の混合物として得ることができる。この混合物をシリカゲルクロマトグラフィーにより分離精製することで、化合物（１１）のｃｉｓ体あるいはｔｒａｎｓ体を単一化合物として得ることができる。
式中、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents an oxygen atom, Z represents —NH—, and Y and W represent
R 1 is
A compound group in which Ar, R 10 , R 11 and R 12 are as defined above is a compound obtained by reducing oxime after oximation of compound (1) as shown in Reaction Scheme 5. Is reacted with triphosgene to give compound (11) as a mixture of cis and trans isomers. By separating and purifying the mixture by silica gel chromatography, it is possible to obtain the cis form or the trans form of the compound (11) as a single compound.
In the formula, Ar, R 10 , R 11 and R 12 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘ及びＺは−ＮＨ−を示し、Ｙは
を示し、Ｗは
を示し、Ｒ1は
を示し、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である化合物群は、反応スキーム６に示したように、化合物（１２）を置換ベンズアルデヒドと反応させることにより、化合物（１３）として得ることができる。
式中、Ａｒ、Ｒ10、Ｒ11及びＲ12は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X and Z represent —NH—, and Y represents
W
R 1 is
Wherein Ar, R 10 , R 11 and R 12 are as defined above, the compound group (13) is obtained by reacting compound (12) with a substituted benzaldehyde as shown in Reaction Scheme 6. Can be obtained as
In the formula, Ar, R 10 , R 11 and R 12 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは−ＮＨ−を示し、Ｙ及びＷは
を示し、Ｚは−ＣＨ2−を示し、Ｒ1は−ＣＯ−ＮＲ6Ｒ7を示し、Ａｒ、Ｒ6及びＲ7は前記と同意義である化合物群は、反応スキーム７に示した方法で合成することができる。すなわち、化合物（１４）をイミノ化後、無水コハク酸と反応させラクタム誘導体とし、アミド化、脱保護を順次行い化合物（１６）を得ることができる。
式中、Ａｒ、Ｒ6及びＲ7は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents —NH—, and Y and W represent
Z represents —CH 2 —, R 1 represents —CO—NR 6 R 7 , and Ar, R 6, and R 7 are as defined above. Can be synthesized. That is, after iminating compound (14), it is reacted with succinic anhydride to give a lactam derivative, and amidation and deprotection are sequentially performed to obtain compound (16).
In the formula, Ar, R 6 and R 7 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは−ＣＨ2−を示し、Ｙは
を示し、Ｚは−ＮＨ−を示し、Ｗは
を示し、Ｒ1は−ＣＯ−ＮＨＲ6を示し、Ａｒ及びＲ6は前記と同意義である化合物群は、反応スキーム８に示したように、化合物（１７）をヒドラジンと反応後、イソシアネート誘導体によりアミド化し化合物（１８）として得ることができる。
式中、Ａｒ及びＲ6は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents —CH 2 —, and Y represents
Z represents -NH-, W represents
Wherein R 1 represents —CO—NHR 6 , Ar and R 6 are as defined above, and the compound group is obtained by reacting compound (17) with hydrazine as shown in Reaction Scheme 8, To obtain a compound (18).
In the formula, Ar and R 6 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは−ＮＨ−を示し、Ｙは
を示し、Ｚは−ＣＨ2−を示し、Ｗは
を示し、Ｒ1は−ＣＯ−ＮＲ6Ｒ7を示し、Ａｒ、Ｒ6及びＲ7は前記と同意義である化合物群は、反応スキーム９に示したように、化合物（１９）をジエチルマレイン酸と反応させ化合物（２０）を得、エステルを加水分解後、アミド化し化合物（２１）として得ることができる。
式中、Ａｒ、Ｒ6及びＲ7は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents —NH—, and Y represents
Z represents —CH 2 —, W represents
Wherein R 1 represents —CO—NR 6 R 7 , and Ar, R 6 and R 7 are as defined above, the compound group represented by The compound (20) can be obtained by reacting with an acid, and the ester can be hydrolyzed and then amidated to obtain the compound (21).
In the formula, Ar, R 6 and R 7 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＨ2−を示しＸは酸素原子を示し、Ｙ及びＷは
を示し、Ｚは-ＣＨ2-を示し、Ｒ1は−ＣＯ−ＮＲ6Ｒ7を示し、Ａｒ、Ｒ6及びＲ7は前記と同意義である化合物群は、反応スキーム１０に示したように、化合物（１４）を４−ブロモ酪酸エチルと反応させ化合物（２２）を得、エステルを加水分解後、アミド化し化合物（２３）として得ることができる。
式中、Ａｒ、Ｒ6及びＲ7は前記と同意義である。 In the formula (I) in the present invention, A represents —CH 2 —, X represents an oxygen atom, and Y and W are
Z represents —CH 2 —, R 1 represents —CO—NR 6 R 7 , and Ar, R 6, and R 7 are as defined above. The compound (14) can be reacted with ethyl 4-bromobutyrate to obtain the compound (22), and the ester can be hydrolyzed and then amidated to obtain the compound (23).
In the formula, Ar, R 6 and R 7 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘ及びＺは−ＣＨ2−を示し、Ｙは
を示し、Ｗは
を示し、Ｒ1は−ＮＨＣＯ−Ｒ9を示し、Ｒ9は

を示し、Ｒ1は
を示し、Ａｒは前記と同意義である化合物群は、反応スキーム１１に示したように、化合物（２４）をアミド化し化合物（２５）を得、脱保護後、アリール化し、水酸基を酸化することにより化合物（２６）として得ることができる。
式中、Ａｒ及びＲ30は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X and Z represent —CH 2 —, and Y represents
W
R 1 represents —NHCO—R 9 and R 9 represents

R 1 is
In the compound group in which Ar is as defined above, compound (24) is amidated to obtain compound (25) as shown in Reaction Scheme 11, and after deprotection, arylation is performed to oxidize the hydroxyl group. To obtain the compound (26).
In the formula, Ar and R 30 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは酸素原子を示し、Ｚは−ＣＨ2−を示し、Ｙ及びＷは
を示し、Ｒ1は−ＣＯ−ＮＲ6Ｒ7、−ＣＯ2−Ｒ8、−ＮＨＣＯ−Ｒ9、
又は
を示し、Ａｒ、Ｒ6、Ｒ7、Ｒ8、Ｒ9及びＲ13は前記と同意義である化合物群を合成するための原料は、反応スキーム１２に示したように、化合物（１４）と無水コハク酸を反応させることにより、化合物（２７）をｃｉｓ体とｔｒａｎｓ体の混合物として得ることができる。化合物（２７）の混合物を、酸存在下で加熱することによりｃｉｓ体をｔｒａｎｓ体へ異性化させた後、エステル化し化合物（２８）を得、シリカゲルクロマトグラフィーで分離精製後、加水分解することで、ｔｒａｎｓ体（２９）を単一化合物として得ることができる。さらに、化合物（２９）を光学活性な１−フェネチルアミンなどとの塩を作製し光学分割することにより、光学活性な化合物（２９）を得ることができる。
式中、Ａｒは前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents an oxygen atom, Z represents —CH 2 —, and Y and W represent
R 1 represents —CO—NR 6 R 7 , —CO 2 —R 8 , —NHCO—R 9 ,
Or
A raw material for synthesizing a compound group in which Ar, R 6 , R 7 , R 8 , R 9, and R 13 have the same meanings as described above is as shown in Reaction Scheme 12 and compound (14) By reacting succinic anhydride, compound (27) can be obtained as a mixture of cis- and trans-isomers. The mixture of compound (27) is heated in the presence of an acid to isomerize the cis form to the trans form, and then esterified to obtain compound (28), which is separated and purified by silica gel chromatography, followed by hydrolysis. , Trans isomer (29) can be obtained as a single compound. Furthermore, an optically active compound (29) can be obtained by preparing a salt of the compound (29) with optically active 1-phenethylamine or the like and optically resolving it.
In the formula, Ar is as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは酸素原子を示し、Ｚは−ＣＨ2−を示し、Ｙ及びＷは
を示し、Ｒ1は−ＮＨＣＯ−Ｒ9を示し、Ｒ9は

又は
を示し、Ａｒは前記と同意義である化合物群は、反応スキーム１３に示したように、反応スキーム１２で得られた化合物（２７）をクルチウス転位後、脱保護し化合物（３１）を得、次いでトリホスゲン存在下アミンと反応させることで、化合物（３２）あるいは化合物（３３）として得ることができる。
式中、Ａｒは前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents an oxygen atom, Z represents —CH 2 —, and Y and W represent
R 1 represents —NHCO—R 9 and R 9 represents

Or
In the compound group in which Ar is as defined above, the compound (27) obtained in the reaction scheme 12 was deprotected after the Curtius rearrangement to obtain the compound (31), as shown in the reaction scheme 13. Subsequently, it can be obtained as compound (32) or compound (33) by reacting with an amine in the presence of triphosgene.
In the formula, Ar is as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは酸素原子を示し、Ｚは−ＣＨ2−を示し、Ｙ及びＷは
を示し、Ｒ1は−ＮＨＣＯ−Ｒ9を示し、Ｒ9は

を示し、Ａｒは前記と同意義である化合物群は、反応スキーム１４に示したように、反応スキーム１３で得られた化合物（３１）をアミド化後、脱保護し、次いで還元的にアミンをベンジル化することで、化合物（３５）として得ることができる。
式中、Ａｒは前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents an oxygen atom, Z represents —CH 2 —, and Y and W represent
R 1 represents —NHCO—R 9 and R 9 represents

In the compound group in which Ar is as defined above, as shown in Reaction Scheme 14, the compound (31) obtained in Reaction Scheme 13 is amidated, deprotected, and then reductively converted to an amine. The compound (35) can be obtained by benzylation.
In the formula, Ar is as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは酸素原子を示し、Ｚは−ＣＨ2−を示し、Ｙ及びＷは
を示し、Ｒ1は
を示し、Ａｒは前記と同意義である化合物群は、反応スキーム１５に示したように、反応スキーム１２で得られた化合物（２７）を１炭素増炭後アミド化することで、化合物（３６）として得ることができる。
式中、Ａｒは前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents an oxygen atom, Z represents —CH 2 —, and Y and W represent
R 1 is
In the compound group in which Ar is as defined above, the compound (27) obtained in the reaction scheme 12 was subjected to a carbonization increase and then amidated, as shown in the reaction scheme 15. ) Can be obtained.
In the formula, Ar is as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは酸素原子を示し、Ｚは−ＣＨ2−を示し、Ｙ及びＷは
を示し、Ｒ1は−ＣＯ2−Ｒ8を示し、Ａｒ及びＲ8は前記と同意義である化合物群は、反応スキーム１６に示したように、反応スキーム１２で得られた化合物（２７）をエステル化することで、化合物（３７）をｃｉｓ体とｔｒａｎｓ体の混合物として得ることができる。この混合物をシリカゲルクロマトグラフィーにより分離精製することで、化合物（３７）のｃｉｓ体あるいはｔｒａｎｓ体を単一化合物として得ることができる。
式中、Ａｒ及びＲ8は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents an oxygen atom, Z represents —CH 2 —, and Y and W represent
Wherein R 1 represents —CO 2 —R 8 , and Ar and R 8 have the same meanings as defined above, the compound group represented by Reaction Scheme 12 as shown in Reaction Scheme 16 (27) Is esterified to give compound (37) as a mixture of cis and trans isomers. By separating and purifying the mixture by silica gel chromatography, it is possible to obtain a cis isomer or trans isomer of compound (37) as a single compound.
In the formula, Ar and R 8 are as defined above.

本発明における前記式（Ｉ）において、Ａは−ＣＯ−を示し、Ｘは酸素原子を示し、Ｚは−ＣＨ2−を示し、Ｙ及びＷは
を示し、Ｒ1は−ＣＯ−ＮＲ6Ｒ7を示し、Ａｒ、Ｒ6及びＲ7は前記と同意義である化合物群は、反応スキーム１７に示したように、反応スキーム１２で得られた化合物（２７）をアミド化することで、化合物（３８）をｃｉｓ体とｔｒａｎｓ体の混合物として得ることができる。この混合物をシリカゲルクロマトグラフィーにより分離精製することで、化合物（３７）のｃｉｓ体あるいはｔｒａｎｓ体を単一化合物として得ることができる。また、反応スキーム１７において、反応出発物質に反応スキーム１２で得られた光学活性な化合物（２９）を用いることにより光学活性な化合物（３８）を得ることができる。
式中、Ａｒ、Ｒ6及びＲ7は前記と同意義である。 In the formula (I) in the present invention, A represents —CO—, X represents an oxygen atom, Z represents —CH 2 —, and Y and W represent
Wherein R 1 represents —CO—NR 6 R 7 , and Ar, R 6 and R 7 are as defined above. Compound (38) can be obtained as a mixture of a cis form and a trans form by amidating compound (27). By separating and purifying the mixture by silica gel chromatography, it is possible to obtain a cis isomer or trans isomer of compound (37) as a single compound. In Reaction Scheme 17, the optically active compound (38) can be obtained by using the optically active compound (29) obtained in Reaction Scheme 12 as a reaction starting material.
In the formula, Ar, R 6 and R 7 are as defined above.

以下に、参考例、実施例及び試験例を示して本発明をさらに具体的に説明する。
（参考例１）
（−）−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸の合成
（１）２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸の合成
４−クロロベンズアルデヒド（１６３ｇ）、無水コハク酸（１７４ｇ）に塩化亜鉛（II）（３３９ｇ）のクロロホルム（１Ｌ）懸濁液に、トリエチルアミン（３４０ｍＬ）を室温で加え、５日間攪拌した。反応液に２Ｎ塩酸を加え、酢酸エチルで抽出、有機層を飽和食塩水で２回洗浄した。硫酸マグネシウムで乾燥後、減圧下溶媒留去し、２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸 （２３７ｇ）をcis体とtrans体の混合物の無色粉末として得た。
1HNMR (300MHz, DMSO-d6) cis体とtrans体の混合物
δ 2.73-3.01 (m, 2H), 3.38-3.77 (m, 1H), 5.60, 5.85 (d, J =8.１Hz, each 1/2H), 7.28-7.52 (m, 4H) Hereinafter, the present invention will be described more specifically with reference to reference examples, examples and test examples.
(Reference Example 1)
Synthesis of (−)-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid (1) Synthesis of 2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid 4-chlorobenzaldehyde ( 163 g), succinic anhydride (174 g), triethylamine (340 mL) was added to a chloroform (1 L) suspension of zinc chloride (II) (339 g) at room temperature, and the mixture was stirred for 5 days. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid (237 g) as a colorless powder of a mixture of cis and trans isomers.
1 HNMR (300 MHz, DMSO-d 6 ) Mixture of cis and trans δ δ 2.73-3.01 (m, 2H), 3.38-3.77 (m, 1H), 5.60, 5.85 (d, J = 8.1 Hz, each 1 / 2H), 7.28-7.52 (m, 4H)

（２）トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸メチルの合成
参考例１（１）で得られた化合物（２３７ｇ）のトリフルオロ酢酸（９７１ｍＬ）溶液に濃硫酸（３１ｍＬ）を加え、４０分間加熱還流した。反応液に食塩水を加え、酢酸エチルで抽出した。硫酸マグネシウムで乾燥後、減圧下溶媒留去し、トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸（２１３ｇ）を得た。
ここで得られた化合物（２１３ｇ）のクロロホルム−メタノール（１：１混合、１．３Ｌ）溶液に１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２５５ｇ）を加え一晩攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和重曹水で２回洗浄した。硫酸マグネシウムで乾燥後、減圧下溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（２０％酢酸エチル−ヘキサン）で精製し、トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸メチル（１６３ｇ）を無色粉末として得た。
1HNMR (300 MHz, CDCl3) δ 2.83-3.07 (m, 2H), 3.22-3.38 (m, 1H), 3.77 (s, 3H), 5.61 (d, J =7.5Hz, 1H), 7.27-7.41 (m, 4H)
（３）トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸エチルの合成
参考例１（２）に示した方法においてエタノールと反応させ、表題化合物トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸エチルを得た。
1HNMR (200MHz, CDCl3) δ(ppm): 1.28 (t, J=7.0 Hz, 3 H), 2.77-3.11 (m, 2 H), 3.16-3.36 (m, 1 H), 4.23 (q, J=7.0 Hz, 2 H), 5.61 (d, J=7.5 Hz, 1 H), 7.26-7.44 (m, 4 H) (2) Synthesis of methyl trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylate Concentrated sulfuric acid was added to a solution of the compound (237 g) obtained in Reference Example 1 (1) in trifluoroacetic acid (971 mL). (31 mL) was added and heated to reflux for 40 minutes. To the reaction solution was added brine and extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid (213 g).
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (255 g) was added to a chloroform-methanol (1: 1 mixture, 1.3 L) solution of the obtained compound (213 g) and stirred overnight. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous sodium hydrogen carbonate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate-hexane) to obtain trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid. Methyl acid (163 g) was obtained as a colorless powder.
1 HNMR (300 MHz, CDCl 3 ) δ 2.83-3.07 (m, 2H), 3.22-3.38 (m, 1H), 3.77 (s, 3H), 5.61 (d, J = 7.5Hz, 1H), 7.27-7.41 (m, 4H)
(3) Synthesis of ethyl trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylate The compound shown in Reference Example 1 (2) was reacted with ethanol to give the title compound trans-2- (4- Chlorophenyl) -5-oxotetrahydrofuran-3-carboxylate was obtained.
1 HNMR (200MHz, CDCl 3 ) δ (ppm): 1.28 (t, J = 7.0 Hz, 3 H), 2.77-3.11 (m, 2 H), 3.16-3.36 (m, 1 H), 4.23 (q, J = 7.0 Hz, 2 H), 5.61 (d, J = 7.5 Hz, 1 H), 7.26-7.44 (m, 4 H)

（４）トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸の合成
参考例１（２）で得られた化合物（１６３ｇ）の１．４−ジオキサン（９６０ｍＬ）液に濃塩酸（６４８ｍＬ）を加え、１時間還流した。反応液に食塩水を加え、飽和重曹水で抽出した。水層に濃塩酸を加え酸性とし、酢酸エチルで抽出、有機層を飽和食塩水で２回洗浄した。硫酸マグネシウムで乾燥後、減圧下溶媒留去し、トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸（９４．０ｇ）を無色粉末として得た。
1HNMR (300 MHz, DMSO-d6) δ 2.93 (dd, J =9.40, 1.8Hz, 2H), 3.40-3.54 (m, 1H), 5.60 (d, J =8.1Hz, 1H), 7.36-7.60 (m, 4H), 13.00 (br. s, 1H) (4) Synthesis of trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid Concentrated in 1.4-dioxane (960 mL) solution of the compound (163 g) obtained in Reference Example 1 (2). Hydrochloric acid (648 mL) was added and refluxed for 1 hour. Brine was added to the reaction mixture, and the mixture was extracted with saturated aqueous sodium hydrogen carbonate. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed twice with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid (94.0 g) as a colorless powder.
1 HNMR (300 MHz, DMSO-d 6 ) δ 2.93 (dd, J = 9.40, 1.8Hz, 2H), 3.40-3.54 (m, 1H), 5.60 (d, J = 8.1Hz, 1H), 7.36-7.60 (m, 4H), 13.00 (br. s, 1H)

（５）（−）−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸の合成
参考例１（４）で得られた化合物（９１．０ｇ）の酢酸エチル−メタノール（1：1混合、１．３Ｌ）溶液に（Ｒ）−１−フェネチルアミンを加えた。生じた結晶を同溶媒より２回再結晶し、（−）−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸（Ｒ）−１−フェネチルアミン塩（１８．０ｇ）を無色粉末として得た。
1HNMR (300 MHz, DMSO-d6) δ 1.44 (d, J =6.8Hz, 3H), 2.66-3.04 (m, 3H), 4.22-4.34 (m, 1H), 5.55 (d, J =7.2Hz, 1H), 7.27-7.51 (m, 9H) (5) Synthesis of (−)-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid The compound (91.0 g) obtained in Reference Example 1 (4) in ethyl acetate-methanol (1: (R) -1-phenethylamine was added to the 1 mixed, 1.3 L) solution. The resulting crystals were recrystallized twice from the same solvent to give (−)-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid (R) -1-phenethylamine salt (18.0 g) as a colorless powder. Got as.
1 HNMR (300 MHz, DMSO-d 6 ) δ 1.44 (d, J = 6.8Hz, 3H), 2.66-3.04 (m, 3H), 4.22-4.34 (m, 1H), 5.55 (d, J = 7.2Hz , 1H), 7.27-7.51 (m, 9H)

また、この化合物を一部とり、２Ｎ塩酸で中和した後に、酢酸エチルにより抽出し、表題化合物（−）−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸を得、旋光度を測定した。
［α］D 20 = -81.9 (c 1.00, MeOH) A part of this compound was taken, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate to obtain the title compound (-)-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxylic acid. The degree was measured.
[Α] D 20 = -81.9 (c 1.00, MeOH)

（参考例２）
（−）−２−（４−シアノフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸の合成
４−シアノベンズアルデヒドを原料として、参考例１に示した方法により、（−）−２−（４−シアノフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸 （Ｒ）−１−フェネチルアミン塩を得た。
1HNMR (300 MHz, DMSO-d6) δ 1.47 (d, J =6.7Hz, 3H), 2.67-3.02 (m, 3H), 4.32 (q, J =6.7Hz, 1H), 5.63 (d, J =7.3Hz, 1H), 7.28-7.43 (m, 3H), 7.45-7.52 (m, 2H), 7.58 (d, J =8.2Hz, 2H), 7.86 (d, J =8.2Hz, 2H) (Reference Example 2)
Synthesis of (−)-2- (4-cyanophenyl) -5-oxotetrahydrofuran-3-carboxylic acid By the method shown in Reference Example 1 using 4-cyanobenzaldehyde as a raw material, (−)-2- (4- Cyanophenyl) -5-oxotetrahydrofuran-3-carboxylic acid (R) -1-phenethylamine salt was obtained.
1 HNMR (300 MHz, DMSO-d 6 ) δ 1.47 (d, J = 6.7Hz, 3H), 2.67-3.02 (m, 3H), 4.32 (q, J = 6.7Hz, 1H), 5.63 (d, J = 7.3Hz, 1H), 7.28-7.43 (m, 3H), 7.45-7.52 (m, 2H), 7.58 (d, J = 8.2Hz, 2H), 7.86 (d, J = 8.2Hz, 2H)

また、この化合物を一部とり、２Ｎ塩酸で中和した後に、酢酸エチルにより抽出し、表題化合物（−）−２−（４−シアノフェニル）−５−オキソテトラヒドロフラン−３−カルボン酸を得、旋光度を測定した。
［α］D 20 = -83.3 (c 1.00, MeOH) A part of this compound was taken and neutralized with 2N hydrochloric acid, followed by extraction with ethyl acetate to obtain the title compound (-)-2- (4-cyanophenyl) -5-oxotetrahydrofuran-3-carboxylic acid. The optical rotation was measured.
[Α] D 20 = -83.3 (c 1.00, MeOH)

（参考例３）
（−）−２−［４−（トリフルオロメチル）フェニル］−５−オキソテトラヒドロフラン−３−カルボン酸の合成
４−（トリフルオロメチル）ベンズアルデヒドを原料として、参考例１に示した方法により、（−）−２−［４−（トリフルオロメチル）フェニル］−５−オキソテトラヒドロフラン−３−カルボン酸 （Ｒ）−１−（ナフタレン−１−イル）エタンアミン塩を得た。
1HNMR (300 MHz, DMSO-d6) δ1.57 (d, J =6.7Hz, 3H), 2.66-2.91 (m, 2H), 2.94-3.07 (m, 1H), 5.19 (q, J =6.7Hz, 1H), 5.64 (d, J =7.2Hz, 1H), 7.50 - 7.65 (m, 5H), 7.68-7.80 (m, 3H), 7.91 (d, J =8.2Hz, 1H), 7.94-8.01 (m, 1H), 8.11-8.20 (m, 1H) (Reference Example 3)
Synthesis of (−)-2- [4- (trifluoromethyl) phenyl] -5-oxotetrahydrofuran-3-carboxylic acid Using 4- (trifluoromethyl) benzaldehyde as a raw material, the method shown in Reference Example 1 -)-2- [4- (Trifluoromethyl) phenyl] -5-oxotetrahydrofuran-3-carboxylic acid (R) -1- (naphthalen-1-yl) ethanamine salt was obtained.
1 HNMR (300 MHz, DMSO-d 6 ) δ1.57 (d, J = 6.7Hz, 3H), 2.66-2.91 (m, 2H), 2.94-3.07 (m, 1H), 5.19 (q, J = 6.7 Hz, 1H), 5.64 (d, J = 7.2Hz, 1H), 7.50-7.65 (m, 5H), 7.68-7.80 (m, 3H), 7.91 (d, J = 8.2Hz, 1H), 7.94-8.01 (m, 1H), 8.11-8.20 (m, 1H)

また、この化合物を一部とり、２Ｎ塩酸で中和した後に、酢酸エチルにより抽出し、表題化合物（−）−２−［４−（トリフルオロメチル）フェニル］−５−オキソテトラヒドロフラン−３−カルボン酸を得、旋光度を測定した。
［α］D 20 = -54.6 (c 1.00, MeOH) A part of this compound was taken, neutralized with 2N hydrochloric acid, extracted with ethyl acetate, and the title compound (-)-2- [4- (trifluoromethyl) phenyl] -5-oxotetrahydrofuran-3-carboxylic acid was extracted. The acid was obtained and the optical rotation was measured.
[Α] D 20 = -54.6 (c 1.00, MeOH)

（参考例４）
1−(２，３，５−トリフルオロベンジル)ピペリジン−４−アミン塩酸塩の合成
４−（ｔ−ブトキシカルボニル）−アミノピペリジン（３０．０ｇ）のジメチルホルムアミド(３００ｍＬ)溶液に２，３，５−トリフルオロベンズアルデヒド（２１ｍＬ）の酢酸（２５ｍＬ）溶液を加え、室温下２時間攪拌した。次いで、反応液にナトリウムトリアセトキシボロヒドリド（９２．０ｇ）を加え、室温下一晩攪拌した。反応液に水を加え、酢酸エチルで２回抽出し、有機層を飽和重曹水で３回洗浄、無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（３３％酢酸エチル−ヘキサン）で精製し、［１−（２，３，５−トリフルオロベンジル）ピペリジン−４−イル）カルバミン酸ｔ−ブチル（４４．０ｇ）を無色油状物として得た。
ここで得られた化合物（４４．０ｇ）のメタノール（３６０ｍＬ）溶液に４Ｎ塩化水素−１，４−ジオキサン溶液（１１２ｍＬ）を加え、３時間加熱還流した。反応液に酢酸エチルを加え、析出した結晶を減圧乾燥し表題化合物1−（２，３，５−トリフルオロベンジル）ピペリジン−４−アミン２塩酸塩水和物（３０．０ｇ）を無色粉末として得た。
1HNMR (300 MHz, DMSO-d6) δ 1.85-2.32 (m, 4H), 2.89-3.60 (m, 4H), 4.17-4.46 (m, 2H), 7.57-7.82 (m, 2H), 8.30-8.62 (m, 2H) (Reference Example 4)
Synthesis of 1- (2,3,5-trifluorobenzyl) piperidin-4-amine hydrochloride To a solution of 4- (t-butoxycarbonyl) -aminopiperidine (30.0 g) in dimethylformamide (300 mL) A solution of 5-trifluorobenzaldehyde (21 mL) in acetic acid (25 mL) was added, and the mixture was stirred at room temperature for 2 hours. Next, sodium triacetoxyborohydride (92.0 g) was added to the reaction solution, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed three times with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (33% Purification with ethyl acetate-hexane) gave t-butyl [1- (2,3,5-trifluorobenzyl) piperidin-4-yl) carbamate (44.0 g) as a colorless oil.
A 4N hydrogen chloride-1,4-dioxane solution (112 mL) was added to a methanol (360 mL) solution of the compound (44.0 g) obtained here, and the mixture was heated to reflux for 3 hours. Ethyl acetate was added to the reaction mixture, and the precipitated crystals were dried under reduced pressure to give the title compound 1- (2,3,5-trifluorobenzyl) piperidin-4-amine dihydrochloride hydrate (30.0 g) as a colorless powder. It was.
1 HNMR (300 MHz, DMSO-d 6 ) δ 1.85-2.32 (m, 4H), 2.89-3.60 (m, 4H), 4.17-4.46 (m, 2H), 7.57-7.82 (m, 2H), 8.30- 8.62 (m, 2H)

（実施例１）トランス−４，５−ジ(４−メトキシフェニル)ジヒドロフラン−２(３Ｈ)−オン及び（実施例２）シス−４，５−ジ(４−メトキシフェニル)ジヒドロフラン−２(３Ｈ)−オンの合成
４，４’−ジメトキシベンゾイン（１０．０ｇ）のクロロホルム５０ｍＬ溶液にジヒドロピラン（４．４ｍＬ）、ピリジニウムｐ−トシル酸（０．４６ｇ）を加え、室温下一晩攪拌した。反応液に水を加え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、溶媒を減圧留去し１，２−ジ(４−メトキシフェニル)−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ)エタノン（１６．３ｇ）を淡黄色油状物質として得た。
次いで、６０％油性水素化ナトリウムをヘキサンで洗浄後、テトラヒドロフラン（５０ｍＬ）を加え、氷冷下ジエチルホスホノ酢酸 エチル（１４．６ｍＬ）を加え、室温下３０分間攪拌した。同温度下、前反応で得られた化合物（１３．１ｇ）のテトラヒドロフラン（１５ｍＬ）を加え、８時間加熱還流した。反応液に水を加え、酢酸エチルで抽出した。抽出した有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（１０％酢酸エチル−ヘキサン）で精製し、エチル ３，４−ジ(４−メトキシフェニル)−４−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ) −２−ブテネート（１５．１ｇ）を淡橙色油状物質として得た。
ここで得られた化合物（５．００ｇ）のテトラヒドロフラン（２５ｍＬ）と水（２．５ｍＬ）溶液にｐ−トシル酸（１．００ｇ）を加え、９時間過熱還流した。反応液に水を加え、酢酸エチルで抽出した。抽出した有機層を飽和重曹水、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、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（２５％酢酸エチル−ヘキサン）で精製し、エチル ３，４−ジ(４−メトキシフェニル)−４−ヒドロキシ−２−ブテネート（２．８９ｇ）を無色油状物質として得た。
ここで得られた化合物（２．８９ｇ）のエタノール（２９ｍＬ）溶液に１０％Ｐｄ−Ｃ（０．２９ｇ）を加え、水素気流下、室温で一晩攪拌した。反応液をセライトろ過し、溶媒を減圧留去し３，４−ジ(４−メトキシフェニル)−４−ヒドロキシ酪酸エチル（２．８０ｇ）を無色油状物質として得た。
ここで得られた化合物（１．００ｇ）の酢酸エチル（１０ｍＬ）溶液に４Ｍ塩化水素−酢酸エチル溶液（１．０ｍＬ）を加え、室温下３日間攪拌した。反応液に水を加え、酢酸エチルで抽出した。抽出し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、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、１８％酢酸エチル−ヘキサン溶出部より実施例１のトランス−４，５−ジ(４−メトキシフェニル)ジヒドロフラン−２(３Ｈ)−オン（０．７５ｇ）を無色油状物質として得、２０％酢酸エチル−ヘキサン溶出部より実施例２のシス−４，５−ジ(４−メトキシフェニル)ジヒドロフラン−２(３Ｈ)−オン（０．４３ｇ）を無色油状物質として得た。 Example 1 trans-4,5-di (4-methoxyphenyl) dihydrofuran-2 (3H) -one and (Example 2) cis-4,5-di (4-methoxyphenyl) dihydrofuran-2 Synthesis of (3H) -one To a solution of 4,4′-dimethoxybenzoin (10.0 g) in chloroform (50 mL) was added dihydropyran (4.4 mL) and pyridinium p-tosylic acid (0.46 g), and the mixture was stirred overnight at room temperature. did. Water was added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and 1,2-di (4-methoxyphenyl) -2- (tetrahydro-2H-pyran- 2-yloxy) ethanone (16.3 g) was obtained as a pale yellow oil.
Next, 60% oily sodium hydride was washed with hexane, tetrahydrofuran (50 mL) was added, ethyl diethylphosphonoacetate (14.6 mL) was added under ice cooling, and the mixture was stirred at room temperature for 30 min. At the same temperature, tetrahydrofuran (15 mL) of the compound (13.1 g) obtained in the previous reaction was added, and the mixture was heated to reflux for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% ethyl acetate-hexane), and ethyl 3,4-di (4-methoxyphenyl) -4- (tetrahydro-2H-pyran-2-yloxy) -2 -Butenate (15.1 g) was obtained as a pale orange oil.
To a solution of the compound (5.00 g) obtained here in tetrahydrofuran (25 mL) and water (2.5 mL) was added p-tosylic acid (1.00 g), and the mixture was heated to reflux for 9 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (25% ethyl acetate-hexane) to give ethyl 3,4-di (4-methoxyphenyl) -4-hydroxy-2-butenate (2.89 g) as a colorless oil. Obtained as material.
10% Pd-C (0.29 g) was added to an ethanol (29 mL) solution of the compound (2.89 g) obtained here, and the mixture was stirred overnight at room temperature under a hydrogen stream. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain ethyl 3,4-di (4-methoxyphenyl) -4-hydroxybutyrate (2.80 g) as a colorless oily substance.
To a solution of the compound obtained here (1.00 g) in ethyl acetate (10 mL) was added 4M hydrogen chloride-ethyl acetate solution (1.0 mL), and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and trans-4,5-di (4-methoxyphenyl) dihydrofuran-2 (3H) -one (Example 1) was eluted from the eluate of 18% ethyl acetate-hexane ( 0.75 g) as a colorless oily substance, and cis-4,5-di (4-methoxyphenyl) dihydrofuran-2 (3H) -one (0.43 g) of Example 2 from an eluate of 20% ethyl acetate-hexane ) Was obtained as a colorless oil.

（実施例３）トランス−４，５−ジ(４−メチルフェニル)ジヒドロフラン−２(３Ｈ)−オン及び（実施例４）シス−４，５−ジ(４−メチルフェニル)ジヒドロフラン−２(３Ｈ)−オンの合成
４，４’−ジメチルベンゾインを原料として、実施例１，２に示した方法により、実施例３のトランス−４，５−ジ(４−メチルフェニル)ジヒドロフラン−２(３Ｈ)−オン及び実施例４のシス−４，５−ジ(４−メチルフェニル)ジヒドロフラン−２(３Ｈ)−オンを得た。 (Example 3) trans-4,5-di (4-methylphenyl) dihydrofuran-2 (3H) -one and (Example 4) cis-4,5-di (4-methylphenyl) dihydrofuran-2 Synthesis of (3H) -one According to the method shown in Examples 1 and 2, starting from 4,4′-dimethylbenzoin, trans-4,5-di (4-methylphenyl) dihydrofuran-2 of Example 3 was used. (3H) -one and cis-4,5-di (4-methylphenyl) dihydrofuran-2 (3H) -one of Example 4 were obtained.

（実施例５）
シス−４，５−ジ(４−クロロフェニル)ジヒドロフラン−２(３Ｈ)−オンの合成
４，４’−ジクロロベンゾインを原料として、実施例１，２に示した方法により、表題化合物シス−４，５−ジ(４−クロロフェニル)ジヒドロフラン−２(３Ｈ)−オンを得た。 (Example 5)
Synthesis of cis-4,5-di (4-chlorophenyl) dihydrofuran-2 (3H) -one According to the method shown in Examples 1 and 2, starting from 4,4′-dichlorobenzoin, the title compound cis-4 , 5-Di (4-chlorophenyl) dihydrofuran-2 (3H) -one was obtained.

（実施例６）
トランス−４−(４−クロロフェニル)−５−(４−メチルフェニル)ジヒドロフラン−２(３Ｈ)−オンの合成
（１）２−(４−クロロフェニル)−１−(４−メチルフェニル)エタノンの合成
４−クロロフェニル酢酸（１０．０ｇ）のＮ，Ｎ−ジメチルホルムアミド（１００ｍＬ）溶液に、Ｎ，Ｏ―ジメチルヒドロキシルアミン塩酸塩（６．９０ｇ）、トリエチルアミン（１１ｍＬ）、１−ヒドロキシベンゾトリアゾール（１０．３ｇ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１４．６ｇ）を加え、室温下２４時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で順次洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し２−（４−クロロフェニル）−Ｎ−メトキシ−Ｎ−メチルアセトアミド（１２．３ｇ）を無色粉末として得た。
ここで得られた化合物（２．００ｇ）のテトラヒドロフラン（３０ｍＬ）溶液に氷冷下、１Ｍ ｐ−トリルマグネシウムブロマイド−テトラヒドロフラン溶液（２８ｍＬ）を滴下し、同温度下５時間攪拌した。反応液に氷冷下、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。抽出した有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（１０％酢酸エチル−ヘキサン）で精製し、表題化合物２−(４−クロロフェニル)−１−(４−メチルフェニル)エタノン（１．３０ｇ）を無色粉末として得た。
1H NMR (200 MHz,CDCｌ3) δ 2.41 (s, 3 H)， 4.23 (s, 2 H)， 7.12 - 7.36 (m, 6 H)， 7.83 - 7.96 (m, 2 H) (Example 6)
Synthesis of trans-4- (4-chlorophenyl) -5- (4-methylphenyl) dihydrofuran-2 (3H) -one (1) of 2- (4-chlorophenyl) -1- (4-methylphenyl) ethanone Synthesis To a solution of 4-chlorophenylacetic acid (10.0 g) in N, N-dimethylformamide (100 mL), N, O-dimethylhydroxylamine hydrochloride (6.90 g), triethylamine (11 mL), 1-hydroxybenzotriazole (10 3 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14.6 g) were added, and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and 2- (4-chlorophenyl) -N-methoxy-N-methylacetamide (12.3 g) was colorless. Obtained as a powder.
A 1M p-tolylmagnesium bromide-tetrahydrofuran solution (28 mL) was added dropwise to a tetrahydrofuran (30 mL) solution of the compound (2.00 g) obtained here under ice cooling, and the mixture was stirred at the same temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% ethyl acetate-hexane) to give the title compound 2- (4-chlorophenyl) -1- (4-methylphenyl) ethanone (1.30 g) as a colorless powder. Obtained.
1 H NMR (200 MHz, CDCl 3 ) δ 2.41 (s, 3 H), 4.23 (s, 2 H), 7.12-7.36 (m, 6 H), 7.83-7.96 (m, 2 H)

（２）３−(４−クロロフェニル)−４−ヒドロキシ−４−(４−メチルフェニル)酪酸の合成
実施例６（１）で得られた化合物（１．３０ｇ）のジメチルスルホキシド（２０ｍＬ）溶液に窒素置換下、６０％油性水素化ナトリウム（０．３２ｇ）を加え、室温下３０分間攪拌した後にブロモ酢酸エチル（０．７ｍＬ）を加え、室温下２４時間攪拌した。反応液に氷冷下、１Ｍ塩酸、水を加え、酢酸エチルで抽出した。抽出した有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別、溶媒を減圧留去する事で３−（４−クロロフェニル）−４−（４−メチルフェニル）−４−オキソブタン酸エチル（１．９０ｇ）を橙色油状物質として得た。
ここで得られた化合物（１．７５ｇ）のエタノール（２０ｍＬ）溶液に氷冷下、水素化ホウ素ナトリウム（０．４０ｇ）を加え、同温度下２．５時間攪拌した。反応液に氷冷下、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。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（２０％酢酸エチル−ヘキサン）で精製し、３−（４−クロロフェニル）−４−ヒドロキシ−４−（４−メチルフェニル）酪酸エチル（１．７０ｇ）を淡黄色油状物質として得た。
ここで得られた化合物（１．７０ｇ）のエタノール（２０ｍＬ）、水（５ｍＬ）混合溶液に水酸化ナトリウム（０．３２ｇ）を加え、室温下２４時間攪拌した。反応液を減圧下溶媒留去した後、水、酢酸エチルを加え、水層のみを分離した。得られた水層を１Ｍ塩酸でｐＨ＝１に調整した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し表題化合物３−(４−クロロフェニル)−４−ヒドロキシ−４−(４−メチルフェニル)ブタン酸（１．１０ｇ）を無色粉末として得た。
1H NMR (200 MHz, DMSO-ｄ6) δ 2.25 (s, 3 H)， 3.16 - 3.38 (m, 2 H)， 4.67 - 4.78 (m, 1 H)， 5.24 - 5.37 (m, 1 H)， 6.93 - 7.30 (m, 8 H) (2) Synthesis of 3- (4-chlorophenyl) -4-hydroxy-4- (4-methylphenyl) butyric acid To a solution of the compound (1.30 g) obtained in Example 6 (1) in dimethyl sulfoxide (20 mL) Under nitrogen substitution, 60% oily sodium hydride (0.32 g) was added, and the mixture was stirred at room temperature for 30 minutes, ethyl bromoacetate (0.7 mL) was added, and the mixture was stirred at room temperature for 24 hours. Under ice-cooling, 1M hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give 3- (4-chlorophenyl) -4- (4-methylphenyl) -4. -Ethyl oxobutanoate (1.90 g) was obtained as an orange oil.
Sodium borohydride (0.40 g) was added to an ethanol (20 mL) solution of the compound (1.75 g) obtained here under ice cooling, and the mixture was stirred at the same temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20% ethyl acetate-hexane) to give ethyl 3- (4-chlorophenyl) -4-hydroxy-4- (4-methylphenyl) butyrate (1.70 g). Obtained as a pale yellow oil.
Sodium hydroxide (0.32 g) was added to a mixed solution of the compound (1.70 g) obtained here in ethanol (20 mL) and water (5 mL), and the mixture was stirred at room temperature for 24 hours. After the solvent was distilled off under reduced pressure, water and ethyl acetate were added, and only the aqueous layer was separated. The obtained aqueous layer was adjusted to pH = 1 with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound 3- (4-chlorophenyl) -4-hydroxy-4- (4-methylphenyl) butanoic acid (1.10 g). ) Was obtained as a colorless powder.
1 H NMR (200 MHz, DMSO-d 6 ) δ 2.25 (s, 3 H), 3.16-3.38 (m, 2 H), 4.67-4.78 (m, 1 H), 5.24-5.37 (m, 1 H) 6.93-7.30 (m, 8 H)

（３）トランス−４−(４−クロロフェニル)−５−(４−メチルフェニル)ジヒドロフラン−２(３Ｈ)−オンの合成
実施例６（２）で得られた化合物（１．１０ｇ）の酢酸エチル（１０ｍＬ）溶液に４Ｍ塩化水素−酢酸エチル溶液（１０ｍＬ）を加え、室温下２４時間攪拌した。反応液を減圧下溶媒留去した後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去しシス−４−(４−クロロフェニル)−５−(４−メチルフェニル)ジヒドロフラン−２(３Ｈ)−オン（１．００ｇ）を無色油状物質として得た。
ここで得られた化合物（１．００ｇ）の酢酸（１０ｍＬ）、水（１ｍＬ）混合溶液を２４時間加熱還流した。室温下放冷後、反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別、溶媒を減圧留去した。得られた残留物をカラムクロマトグラフィー（１０％酢酸エチル−ヘキサン）で精製し、表題化合物トランス−４−(４−クロロフェニル)−５−(４−メチルフェニル)ジヒドロフラン−２(３Ｈ)−オン（０．４５ｇ）を無色粉末として得た。 (3) Synthesis of trans-4- (4-chlorophenyl) -5- (4-methylphenyl) dihydrofuran-2 (3H) -one Acetic acid of the compound (1.10 g) obtained in Example 6 (2) A 4M hydrogen chloride-ethyl acetate solution (10 mL) was added to the ethyl (10 mL) solution, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give cis-4- (4-chlorophenyl) -5- (4-methylphenyl) dihydrofuran-2 (3H) -one ( 1.00 g) as a colorless oil.
A mixed solution of the compound (1.00 g) obtained here in acetic acid (10 mL) and water (1 mL) was heated to reflux for 24 hours. After allowing to cool at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (10% ethyl acetate-hexane) to give the title compound trans-4- (4-chlorophenyl) -5- (4-methylphenyl) dihydrofuran-2 (3H) -one. (0.45 g) was obtained as a colorless powder.

（実施例７）
トランス−４−（４−クロロフェニル）−５−ｐ−トリル−１，３−ジオキソラン−２−オンの合成
１−（４−クロロフェニル）−５−ｐ−トリルエタン−１，２−ジオン（１０．０ｇ）のメタノール（１００ｍＬ）溶液に水素化ホウ素ナトリウム（１．４６ｇ）を加え、氷冷下２時間攪拌した。反応液に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、有機層を水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−ジオールのシス体とトランス体の混合物としての無色粉末（１０．４ｇ）を得た。
ここで得られた化合物（１０．４ｇ）のクロロホルム（８０ｍＬ）溶液に、氷冷下トリホスゲン（４．６０ｇ）のクロロホルム（２０ｍＬ）溶液を滴下し、同温度下１．５時間攪拌した。反応液に水を加え、クロロホルムで抽出し有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（１０％酢酸エチル−ヘキサン）で精製し、表題化合物トランス−４−（４−クロロフェニル）−５−ｐ−トリル−１，３−ジオキソラン−２−オン（２．２５ｇ）を無色油状物として得た。 (Example 7)
Synthesis of trans-4- (4-chlorophenyl) -5-p-tolyl-1,3-dioxolan-2-one 1- (4-chlorophenyl) -5-p-tolylethane-1,2-dione (10.0 g ) In methanol (100 mL) was added sodium borohydride (1.46 g), and the mixture was stirred for 2 hours under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and colorless powder (10.4 g) as a mixture of cis- and trans-isomers of 1- (4-chlorophenyl) -2-p-tolylethane-1,2-diol Got.
To a chloroform (80 mL) solution of the compound (10.4 g) obtained here was added dropwise a solution of triphosgene (4.60 g) in chloroform (20 mL) under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% ethyl acetate-hexane) to give the title compound trans-4- (4-chlorophenyl) -5-p-tolyl-1,3-dioxolan-2-one ( 2.25 g) was obtained as a colorless oil.

（実施例８）
トランス−４−（４−クロロフェニル）−５−ｐ−トリルイミダゾリジン−２−オンの合成
実施例７で得られた化合物（２．７７ｇ）のメタノール（１４ｍＬ）、水（１．５ｍＬ）溶液に炭酸カリウム（１．４６ｇ）を加え、室温下１時間攪拌した。反応液に水を加え、析出した結晶を濾取後、水で洗浄しトランス−１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−ジオール（２．３７ｇ）を無色粉末として得た。
ここで得られた化合物（２．３７ｇ）のクロロホルム（２４ｍＬ）溶液に、トリエチルアミン（２．８ｍＬ）を加え、次いで氷冷下メタンスルフォニルクロライド（１．５ｍＬ）を滴下し、同温度下１時間攪拌した。反応液に水を加え、クロロホルムで抽出し有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、トランス−１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−ジイル ジメタンスルホネート（３．８７ｇ）を無色アモルファスとして得た。 (Example 8)
Synthesis of trans-4- (4-chlorophenyl) -5-p-tolyrimidazolidin-2-one In a solution of the compound obtained in Example 7 (2.77 g) in methanol (14 mL) and water (1.5 mL) Potassium carbonate (1.46 g) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water to obtain trans-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diol (2.37 g) as a colorless powder. It was.
Triethylamine (2.8 mL) was added to a chloroform (24 mL) solution of the obtained compound (2.37 g), and then methanesulfonyl chloride (1.5 mL) was added dropwise under ice cooling, followed by stirring at the same temperature for 1 hour. did. Water was added to the reaction solution, extracted with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain trans-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diyl dimethanesulfonate (3.87 g) as a colorless amorphous.

ここで得られた化合物（３．８７ｇ）のジメチルホルムアミド（２０ｍＬ）溶液に、アジ化ナトリウム（１．４１ｇ）を加え、１２０℃油浴上で２時間攪拌した。反応液に水を加え、酢酸エチルで抽出し有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（７％酢酸エチル−ヘキサン）で精製し、トランス−１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−ジアジド（１．５０ｇ）を無色油状物として得た。
ここで得られた化合物（１．５０ｇ）のエタノール（１５ｍＬ）溶液に、１０％Ｐｄ-Ｃ（０．１５ｇ）を加え、水素気流下室温で５時間攪拌後、セライト濾過し溶媒留去した。残留物に１０％塩酸を加え酢酸エチルで洗浄後、水層に水酸化カリウムを加え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後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、トランス−１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−ジアミン（０．８８ｇ）を黄色粉末として得た。
ここで得られた化合物（０．８７ｇ）のクロロホルム（１０ｍＬ）溶液に、トリエチルアミン（１．２ｍｌ）を加え、次いで氷冷下トリホスゲン（０．４０ｇ）を加え、同温度下２時間攪拌した。反応液に水を加え、酢酸エチルで抽出し有機層を水、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、溶媒を減圧留去した。得られた残留物をクロロホルム−へキサンより再結晶し、表題化合物トランス−４−（４−クロロフェニル）−５−ｐ−トリルイミダゾリジン−２−オン（０．２７ｇ）を無色粉末として得た。 Sodium azide (1.41 g) was added to a solution of the compound obtained here (3.87 g) in dimethylformamide (20 mL), and the mixture was stirred on a 120 ° C. oil bath for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (7% ethyl acetate-hexane), and trans-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diazide (1.50 g) was colorless. Obtained as an oil.
To a solution of the compound obtained here (1.50 g) in ethanol (15 mL) was added 10% Pd—C (0.15 g), and the mixture was stirred at room temperature for 5 hours under a hydrogen stream, filtered through Celite, and the solvent was distilled off. To the residue was added 10% hydrochloric acid and washed with ethyl acetate. The aqueous layer was neutralized with potassium hydroxide and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain trans-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diamine (0.88 g) as a yellow powder.
Triethylamine (1.2 ml) was added to a solution of the compound obtained here (0.87 g) in chloroform (10 mL), then triphosgene (0.40 g) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from chloroform-hexane to give the title compound trans-4- (4-chlorophenyl) -5-p-tolylimidazolidin-2-one (0.27 g) as a colorless powder.

（実施例９）
シス−４−（４−クロロフェニル）−５−ｐ−トリルイミダゾリジン−２−オンの合成
１−（４−クロロフェニル）−２−ｐ−トリルエタン−１，２−ジオン（１０．０ｇ）のメタノール（１００ｍＬ）溶液に水素化ホウ素ナトリウム（１．４６ｇ）を加え、氷冷下２時間攪拌した。反応液に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、有機層を水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−ジオールのシス体とトランス体の混合物（１０．４ｇ）としての無色粉末を得た。
ここで得られた化合物（１．５４ｇ）のクロロホルム（１６ｍＬ）溶液に、トリエチルアミン（２．０ｍＬ）を加え、次いで氷冷下メタンスルフォニルクロライド（１．０ｍＬ）を滴下し、同温度下３０分間攪拌した。反応液に水を加え、析出した結晶を濾取後、水で洗浄しシス−１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−−ジイル ジメタンスルホネート（２．１２ｇ）を無色粉末として得た。 Example 9
Synthesis of cis-4- (4-chlorophenyl) -5-p-tolyrimidazolidin-2-one 1- (4-chlorophenyl) -2-p-tolylethane-1,2-dione (10.0 g) in methanol ( 100 mL) solution was added sodium borohydride (1.46 g) and stirred for 2 hours under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and colorless powder as a mixture (10.4 g) of 1- (4-chlorophenyl) -2-p-tolylethane-1,2-diol cis isomer and trans isomer Got.
Triethylamine (2.0 mL) was added to a chloroform (16 mL) solution of the compound obtained here (1.54 g), and then methanesulfonyl chloride (1.0 mL) was added dropwise under ice cooling, followed by stirring at the same temperature for 30 minutes. did. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water to give cis-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diyl dimethanesulfonate (2.12 g). Obtained as a colorless powder.

同様にして合成したシス−１−（４−クロロフェニル）−２−ｐ−トリルエタン−１，２−ジイル ジメタンスルホネート（２．２５ｇ）のジメチルホルムアミド（２０ｍＬ）溶液に、アジ化ナトリウム（０．８４ｇ）を加え、１２０℃油浴上で２時間攪拌した。反応液に水を加え、酢酸エチルで抽出し有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン）で精製し、シス−１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−ジアジド（０．７５ｇ）を淡黄色粉末として得た。
ここで得られた化合物（０．７５ｇ）のエタノール（１５ｍＬ）溶液に、１０％Ｐｄ-Ｃ（０．０８ｇ）を加え、水素気流下室温で一晩攪拌後、セライト濾過、溶媒留去し、シス−１-(４-クロロフェニル）−２−ｐ−トリルエタン−１，２−ジアミン（０．６０ｇ）を緑色粉末として得た。
ここで得られた化合物（０．６０ｇ）のクロロホルム（１０ｍＬ）溶液に、トリエチルアミン（０．８ｍｌ）を加え、次いで氷冷下トリホスゲン（０．２７ｇ）を加え、同温度下２時間攪拌した。反応液に水を加え、酢酸エチルで抽出し有機層を水、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、溶媒を減圧留去した。得られた残留物をクロロホルムで洗浄し、表題化合物シス−４−（４−クロロフェニル）−５−ｐ−トリルイミダゾリジン−２−オン（０．２２ｇ）を無色粉末として得た。 To a solution of cis-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diyl dimethanesulfonate (2.25 g) synthesized in the same manner in dimethylformamide (20 mL), sodium azide (0.84 g ) And stirred on a 120 ° C. oil bath for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane) to obtain cis-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diazide (0.75 g) as a pale yellow powder. .
10% Pd—C (0.08 g) was added to an ethanol (15 mL) solution of the compound (0.75 g) obtained here, and the mixture was stirred overnight at room temperature under a hydrogen stream, then filtered through Celite, and the solvent was distilled off. Cis-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diamine (0.60 g) was obtained as a green powder.
Triethylamine (0.8 ml) was added to a chloroform (10 mL) solution of the compound obtained here (0.60 g), and then triphosgene (0.27 g) was added under ice cooling, followed by stirring at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with chloroform to give the title compound cis-4- (4-chlorophenyl) -5-p-tolyrimidazolidin-2-one (0.22 g) as a colorless powder.

（実施例１０）
シス−４，５−ジ（ｐ−トリル）イミダゾリジン−２−オンの合成
１−（４−クロロフェニル）−２−ｐ−トリルエタン−１，２−ジオンを原料として、実施例９に示した方法により、表題化合物シス−４，５−ジ（ｐ−トリル）イミダゾリジン−２−オンを得た。 (Example 10)
Synthesis of cis-4,5-di (p-tolyl) imidazolidin-2-one The method shown in Example 9 starting from 1- (4-chlorophenyl) -2-p-tolylethane-1,2-dione Gave the title compound cis-4,5-di (p-tolyl) imidazolidin-2-one.

（実施例１１）
４，５−ジ（ｐ−トリル）オキサゾリジン−２−オンの合成
２−ヒドロキシ−１，２−ジ（ｐ−トリル）エタノン（２．００ｇ）のエタノール（２０ｍＬ）溶液に、ヒドロキシアミン塩酸塩（０．７０ｇ）、酢酸ナトリウム（０．８２ｇ）を加え、１時間加熱還流した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、２−ヒドロキシ−１，２−ジ（ｐ−トリル）エタノン（２．４９ｇ）を無色油状物として得た。
ここで得られた化合物（２．３４ｇ）のテトラヒドロフラン（２５ｍＬ）溶液に、氷冷下水素化リチウムアルミニウム（０．７０ｇ）を加え、１００℃油浴上で３時間攪拌した。反応液に、飽和塩化アンモニウム水溶液を加えセライト濾過し、１０％塩酸を加え中和し酢酸エチルで洗浄した。水層に重曹を加え中和し、酢酸エチルで抽出後、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、２−アミノ−１，２−ジ（ｐ−トリル）エタノール（０．５９ｇ）を淡褐色粉末として得た。
ここで得られた化合物（０．５８ｇ）のクロロホルム（１０ｍＬ）溶液に、トリエチルアミン（０．４ｍｌ）を加え、次いで氷冷下トリホスゲン（０．２８ｇ）を加え、同温度下1時間攪拌した。反応液に水を加え、酢酸エチルで抽出し有機層を水、１０％塩酸、飽和重曹水、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、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（３５％酢酸エチル−ヘキサン）で精製し、表題化合物４，５−ジ（ｐ−トリル）オキサゾリジン−２−オン（０．３５ｇ）を無色粉末として得た。 (Example 11)
Synthesis of 4,5-di (p-tolyl) oxazolidine-2-one 2-Hydroxy-1,2-di (p-tolyl) ethanone (2.00 g) in ethanol (20 mL) was added to hydroxyamine hydrochloride ( 0.70 g) and sodium acetate (0.82 g) were added, and the mixture was heated to reflux for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2-hydroxy-1,2-di (p-tolyl) ethanone (2.49 g) as a colorless oil.
Lithium aluminum hydride (0.70 g) was added to a tetrahydrofuran (25 mL) solution of the compound (2.34 g) obtained here under ice-cooling, and the mixture was stirred on an oil bath at 100 ° C. for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was filtered through celite, neutralized with 10% hydrochloric acid, and washed with ethyl acetate. Sodium bicarbonate was added to the aqueous layer for neutralization, followed by extraction with ethyl acetate and washing with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2-amino-1,2-di (p-tolyl) ethanol (0.59 g) as a light brown powder.
Triethylamine (0.4 ml) was added to a chloroform (10 mL) solution of the compound (0.58 g) obtained here, and then triphosgene (0.28 g) was added under ice cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (35% ethyl acetate-hexane) to give the title compound 4,5-di (p-tolyl) oxazolidine-2-one (0.35 g) as a colorless powder. .

（実施例１２）
５−クロロフェニル−１−フェニル−１，２，４−トリアゾリジン−３−オンの合成
２−フェニルヒドラジンカルボキサミド（１．００ｇ）のエタノール（２０ｍＬ）溶液に、ｐ−クロロベンズアルデヒド(１．１２ｇ)、ｐ-トルエンスルホン酸（０．１３ｇ）を加え、室温下一晩攪拌した。反応後、溶媒留去し酢酸エチルを加え、飽和重曹水、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（４０％酢酸エチル−ヘキサン）で精製し、表題化合物５−クロロフェニル−１−フェニル−１，２，４−トリアゾリジン−３−オン（０．２７ｇ）を無色粉末として得た。 (Example 12)
Synthesis of 5-chlorophenyl-1-phenyl-1,2,4-triazolidin-3-one In a solution of 2-phenylhydrazinecarboxamide (1.00 g) in ethanol (20 mL), p-chlorobenzaldehyde (1.12 g), p -Toluenesulfonic acid (0.13 g) was added, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off, ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (40% ethyl acetate-hexane) to give the title compound 5-chlorophenyl-1-phenyl-1,2, 4-Triazolidin-3-one (0.27 g) was obtained as a colorless powder.

（実施例１３）
５−メチルフェニル−１−フェニル−１，２，４−トリアゾリジン−３−オンの合成
ｐ−トリルアルデヒドを原料として、実施例１２に示した方法により、表題化合物５−メチルフェニル−１−フェニル−１，２，４−トリアゾリジン−３−オンを得た。 (Example 13)
Synthesis of 5-methylphenyl-1-phenyl-1,2,4-triazolidin-3-one According to the method shown in Example 12 using p-tolylaldehyde as a starting material, the title compound 5-methylphenyl-1-phenyl- 1,2,4-triazolidin-3-one was obtained.

（実施例１４）
５−メトキシフェニル−１−フェニル−１，２，４−トリアゾリジン−３−オンの合成
ｐ−メトキシベンズアルデヒドを原料として、実施例１２に示した方法により、表題化合物５−メトキシフェニル−１−フェニル−１，２，４−トリアゾリジン−３−オンを得た。 (Example 14)
Synthesis of 5-methoxyphenyl-1-phenyl-1,2,4-triazolidin-3-one According to the method shown in Example 12 using p-methoxybenzaldehyde as a starting material, the title compound 5-methoxyphenyl-1-phenyl- 1,2,4-triazolidin-3-one was obtained.

（実施例１５）
トランス−Ｎ−(１−ベンジルピペリジン−４−イル)−２−(４−クロロフェニル)−５−オキソピロリジン−３−カルボキサミドの合成
（１）Ｎ−［（４−クロロフェニル）メチリデン］−１−（４−メトキシフェニル）メタンアミンの合成
４−クロロベンズアルデヒド（１０．０ｇ）のベンゼン溶液（４０ｍＬ）に１−（４−メトキシフェニル）メタンアミン（１０．７ｇ）を加え、１９時間加熱還流した。室温下放冷後、反応液を減圧下留去し表題化合物Ｎ−［（４−クロロフェニル）メチリデン］−１−（４−メトキシフェニル）メタンアミン（１８．５ｇ）を淡黄色粉末として得た。
1HNMR (200 MHz, CDCl3) δ3.80 (s, 3 H), 4.75 (s, 2 H), 6.78 - 6.98 (m, 2 H), 7.17 - 7.30 (m, 2 H), 7.31 - 7.44 (m, 2 H), 7.61 - 7.77 (m, 2 H), 8.32 (s, 1 H) (Example 15)
Synthesis of trans-N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxopyrrolidine-3-carboxamide (1) N-[(4-chlorophenyl) methylidene] -1- ( Synthesis of 4-methoxyphenyl) methanamine To a benzene solution (40 mL) of 4-chlorobenzaldehyde (10.0 g) was added 1- (4-methoxyphenyl) methanamine (10.7 g), and the mixture was heated to reflux for 19 hours. After allowing to cool at room temperature, the reaction mixture was evaporated under reduced pressure to give the title compound N-[(4-chlorophenyl) methylidene] -1- (4-methoxyphenyl) methanamine (18.5 g) as a pale yellow powder.
1 HNMR (200 MHz, CDCl 3 ) δ3.80 (s, 3 H), 4.75 (s, 2 H), 6.78-6.98 (m, 2 H), 7.17-7.30 (m, 2 H), 7.31-7.44 (m, 2 H), 7.61-7.77 (m, 2 H), 8.32 (s, 1 H)

（２）トランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソピロリジン−３−カルボキサミドの合成
実施例１５（１）で得られた化合物（１０．４ｇ）のベンゼン溶液（２５ｍＬ）に無水コハク酸（４．００ｇ）を加え、１８時間加熱還流した。室温下放冷後、反応液を減圧下留去しトランス−２−（４−クロロフェニル）−１−（４−メトキシベンジル）−５−オキソピロリジン−３−カルボン酸（１３．７ｇ）を黄色粉末として得た。
ここで得られた化合物（２．００ｇ）のＮ，Ｎ−ジメチルホルムアミド（１５ｍＬ）溶液に４−アミノ−１−ベンジルピペリジン（１．０４ｇ）、１−ヒドロキシベンゾトリアゾール（１．８０ｇ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２．２４ｇ）を加え、室温下２４時間攪拌した。反応液に重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をカラムクロマトグラフィー（６％メタノール−クロロホルム）で精製し、トランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−１−（４−メトキシベンジル）−５−オキソピロリジン−３−カルボキサミド（１．１９ｇ）を得た。 (2) Synthesis of trans-N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxopyrrolidine-3-carboxamide The compound obtained in Example 15 (1) (10. To a benzene solution (25 mL) of 4 g), succinic anhydride (4.00 g) was added, and the mixture was heated to reflux for 18 hours. After allowing to cool at room temperature, the reaction mixture was evaporated under reduced pressure, and trans-2- (4-chlorophenyl) -1- (4-methoxybenzyl) -5-oxopyrrolidine-3-carboxylic acid (13.7 g) was obtained as a yellow powder. Obtained.
To a solution of the compound (2.00 g) obtained here in N, N-dimethylformamide (15 mL), 4-amino-1-benzylpiperidine (1.04 g), 1-hydroxybenzotriazole (1.80 g), 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.24 g) was added, and the mixture was stirred at room temperature for 24 hours. Sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (6% methanol-chloroform) and trans-N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -1- (4-methoxybenzyl). ) -5-oxopyrrolidine-3-carboxamide (1.19 g) was obtained.

ここで得られた化合物（１．１９ｇ）のアセトニトリル（１０ｍＬ）溶液に水（０．２ｍＬ）、硝酸セリウム(IV)アンモニウム（６．１３ｇ）を加え、室温下７時間攪拌した。反応液に飽和重曹水を加え、生じた不溶物を濾別し、濾液を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（１４％メタノール−クロロホルム）で精製し、表題化合物トランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソピロリジン−３−カルボキサミド（０．１０ｇ）を薄茶色粉末として得た。
1HNMR (200 MHz, CDCl3) δ 1.40-2.03 (m, 4H), 2.23 (t, J =12.1Hz, 2H), 2.51-3.04 (m, 5H), 3.56-3.71 (m, 2H), 3.90 (br. s., 1H), 4.88 (d, J =7.0Hz, 1H), 5.43 (br. s., 1H), 5.69 (s, 1H), 7.16-7.46 (m, 9H) Water (0.2 mL) and cerium (IV) ammonium nitrate (6.13 g) were added to a solution of the compound (1.19 g) obtained here in acetonitrile (10 mL), and the mixture was stirred at room temperature for 7 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, the resulting insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (14% methanol-chloroform) to give the title compound trans-N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxopyrrolidine. -3-Carboxamide (0.10 g) was obtained as a light brown powder.
1 HNMR (200 MHz, CDCl 3 ) δ 1.40-2.03 (m, 4H), 2.23 (t, J = 12.1Hz, 2H), 2.51-3.04 (m, 5H), 3.56-3.71 (m, 2H), 3.90 (br. s., 1H), 4.88 (d, J = 7.0Hz, 1H), 5.43 (br. s., 1H), 5.69 (s, 1H), 7.16-7.46 (m, 9H)

（実施例１６）
トランス−Ｎ−［２−(４−クロロフェニル)エチル］−２−フェニル−５−オキソピロリジン−３−カルボキサミドの合成
ベンズアルデヒドを原料として、実施例１５に示した方法により、表題化合物トランス−Ｎ−［２−(４−クロロフェニル)エチル］−２−フェニル−５−オキソピロリジン−３−カルボキサミドを得た。 (Example 16)
Synthesis of trans-N- [2- (4-chlorophenyl) ethyl] -2-phenyl-5-oxopyrrolidine-3-carboxamide Using the benzaldehyde as a raw material, the title compound trans-N- [ 2- (4-Chlorophenyl) ethyl] -2-phenyl-5-oxopyrrolidine-3-carboxamide was obtained.

（実施例１７）
トランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−フェニル−５−オキソピロリジン−３−カルボキサミドの合成
ベンズアルデヒドを原料として、実施例１５に示した方法により、表題化合物トランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−フェニル−５−オキソピロリジン−３−カルボキサミドを得た。 (Example 17)
Synthesis of trans-N- (1-benzylpiperidin-4-yl) -2-phenyl-5-oxopyrrolidine-3-carboxamide Using the benzaldehyde as a starting material, the title compound trans-N- ( 1-Benzylpiperidin-4-yl) -2-phenyl-5-oxopyrrolidine-3-carboxamide was obtained.

（実施例１８）
トランス−Ｎ−［２−(４−クロロフェニル)エチル］−２−フェニル−５−オキソピロリジン−３−カルボキサミドの合成
実施例１５に合成中間体として示したトランス−２−（４−クロロフェニル）−１−（４−メトキシベンジル）−５−オキソピロリジン−３−カルボン酸と２−(４−クロロフェニル)エチルアミンを、実施例１５に示した方法により縮合、脱保護し、表題化合物トランス−Ｎ−［２−(４−クロロフェニル)エチル］−２−フェニル−５−オキソピロリジン−３−カルボキサミドを得た。 (Example 18)
Synthesis of trans-N- [2- (4-chlorophenyl) ethyl] -2-phenyl-5-oxopyrrolidine-3-carboxamide Trans-2- (4-chlorophenyl) -1 shown as a synthetic intermediate in Example 15 -(4-Methoxybenzyl) -5-oxopyrrolidine-3-carboxylic acid and 2- (4-chlorophenyl) ethylamine were condensed and deprotected by the method shown in Example 15 to give the title compound trans-N- [2 -(4-Chlorophenyl) ethyl] -2-phenyl-5-oxopyrrolidine-3-carboxamide was obtained.

（実施例１９）
５−（４−メトキシフェニル）−３−オキソ−Ｎ−［4−（トリフルオロメチル）フェニル］ピラゾリジン−１−カルボキサミドの合成
ｐ−メトキシけい皮酸（５．００ｇ）のトルエン（２５ｍＬ）溶液に、ヒドラジン一水和物（２．８ｍＬ）を加え、１００℃油浴上１０時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、得られた残留物を酢酸エチルで洗浄し５−（４−メトキシフェニル）ピラゾリジン−３−オン（１．１６ｇ）を淡褐色粉末として得た。
ここで得られた化合物（０．３０ｇ）のＮ，Ｎ−ジメチルホルムアミド（１ｍＬ）、テトラヒドロフラン(９ｍＬ)の混合溶液に、ｐ−トリフルオロメチルフェニルイソシアネート（０．３５ｍＬ）を加え、室温下３０分間攪拌した。反応液に、水を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた残留物をクロロホルム洗浄し、表題化合物５−（４−メトキシフェニル）−３−オキソ−Ｎ−［4−（トリフルオロメチル）フェニル］ピラゾリジン−１−カルボキサミド（０．４９ｇ）を無色粉末として得た。 (Example 19)
Synthesis of 5- (4-methoxyphenyl) -3-oxo-N- [4- (trifluoromethyl) phenyl] pyrazolidine-1-carboxamide To a solution of p-methoxycinnamic acid (5.00 g) in toluene (25 mL) Hydrazine monohydrate (2.8 mL) was added, and the mixture was stirred for 10 hours on a 100 ° C. oil bath. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was washed with ethyl acetate to obtain 5- (4-methoxyphenyl) pyrazolidine-3-one (1.16 g) as a light brown powder. .
To a mixed solution of the compound obtained here (0.30 g) in N, N-dimethylformamide (1 mL) and tetrahydrofuran (9 mL), p-trifluoromethylphenyl isocyanate (0.35 mL) is added, and then at room temperature for 30 minutes. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with chloroform, and the title compound 5- (4-methoxyphenyl) -3-oxo-N- [4- (trifluoromethyl) phenyl] pyrazolidine-1-carboxamide (0.49 g) was colorless powder. Got as.

（実施例２０）
Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボキサミド マレイン酸塩の合成
（１）２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボン酸エチルエステルの合成
２０％ナトリウムエトキシド−エタノール溶液（９．２ｍＬ）へｐ−クロロフェニルヒドラジン塩酸（２．２０ｇ）を加え、室温下２０分間攪拌した。反応液に、ジエチルマレイン酸（２．００ｇ）を加え同温度下６時間攪拌した。反応後、溶媒留去し水を加え、酢酸エチルで抽出した。有機層を、５％塩酸、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した。溶媒を減圧留去し、得られた残留物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）で精製し、２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボン酸エチルエステル（０．７４ｇ）を褐色粉末として得た。 (Example 20)
Synthesis of N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxamide maleate (1) 2- (4-chlorophenyl) -5-oxo Synthesis of pyrazolidine-3-carboxylic acid ethyl ester To a 20% sodium ethoxide-ethanol solution (9.2 mL) was added p-chlorophenylhydrazine hydrochloride (2.20 g), and the mixture was stirred at room temperature for 20 minutes. Diethyl maleic acid (2.00 g) was added to the reaction solution, and the mixture was stirred at the same temperature for 6 hours. After the reaction, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 5% hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (30% ethyl acetate-hexane) to give 2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxylic acid ethyl ester. (0.74 g) was obtained as a brown powder.

（２）Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボキサミド マレイン酸塩の合成
実施例２０（１）で得られた化合物（１．０１ｇ）のジオキサン（５ｍＬ）溶液に、濃塩酸（４ｍＬ）を加え、５０分間加熱還流した。反応後、水を加え、酢酸エチルで抽出し、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した。溶媒を減圧留去し、２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボン酸（０．７６ｇ）を褐色アモルファスとして得た。
ここで得られた化合物（０．４５ｇ）のクロロホルム（５ｍＬ）溶液に、４−アミノ−１−ベンジルピペラジン（０．４３ｇ）、１−ヒドロキシベンゾトリアゾール（０．４３ｇ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．３０ｇ）を加え、室温下一晩攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和重曹水、水、飽和食塩水で順次洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（５％メタノール−クロロホルム）で精製し、Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボキサミド（０．３８ｇ）を褐色粉末として得た。
ここで得られた化合物（０．３８ｇ）の酢酸エチル（２ｍＬ）、エタノール（２ｍＬ）の混合溶液にマレイン酸（０．１１ｇ）の酢酸エチル（２ｍＬ）溶液を加え、室温下３０分間攪拌拌した。エーテル（５ｍＬ）を加え析出した結晶を減圧乾燥し、表題化合物Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボキサミド マレイン酸塩（０．３２ｇ）を無色粉末として得た。 (2) Synthesis of N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxamide maleate Compound obtained in Example 20 (1) Concentrated hydrochloric acid (4 mL) was added to a solution of (1.01 g) in dioxane (5 mL), and the mixture was heated to reflux for 50 minutes. After the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxylic acid (0.76 g) as a brown amorphous substance.
To a chloroform (5 mL) solution of the compound (0.45 g) obtained here, 4-amino-1-benzylpiperazine (0.43 g), 1-hydroxybenzotriazole (0.43 g), 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.30 g) was added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5% methanol-chloroform), and N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxopyrazolidine-3 Carboxamide (0.38 g) was obtained as a brown powder.
A solution of maleic acid (0.11 g) in ethyl acetate (2 mL) was added to a mixed solution of the obtained compound (0.38 g) in ethyl acetate (2 mL) and ethanol (2 mL), and the mixture was stirred at room temperature for 30 minutes. . Ether (5 mL) was added and the precipitated crystals were dried under reduced pressure to give the title compound N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxamide maleate (0.32 g) was obtained as a colorless powder.

（実施例２１）
Ｎ−［１−（２，３，５−トリフルオロベンジル）ピペリジン−４−イル］−２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボキサミド マレイン酸塩の合成
実施例２０に合成中間体として示した２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボン酸と、参考例４で得られた化合物を、実施例１５に示した方法により縮合後、マレイン酸塩とし表題化合物Ｎ−［１−（２，３，５−トリフルオロベンジル）ピペリジン−４−イル］−２−（４−クロロフェニル）−５−オキソピラゾリジン−３−カルボキサミド マレイン酸塩を得た。 (Example 21)
Synthesis of N- [1- (2,3,5-trifluorobenzyl) piperidin-4-yl] -2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxamide maleate Example 20 After condensing 2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxylic acid shown as a synthetic intermediate with the compound obtained in Reference Example 4 by the method shown in Example 15, maleic acid The title compound N- [1- (2,3,5-trifluorobenzyl) piperidin-4-yl] -2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxamide maleate was obtained as a salt. It was.

（実施例２２）
トランス−Ｎ−（１−ベンジルピペリジン−４−イル）２−（４−クロロフェニル）テトラヒドロフラン−３−カルボキサミド塩酸塩の合成
（１）トランス−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボン酸エチルの合成
４−ブロモ酪酸エチル（４．００ｇ）と４−クロロベンズアルデヒド（３．５０ｇ）のテトラヒドロフラン（４１ｍＬ）溶液に、ｔ−ブトキシカリウム（４．１４ｇ）を４回に分けて−４０℃で加え、同温度下２時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（５％酢酸エチル−ヘキサン）で精製し、トランス−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボン酸エチル（１．３０ｇ）を無色油状物として得た。
1HNMR (300 MHz, CDCl3) δ 1.25 (t, J =7.2Hz, 3H), 2.21-2.41 (m, 2H), 2.83-2.95 (m, 1H), 3.97-4.09 (m, 1H), 4.11-4.25 (m, 3H), 5.01 (d, J =7.3Hz, 1H), 7.27-7.34 (m, 4H) (Example 22)
Synthesis of trans-N- (1-benzylpiperidin-4-yl) 2- (4-chlorophenyl) tetrahydrofuran-3-carboxamide hydrochloride (1) of trans-2- (4-chlorophenyl) tetrahydrofuran-3-carboxylate Synthesis To a solution of ethyl 4-bromobutyrate (4.00 g) and 4-chlorobenzaldehyde (3.50 g) in tetrahydrofuran (41 mL) was added t-butoxypotassium (4.14 g) in 4 portions at −40 ° C., The mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate-hexane), and trans-2- (4-chlorophenyl) tetrahydrofuran-3-carboxyl. Ethyl acid (1.30 g) was obtained as a colorless oil.
1 HNMR (300 MHz, CDCl 3 ) δ 1.25 (t, J = 7.2Hz, 3H), 2.21-2.41 (m, 2H), 2.83-2.95 (m, 1H), 3.97-4.09 (m, 1H), 4.11 -4.25 (m, 3H), 5.01 (d, J = 7.3Hz, 1H), 7.27-7.34 (m, 4H)

（２）トランス−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボン酸の合成
実施例２２（１）で得られた化合物（１．３０ｇ）のメタノール−水混合４ｍＬ溶液に室温下水酸化リチウム一水和物（０．６４ｇ）を加え、同温度下２時間攪拌した。反応液に酢酸エチルを加え、飽和重曹水で抽出した。有機層を除去後、水層に２Ｎ塩酸を加え酸性とし、酢酸エチルで２回抽出した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、トランス−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボン酸（１．１０ｇ）を無色油状物として得た。
1HNMR (300 MHz, CDCl3) δ 2.24-2.45 (m, 2H), 2.89-3.04 (m, 1H), 3.98-4.25 (m, 2H), 5.07 (d, J =7.0Hz, 1H), 7.23-7.39 (m, 4H), 10.07 (br. s, 1H) (2) Synthesis of trans-2- (4-chlorophenyl) tetrahydrofuran-3-carboxylic acid To a 4 mL methanol-water mixed solution of the compound (1.30 g) obtained in Example 22 (1), lithium hydroxide monohydrate at room temperature. A Japanese product (0.64 g) was added and stirred at the same temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was extracted with saturated aqueous sodium hydrogen carbonate. After removing the organic layer, the aqueous layer was acidified with 2N hydrochloric acid and extracted twice with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain trans-2- (4-chlorophenyl) tetrahydrofuran-3-carboxylic acid (1.10 g) as a colorless oil.
1 HNMR (300 MHz, CDCl 3 ) δ 2.24-2.45 (m, 2H), 2.89-3.04 (m, 1H), 3.98-4.25 (m, 2H), 5.07 (d, J = 7.0Hz, 1H), 7.23 -7.39 (m, 4H), 10.07 (br.s, 1H)

（３）トランス−Ｎ−（１−ベンジルピペリジン−４−イル)−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボキサミド塩酸塩の合成
実施例２２（２）で得られた化合物（０．５０ｇ）、４−アミノ−１−ベンジルピペリジン（０．５４ｍＬ）、１−ヒドロキシベンゾトリアゾール（０．５１ｇ）のクロロホルム（４．６ｍＬ）溶液に１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．６４ｇ）を加え室温下一晩攪拌した。反応液に飽和重曹水を加え、クロロホルムで３回抽出した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、残留物をシリカゲルカラムクロマトグラフィーで精製した後に、酢酸エチルに溶解させ、４Ｎ塩化水素−酢酸エチル溶液を加え結晶を析出させた。結晶を濾取後、減圧乾燥させ、表題化合物トランス−Ｎ−（１−ベンジルピペリジン−４−イル)−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボキサミド塩酸塩（０．７０ｇ）を無色粉末として得た。 (3) Synthesis of trans-N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) tetrahydrofuran-3-carboxamide hydrochloride Compound (0.50 g) obtained in Example 22 (2) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in a solution of 4-amino-1-benzylpiperidine (0.54 mL) and 1-hydroxybenzotriazole (0.51 g) in chloroform (4.6 mL) (0.64 g) was added and stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, dissolved in ethyl acetate, and 4N hydrogen chloride-ethyl acetate solution was added to precipitate crystals. The crystals were collected by filtration and dried under reduced pressure to give the title compound trans-N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) tetrahydrofuran-3-carboxamide hydrochloride (0.70 g) as a colorless powder. Obtained.

（実施例２３）
トランス−Ｎ−｛［１−（４−クロロベンジル）ピペラジン］−４−イル｝−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボキサミド塩酸塩の合成
実施例２２に合成中間体として示したトランス−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボン酸と１−（４−クロロベンジル）ピペラジンを、実施例２２に示した方法により縮合後、塩酸塩とし表題化合物トランス−Ｎ−｛［１−（４−クロロベンジル）ピペラジン］−４−イル｝−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボキサミド塩酸塩を得た。 (Example 23)
Synthesis of trans-N-{[1- (4-chlorobenzyl) piperazin] -4-yl} -2- (4-chlorophenyl) tetrahydrofuran-3-carboxamide hydrochloride 2- (4-Chlorophenyl) tetrahydrofuran-3-carboxylic acid and 1- (4-chlorobenzyl) piperazine were condensed by the method shown in Example 22 to give the hydrochloride, and the title compound trans-N-{[1- ( 4-Chlorobenzyl) piperazine] -4-yl} -2- (4-chlorophenyl) tetrahydrofuran-3-carboxamide hydrochloride was obtained.

（実施例２４）
トランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−Ｎ−メチル−テトラヒドロフラン−３−カルボキサミドの合成
実施例２２に合成中間体として示したトランス−２−（４−クロロフェニル）テトラヒドロフラン−３−カルボン酸と４−メチルアミノ−１−ベンジルピペリジンを、実施例２２に示した方法により縮合し、表題化合物トランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−Ｎ−メチル−テトラヒドロフラン−３−カルボキサミドを得た。 (Example 24)
Synthesis of trans-N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -N-methyl-tetrahydrofuran-3-carboxamide Trans-2- (4 shown as a synthetic intermediate in Example 22 -Chlorophenyl) tetrahydrofuran-3-carboxylic acid and 4-methylamino-1-benzylpiperidine were condensed by the method shown in Example 22 to give the title compound trans-N- (1-benzylpiperidin-4-yl) -2. -(4-Chlorophenyl) -N-methyl-tetrahydrofuran-3-carboxamide was obtained.

（実施例２５）
Ｎ−（１−ベンジルピペリジン−４−イル）−４−オキソ−１−[４−（トリフルオロメチル）フェニル]−Ｌ−プロリンアミドの合成
（１）（２Ｓ,４Ｒ）−２−[（１−ベンジルピペリジン−４−イル）カルバモイル]−４−ヒドロキシピロリジン−１−カルボン酸ｔ−ブチルの合成
（４Ｒ）−１−（t−ブトキシカルボニル）−４−ヒドロキシ−Ｌ−プロリン（２．８０ｇ）のＮ，Ｎ−ジメチルホルムアミド（３０ｍＬ）溶液に４−アミノ−１−ベンジルピペリジン（２．８０ｇ）、１−ヒドロキシベンゾトリアゾール（２．１ｇ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（３．００ｇ）を加え、室温下２４時間攪拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（１０％メタノール−クロロホルム）で精製し、表題化合物（２Ｓ,４Ｒ）−２−[（１−ベンジルピペリジン−４−イル）カルバモイル]−４−ヒドロキシピロリジン−１−カルボン酸t−ブチル（３．７０ｇ）を無色粉末として得た。
1H NMR (200 MHz,CDCｌ3) δ 1.37 - 1.51 (m, 11 H)， 1.63 - 2.22 (m, 8 H)， 2.67 - 2.89 (m, 2 H)， 3.41 - 3.55 (m, 3 H)， 3.67 - 3.87 (m, 1 H)， 4.26 - 4.56 (m, 2 H)， 7.17 - 7.37 (m, 5 H) (Example 25)
Synthesis of N- (1-benzylpiperidin-4-yl) -4-oxo-1- [4- (trifluoromethyl) phenyl] -L-prolinamide (1) (2S, 4R) -2-[(1 -Benzylpiperidin-4-yl) carbamoyl] -4-hydroxypyrrolidine-1-carboxylate t-butyl synthesis (4R) -1- (t-butoxycarbonyl) -4-hydroxy-L-proline (2.80 g) Of N, N-dimethylformamide (30 mL) in 4-amino-1-benzylpiperidine (2.80 g), 1-hydroxybenzotriazole (2.1 g), 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide hydrochloride (3.00 g) was added, and the mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% methanol-chloroform), and the title compound (2S, 4R) -2-[(1-benzylpiperidin-4-yl) carbamoyl] -4-hydroxypyrrolidine- T-Butyl 1-carboxylate (3.70 g) was obtained as a colorless powder.
1 H NMR (200 MHz, CDCl 3 ) δ 1.37-1.51 (m, 11 H), 1.63-2.22 (m, 8 H), 2.67-2.89 (m, 2 H), 3.41-3.55 (m, 3 H) , 3.67-3.87 (m, 1 H), 4.26-4.56 (m, 2 H), 7.17-7.37 (m, 5 H)

（２）（４Ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−ヒドロキシ−１−[４−（トリフルオロメチル）フェニル]−Ｌ−プロリンアミドの合成
実施例２５（１）で得られた（２Ｓ,４Ｒ）−２−[（１−ベンジルピペリジン−４−イル）カルバモイル]−４−ヒドロキシピロリジン−１−カルボン酸ｔ−ブチル（３．７ｇ）のメタノール(２５ｍＬ)溶液に４Ｍ塩化水素−１，４−ジオキサン(６ｍＬ)を加え、１時間加熱還流した。反応液を減圧下溶媒留去し、水、酢酸エチルを加え、水層のみを分離した。得られた水層を２Ｍ水酸化ナトリウム水溶液でｐＨ＝１２に調整した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し（４Ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−ヒドロキシ−Ｌ−プロリンアミド（１．５ｇ）を無色粉末として得た。
ここで得られた化合物（１．０ｇ）のトルエン（１０ｍＬ）懸濁溶液に４−トリフルオロメチルフェニルブロマイド（０．５ｍＬ）、トリス（ジベンジリデンアセトン）ジパラジウム（０．３０ｇ）、(±)−２，２−ビス（ジフェニルホスフィノ）−１，１−ビナフチル（０．２１ｇ）、炭酸セシウム（２．２ｇ）を加え、７０℃で１１時間攪拌した。反応液をセライトろ過、濾液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（２％メタノール−クロロホルム）で精製し、表題化合物（４Ｒ）−Ｎ−（１−ベンジルピペリジン−４−イル）−４−ヒドロキシ−１−[４−（トリフルオロメチル）フェニル]−Ｌ−プロリンアミド（０．１３ｇ）を茶褐色アモルファスとして得た。
1H NMR (200 MHz,CDCｌ3) δ 1.28 - 1.45 (m, 2 H)， 1.67 - 1.89 (m, 2 H)， 1.98 - 2.16 (m, 2 H)， 2.23 - 2.53 (m, 2 H)， 2.58 - 2.80 (m, 2 H)， 3.28 - 3.40 (m, 1 H)， 3.43 (s, 2 H)， 3.68 - 3.84 (m, 1 H)， 3.84 - 3.96 (m, 1 H)， 4.15 - 4.29 (m, 1 H)， 4.51 - 4.70 (m, 1 H)， 6.03 (d, J=9.3 Hz, 1 H)， 6.61 (d, J=8.6 Hz, 2 H)， 7.13 - 7.39 (m, 5 H)， 7.47 (d, J=8.6 Hz, 2 H) (2) Synthesis of (4R) -N- (1-benzylpiperidin-4-yl) -4-hydroxy-1- [4- (trifluoromethyl) phenyl] -L-prolinamide In Example 25 (1) The resulting (2S, 4R) -2-[(1-benzylpiperidin-4-yl) carbamoyl] -4-hydroxypyrrolidine-1-carboxylate t-butyl (3.7 g) in methanol (25 mL) was added 4M. Hydrogen chloride-1,4-dioxane (6 mL) was added, and the mixture was heated to reflux for 1 hr. The reaction mixture was evaporated under reduced pressure, water and ethyl acetate were added, and only the aqueous layer was separated. The obtained aqueous layer was adjusted to pH = 12 with 2M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give (4R) -N- (1-benzylpiperidin-4-yl) -4-hydroxy-L-prolinamide (1. 5 g) was obtained as a colorless powder.
4-trifluoromethylphenyl bromide (0.5 mL), tris (dibenzylideneacetone) dipalladium (0.30 g), (±) in a suspension solution of the compound (1.0 g) obtained in toluene (10 mL). -2,2-bis (diphenylphosphino) -1,1-binaphthyl (0.21 g) and cesium carbonate (2.2 g) were added, and the mixture was stirred at 70 ° C. for 11 hours. The reaction solution was filtered through Celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% methanol-chloroform), and the title compound (4R) -N- (1-benzylpiperidin-4-yl) -4-hydroxy-1- [4- ( Trifluoromethyl) phenyl] -L-prolinamide (0.13 g) was obtained as a brown amorphous.
1 H NMR (200 MHz, CDCl 3 ) δ 1.28-1.45 (m, 2 H), 1.67-1.89 (m, 2 H), 1.98-2.16 (m, 2 H), 2.23-2.53 (m, 2 H) 2.58-2.80 (m, 2 H), 3.28-3.40 (m, 1 H), 3.43 (s, 2 H), 3.68-3.84 (m, 1 H), 3.84-3.96 (m, 1 H), 4.15 -4.29 (m, 1 H), 4.51-4.70 (m, 1 H), 6.03 (d, J = 9.3 Hz, 1 H), 6.61 (d, J = 8.6 Hz, 2 H), 7.13-7.39 (m , 5 H), 7.47 (d, J = 8.6 Hz, 2 H)

（３）Ｎ−（１−ベンジルピペリジン−４−イル）−４−オキソ−１−[４−（トリフルオロメチル）フェニル]−Ｌ−プロリンアミドの合成
実施例２５（２）で得られた化合物（０．１３ｇ）のジメチルスルホキシド（２ｍＬ）溶液にデスマーチン試薬（０．２８ｇ）を加え、室温下２４時間攪拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（５％メタノール−クロロホルム）で精製し、表題化合物Ｎ−（１−ベンジルピペリジン−４−イル）−４−オキソ−１−[４−（トリフルオロメチル）フェニル]−Ｌ−プロリンアミド（６０ｍｇ）を淡褐色アモルファスとして得た。 (3) Synthesis of N- (1-benzylpiperidin-4-yl) -4-oxo-1- [4- (trifluoromethyl) phenyl] -L-prolinamide Compound obtained in Example 25 (2) To a solution of (0.13 g) in dimethyl sulfoxide (2 mL), Dess-Martin reagent (0.28 g) was added and stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5% methanol-chloroform), and the title compound N- (1-benzylpiperidin-4-yl) -4-oxo-1- [4- (trifluoromethyl) Phenyl] -L-prolinamide (60 mg) was obtained as a light brown amorphous.

（実施例２６）
１−（１−ベンジルピペリジン−４−イル）−３−[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]尿素の合成
（１）[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]カルバミン酸ｔ−ブチルの合成
参考例１（１）で得られた化合物（１０．０ｇ）のクロロホルム（５０ｍＬ）、テトラヒドロフラン（５０ｍＬ）混合溶液にチオニルクロライド（４．５ｍＬ）を加え、２時間加熱還流した。室温下放冷後、反応液を減圧下溶媒留去した。得られた残留物をクロロホルム（５０ｍＬ）に溶解させ、氷冷下、テトラブチルアンモニウムブロマイド（０．１４ｇ）、アジ化ナトリウム（８．２０ｇ）、水（５ｍＬ）を加え、同温度下１．５時間攪拌した。反応液に水を加え、クロロホルム（１００ｍＬ）を用いて抽出した。抽出した有機層を水、飽和食塩水で順次洗浄、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。得られた濾液にｔ−ブチルアルコール（８０ｍＬ）を加え、１．５時間加熱還流した。室温下放冷後、反応液に水を加え、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（２０％酢酸エチル−ヘキサン）で精製後、ヘキサン−酢酸エチル系で再結晶し表題化合物[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]カルバミン酸ｔ−ブチル（１．５０ｇ）を無色粉末として得た。
1H NMR (200 MHz,CDCｌ3) δ 1.46 (s, 9 H)， 2.44 - 2.54 (m, 1 H), 2.82 - 2.94 (m, 1 H)， 4.17 - 4.30 (m, 1 H)， 4.84 - 4.96 (m, 1 H)， 5.41 - 5.51 (m, 1 H)， 7.32 - 7.42 (m, 4 H) (Example 26)
Synthesis of 1- (1-benzylpiperidin-4-yl) -3- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] urea (1) [trans-2- (4-chlorophenyl] Synthesis of t-butyl) -5-oxotetrahydrofuran-3-yl] carbamate To a mixed solution of the compound (10.0 g) obtained in Reference Example 1 (1) in chloroform (50 mL) and tetrahydrofuran (50 mL), thionyl chloride ( (4.5 mL) was added and the mixture was heated to reflux for 2 hours. After allowing to cool at room temperature, the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was dissolved in chloroform (50 mL), and tetrabutylammonium bromide (0.14 g), sodium azide (8.20 g) and water (5 mL) were added under ice cooling, and 1.5 ° C. was added at the same temperature. Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform (100 mL). The extracted organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. T-Butyl alcohol (80 mL) was added to the obtained filtrate and heated under reflux for 1.5 hours. After allowing to cool at room temperature, water was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20% ethyl acetate-hexane) and recrystallized from hexane-ethyl acetate system to give the title compound [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3. -Il] t-butyl carbamate (1.50 g) was obtained as a colorless powder.
1 H NMR (200 MHz, CDCl 3 ) δ 1.46 (s, 9 H), 2.44-2.54 (m, 1 H), 2.82-2.94 (m, 1 H), 4.17-4.30 (m, 1 H), 4.84 -4.96 (m, 1 H), 5.41-5.51 (m, 1 H), 7.32-7.42 (m, 4 H)

（２）トランス−４−アミノ−５−（４−クロロフェニル）ジヒドロフラン−２（３Ｈ）−オン塩酸塩の合成
実施例２６（１）で得られた化合物（１．４０ｇ）の酢酸エチル（２０ｍＬ）溶液に４Ｍ塩化水素−酢酸エチル溶液（５ｍＬ）を加え、室温下３日間攪拌した。析出してきた固体を濾取し、減圧加熱乾燥し表題化合物トランス−４−アミノ−５−（４−クロロフェニル）ジヒドロフラン−２（３Ｈ）−オン塩酸塩（１．００ｇ）を無色粉末として得た。
1H NMR (200 MHz, DMSO-ｄ6) δ 2.73 (dd, J=18.6, 3.7 Hz, 1 H)， 3.23 (dd, J=18.6, 8.7 Hz, 1 H)， 4.03 (dt, J=8.7, 3.7 Hz, 1 H)， 5.70 (d, J=3.7 Hz, 1 H)， 7.44 - 7.58 (m, 4 H)． (2) Synthesis of trans-4-amino-5- (4-chlorophenyl) dihydrofuran-2 (3H) -one hydrochloride The compound (1.40 g) obtained in Example 26 (1) in ethyl acetate (20 mL) 4M Hydrogen chloride-ethyl acetate solution (5 mL) was added to the solution, and the mixture was stirred at room temperature for 3 days. The precipitated solid was collected by filtration and dried by heating under reduced pressure to give the title compound trans-4-amino-5- (4-chlorophenyl) dihydrofuran-2 (3H) -one hydrochloride (1.00 g) as a colorless powder. .
1 H NMR (200 MHz, DMSO-d 6 ) δ 2.73 (dd, J = 18.6, 3.7 Hz, 1 H), 3.23 (dd, J = 18.6, 8.7 Hz, 1 H), 4.03 (dt, J = 8.7 , 3.7 Hz, 1 H), 5.70 (d, J = 3.7 Hz, 1 H), 7.44-7.58 (m, 4 H).

（３）１−（１−ベンジルピペリジン−４−イル）−３−[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]尿素の合成
トリホスゲン（０．２４ｇ）のクロロホルム（１０ｍＬ）溶液に実施例２６（２）で得られた化合物（０．５０ｇ）、Ｎ，Ｎ−ジイソプロピルエチルアミン（１．２ｍＬ）のクロロホルム（２０ｍＬ）溶液を室温下３０分間で滴下した。同温度下５分間攪拌した後、４−アミノ−１−ベンジルピペリジン（０．３８ｍＬ）のクロロホルム（２０ｍＬ）溶液を室温下１０分間で滴下し、同温度下２０分間攪拌した。反応液に飽和重曹水を加え、同温度下３０分間攪拌した後、有機層を分離した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、表題化合物１−（１−ベンジルピペリジン−４−イル）−３−[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]尿素（０．４３ｇ）を無色アモルファスとして得た。 (3) Synthesis of 1- (1-benzylpiperidin-4-yl) -3- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] urea Triphosgene (0.24 g) in chloroform ( A solution of the compound obtained in Example 26 (2) (0.50 g) and N, N-diisopropylethylamine (1.2 mL) in chloroform (20 mL) was added dropwise to the solution at room temperature over 30 minutes. After stirring at the same temperature for 5 minutes, a solution of 4-amino-1-benzylpiperidine (0.38 mL) in chloroform (20 mL) was added dropwise at room temperature for 10 minutes and stirred at the same temperature for 20 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was stirred at the same temperature for 30 minutes, and then the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound 1- (1-benzylpiperidin-4-yl) -3- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran. -3-yl] urea (0.43 g) was obtained as a colorless amorphous.

（実施例２７）
４−（４−クロロベンジル）−Ｎ−［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル）ピペラジン−１−カルボキサミドの合成
実施例２６に合成中間体として示したトランス−４−アミノ−５−（４−クロロフェニル）ジヒドロフラン−２（３Ｈ）−オンと（４−クロロベンジル）ピペラジンを、実施例２６に示した方法により反応し、表題化合物４−（４−クロロベンジル）−Ｎ−［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル）ピペラジン−１−カルボキサミドを得た。 (Example 27)
Synthesis of 4- (4-chlorobenzyl) -N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl) piperazine-1-carboxamide trans- shown as a synthetic intermediate in Example 26 4-Amino-5- (4-chlorophenyl) dihydrofuran-2 (3H) -one and (4-chlorobenzyl) piperazine are reacted by the method shown in Example 26 to give the title compound 4- (4-chlorobenzyl). ) -N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl) piperazine-1-carboxamide was obtained.

（実施例２８）
４−（４−トリフルオロベンジル）−Ｎ−［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル）ピペラジン−１−カルボキサミドの合成
４−トリフルオロベンズアルデヒドを原料として、参考例１（１）示した方法に続き、実施例２６に示した方法により合成し、表題化合物４−（４−トリフルオロベンジル）−Ｎ−［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル）ピペラジン−１−カルボキサミドを得た。 (Example 28)
Synthesis of 4- (4-trifluorobenzyl) -N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl) piperazine-1-carboxamide Reference example using 4-trifluorobenzaldehyde as a raw material 1 (1) Following the indicated method, the title compound 4- (4-trifluorobenzyl) -N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran was synthesized by the method shown in Example 26. -3-yl) piperazine-1-carboxamide was obtained.

（実施例２９）
１−ベンジル−Ｎ−[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]ピペリジン−４−カルボキサミド マレイン酸塩の合成
（１）４−｛[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]カルバモイル｝ピペリジン−１−カルボン酸 t−ブチルの合成
実施例２６（２）で得られた化合物（１．００ｇ）のクロロホルム（１０ｍＬ）懸濁溶液にＮ−Ｂｏｃ−イソニペコチン酸（１．１０ｇ）、トリエチルアミン（０．７４ｍＬ）、１−ヒドロキシベンゾトリアゾール（０．７０ｇ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１．００ｇ）を加え、室温下２４時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で順次洗浄、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（５０％酢酸エチル−ヘキサン）で精製し表題化合物４−｛[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]カルバモイル｝ピペリジン−１−カルボン酸ｔ−ブチル（１．４０ｇ）を無色アモルファスとして得た。
1H NMR (200 MHz,CDCｌ3) δ 1.46 (s, 9 H)， 1.59 - 1.76 (m, 2 H)， 1.78 - 1.93 (m, 2 H)， 2.23 - 2.41 (m, 1 H)， 2.43 - 2.59 (m, 1 H)， 2.68 - 3.00 (m, 3 H)， 4.00 - 4.29 (m, 2 H)， 4.41 - 4.59 (m, 1 H)， 5.48 (d, J=2.3 Hz, 1 H)， 6.52 (d, J=5.9 Hz, 1 H)， 7.27 - 7.56 (m, 4 H) (Example 29)
Synthesis of 1-benzyl-N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] piperidine-4-carboxamide maleate (1) 4-{[trans-2- (4- Synthesis of chlorophenyl) -5-oxotetrahydrofuran-3-yl] carbamoyl} piperidine-1-carboxylate t-butyl To a suspension of the compound (1.00 g) obtained in Example 26 (2) in chloroform (10 mL) N-Boc-isonipecotic acid (1.10 g), triethylamine (0.74 mL), 1-hydroxybenzotriazole (0.70 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.00 g ) And stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (50% ethyl acetate-hexane) to give the title compound 4-{[trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] carbamoyl} piperidine- T-butyl 1-carboxylate (1.40 g) was obtained as a colorless amorphous.
1 H NMR (200 MHz, CDCl 3 ) δ 1.46 (s, 9 H), 1.59-1.76 (m, 2 H), 1.78-1.93 (m, 2 H), 2.23-2.41 (m, 1 H), 2.43 -2.59 (m, 1 H), 2.68-3.00 (m, 3 H), 4.00-4.29 (m, 2 H), 4.41-4.59 (m, 1 H), 5.48 (d, J = 2.3 Hz, 1 H ), 6.52 (d, J = 5.9 Hz, 1 H), 7.27-7.56 (m, 4 H)

（２）１−ベンジル−Ｎ−[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル］ピペリジン−４−カルボキサミド マレイン酸塩の合成
実施例２９（１）で得られた化合物（１．４０ｇ）の酢酸エチル（１５ｍＬ）溶液に４Ｍ塩化水素−酢酸エチル溶液（１２ｍＬ）を加え、室温下６時間攪拌し、反応液を減圧下溶媒留去し無色粉末（０．７２ｇ）を得た。ここで得られた無色粉末のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）懸濁溶液にベンズアルデヒド（０．５３ｇ）、酢酸（０．５７ｍＬ）を加え、室温下１時間攪拌した。そこにトリアセトキシ水素化ホウ素ナトリウム（２．１０ｇ）を加え、室温下２４時間攪拌した。反応液に飽和重曹水を加え、酢酸エチルを用いて抽出した。抽出した有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をカラムクロマトグラフィー（酢酸エチル）で精製し、１−ベンジル−Ｎ−[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]ピペリジン−４−カルボキサミド（０．７２ｇ）を無色粉末として得た。
ここで得られた化合物（０．３０ｇ）の酢酸エチル（３ｍＬ）溶液にマレイン酸（８４ｍｇ）の酢酸エチル（２．６ｍＬ）溶液を加え、室温下３時間攪拌した。析出した固体を濾取、減圧加熱乾燥し表題化合物１−ベンジル−Ｎ−[トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル]ピペリジン−４−カルボキサミド マレイン酸塩（０．２９ｇ）を無色粉末として得た。 (2) Synthesis of 1-benzyl-N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] piperidine-4-carboxamide maleate Compound obtained in Example 29 (1) 4M hydrogen chloride-ethyl acetate solution (12 mL) was added to a solution of (1.40 g) in ethyl acetate (15 mL), and the mixture was stirred at room temperature for 6 hours. Obtained. Benzaldehyde (0.53 g) and acetic acid (0.57 mL) were added to a suspension of the colorless powder obtained here in N, N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 1 hour. Thereto was added sodium triacetoxyborohydride (2.10 g), and the mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate), and 1-benzyl-N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] piperidine-4-carboxamide (0 .72 g) as a colorless powder.
To a solution of the obtained compound (0.30 g) in ethyl acetate (3 mL) was added maleic acid (84 mg) in ethyl acetate (2.6 mL), and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, dried by heating under reduced pressure, and the title compound 1-benzyl-N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] piperidine-4-carboxamide maleate (0. 29 g) was obtained as a colorless powder.

（実施例３０）
１−ベンジル−Ｎ−[トランス−２−（４−トリフルオロフェニル）−５−オキソテトラヒドロフラン−３−イル]ピペリジン−４−カルボキサミド マレイン酸塩の合成
４−トリフルオロベンズアルデヒドを原料として、参考例１（１）に示した方法に続き、実施例２９に示した方法により合成し、表題化合物１−ベンジル−Ｎ−[トランス−２−（４−トリフルオロフェニル）−５−オキソテトラヒドロフラン−３−イル]ピペリジン−４−カルボキサミド マレイン酸塩を得た。 (Example 30)
Synthesis of 1-benzyl-N- [trans-2- (4-trifluorophenyl) -5-oxotetrahydrofuran-3-yl] piperidine-4-carboxamide maleate Reference Example 1 using 4-trifluorobenzaldehyde as a raw material Following the method shown in (1), the title compound 1-benzyl-N- [trans-2- (4-trifluorophenyl) -5-oxotetrahydrofuran-3-yl was synthesized by the method shown in Example 29. Piperidine-4-carboxamide maleate was obtained.

（実施例３１）
Ｎ−（１−ベンジルピペリジン−４−イル）−２−［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル］アセトアミドの合成
（１）トランス−５−（４−クロロフェニル）−４−（２−ジアゾアセチル）ジヒドロフラン−２（３Ｈ）−オンの合成
参考例１（３）で得られた化合物（１．０２ｇ）のクロロホルム（８ｍＬ）溶液にオキサリルクロリド（０．５５ｍＬ）、ジメチルホルムアミド１滴を加え、室温下２時間攪拌した。反応液を減圧濃縮した後に、テトラヒドロフラン（８ｍＬ）に溶解させ、氷冷下でトリメチルシリルジアゾメタン４．３ｍＬを加え、同温度下２時間攪拌した。反応液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー（５０％酢酸エチル−ヘキサン）で精製し、トランス−５−（４−クロロフェニル）−４−（２−ジアゾアセチル）ジヒドロフラン−２（３Ｈ）−オン（０．８８ｇ）を黄色油状物として得た。
1HNMR (300 MHz, CDCｌ3) δ(δ): 2.75-2.88 (m, 1H), 3.00-3.26 (m, 2H), 5.16 (s, 1H), 5.54 (d, J =8.2Hz, 1H), 7.24-7.42 (m, 4H) (Example 31)
Synthesis of N- (1-benzylpiperidin-4-yl) -2- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] acetamide (1) trans-5- (4-chlorophenyl) Synthesis of -4- (2-diazoacetyl) dihydrofuran-2 (3H) -one To a solution of the compound (1.02 g) obtained in Reference Example 1 (3) in chloroform (8 mL), oxalyl chloride (0.55 mL) Then, 1 drop of dimethylformamide was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in tetrahydrofuran (8 mL), added with 4.3 mL of trimethylsilyldiazomethane under ice cooling, and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate-hexane), and trans-5- (4-chlorophenyl) -4- (2-diazoacetyl) dihydrofuran-2 (3H ) -One (0.88 g) was obtained as a yellow oil.
1 HNMR (300 MHz, CDCl 3 ) δ (δ): 2.75-2.88 (m, 1H), 3.00-3.26 (m, 2H), 5.16 (s, 1H), 5.54 (d, J = 8.2Hz, 1H) , 7.24-7.42 (m, 4H)

（２）Ｎ−（１−ベンジルピペリジン−４−イル）−２−［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル］アセトアミドの合成
実施例３１（１）で得られた化合物（０．８８ｇ）のメタノール（３．３ｍＬ）溶液に安息香酸銀（I）（０．０６ｇ）のトリエチルアミン（０．６ｍＬ）溶液を室温で加え、同温度下３０分間攪拌した
。反応液をセライト濾過後、減圧濃縮し、残留物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）で精製し、［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル］酢酸メチル（０．８１ｇ）を無色油状物として得た。
ここで得られた化合物（０．７６ｇ）の５０％メタノール−水（４ｍＬ）溶液に室温下水酸化リチウム一水和物（０．３７ｇ）を加え、同温度下４時間攪拌した。反応液を濃縮後、酢酸エチルを加え飽和重曹水で抽出した。水層に２Ｎ塩酸を加え酸性とし、酢酸エチルで抽出し、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル］酢酸（０．７０ｇ）を無色粉末として得た。 (2) Synthesis of N- (1-benzylpiperidin-4-yl) -2- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] acetamide obtained in Example 31 (1) A solution of silver (I) benzoate (0.06 g) in triethylamine (0.6 mL) was added to a solution of the compound (0.88 g) in methanol (3.3 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate-hexane) to give [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl]. Methyl acetate (0.81 g) was obtained as a colorless oil.
To a 50% methanol-water (4 mL) solution of the compound obtained here (0.76 g), lithium hydroxide monohydrate (0.37 g) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was extracted with saturated aqueous sodium hydrogen carbonate. The aqueous layer was acidified with 2N hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] acetic acid (0.70 g) as a colorless powder.

ここで得られた化合物（０．２０ｇ）、４−アミノ−１−ベンジルピペリジン（０．２０ｍＬ）、１−ヒドロキシベンゾトリアゾール（０．１８ｇ）のクロロホルム（１．６ｍＬ）溶液に１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．２３ｇ）を加え室温下４時間攪拌した。反応液に飽和重曹水を加え、クロロホルムで３回抽出した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（１３％ヘキサン−酢酸エチル）で精製し、Ｎ−（１−ベンジルピペリジン−４−イル）−２−［トランス−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−イル］アセトアミド（０．２２ｇ）を無色粉末として得た。   To a solution of the compound obtained here (0.20 g), 4-amino-1-benzylpiperidine (0.20 mL) and 1-hydroxybenzotriazole (0.18 g) in chloroform (1.6 mL) was added 1-ethyl-3. -(3-Dimethylaminopropyl) carbodiimide hydrochloride (0.23 g) was added and stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (13% hexane-ethyl acetate), and N- (1-benzylpiperidin-4-yl) -2- [trans 2- (4-Chlorophenyl) -5-oxotetrahydrofuran-3-yl] acetamide (0.22 g) was obtained as a colorless powder.

（実施例３２）
トランス−１−ベンジルピペリジン−４−イル ２−（４−クロロフェニル）−テトラヒドロ−５−フラノン−３−カルボキシレートの合成
参考例１（３）で得られた化合物（０．２９ｇ）のクロロホルム（１５ｍＬ）溶液に、1−ベンジルピペリジン−４−オール（０．１９ｇ）、１−ヒドロキシベンゾトリアゾール１水和物（０．２３ｇ）を室温で加え、Ｎ−（３−ジメチルアミノプロピル）−Ｎ'−エチルカルボジイミド塩酸塩（０．２９ｇ）を添加した。室温下一晩撹拌し、反応液に飽和重曹水を加え、クロロホルムで３回抽出した。有機層を硫酸マグネシウムで乾燥後、減圧下溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（２．５％メタノール−クロロホルム）で精製し、粗生成物（０．１９ｇ）を得た。これを再度シリカゲルカラムクロマトグラフィー（２％メタノール−クロロホルム）で精製し、トランス−１−ベンジルピペリジン−４−イル ２−（４−クロロフェニル）−テトラヒドロ−５−フラノン−３−カルボキシレートの黄色油状物質（０．１５ｇ）を得た。 (Example 32)
Synthesis of trans-1-benzylpiperidin-4-yl 2- (4-chlorophenyl) -tetrahydro-5-furanone-3-carboxylate Chloroform (15 mL) of the compound (0.29 g) obtained in Reference Example 1 (3) ) 1-Benzylpiperidin-4-ol (0.19 g) and 1-hydroxybenzotriazole monohydrate (0.23 g) were added to the solution at room temperature, and N- (3-dimethylaminopropyl) -N′- Ethyl carbodiimide hydrochloride (0.29 g) was added. The mixture was stirred overnight at room temperature, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol-chloroform) to obtain a crude product (0.19 g). This was purified again by silica gel column chromatography (2% methanol-chloroform), and trans-1-benzylpiperidin-4-yl 2- (4-chlorophenyl) -tetrahydro-5-furanone-3-carboxylate as a yellow oily substance (0.15 g) was obtained.

実施例３３、３４の化合物は、実施例３２に示した方法により参考例１（４）で得られた化合物と対応するアルコール化合物と縮合することにより合成した。   The compounds of Examples 33 and 34 were synthesized by condensing the compound obtained in Reference Example 1 (4) with the corresponding alcohol compound by the method shown in Example 32.

（実施例３５）
トランス−１−ベンジルピペリジン−４−イル ２−（４−シアノフェニル）−テトラヒドロ−５−フラノン−３−カルボキシレートの合成
４−シアノベンズアルデヒドを原料として、参考例１（１）〜参考例１（４）に示した方法に続き、実施例３２に示した方法により合成し、表題化合物トランス−１−ベンジルピペリジン−４−イル ２−（４−シアノフェニル）−テトラヒドロ−５−フラノン−３−カルボキシレートを得た。 (Example 35)
Synthesis of trans-1-benzylpiperidin-4-yl 2- (4-cyanophenyl) -tetrahydro-5-furanone-3-carboxylate Using 4-cyanobenzaldehyde as a raw material, Reference Example 1 (1) to Reference Example 1 ( Following the method shown in 4), the title compound trans-1-benzylpiperidin-4-yl 2- (4-cyanophenyl) -tetrahydro-5-furanone-3-carboxyl was synthesized by the method shown in Example 32. Got the rate.

（実施例３６）
（−）−トランス−２−（４−クロロフェニル）−５−オキソ−Ｎ−［１−（２，３，５−トリフルオロベンジル）ピペリジン−４−イル］テトラヒドロフラン−３−カルボキサミド マレイン酸塩の合成
（１）トランス−２−（４−クロロフェニル）−５−オキソ−Ｎ−［１−（２，３，５−トリフルオロベンジル）ピペリジン−４−イル］テトラヒドロフラン−３−カルボキサミドの合成
参考例４で得られた化合物（２３．０ｇ）に飽和重曹水を加え、クロロホルムで３回抽出した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、１−（２，３，５−トリフルオロベンジル）ピペリジン−４−アミン（２０．０ｇ）を無色油状物として得た。
ここで得られた化合物（２０．０ｇ）、参考例１（５）で得られた化合物（１８．０ｇ）、１−ヒドロキシベンゾトリアゾール（１３．０ｇ）のクロロホルム（１００ｍＬ）溶液に１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（１６．０ｇ）を加え、室温下１時間攪拌した。反応液に飽和重曹水を加え、クロロホルムで２回抽出した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（５％メタノール−クロロホルム）で精製し、トランス−２−（４−クロロフェニル）−５−オキソ−Ｎ−［１−（２，３，５−トリフルオロベンジル）ピペリジン−４−イル］テトラヒドロフラン−３−カルボキサミド（２２．０ｇ）を無色油状物として得た。
1HNMR (300 MHz, CDCl3) δ 1.23-1.49 (m, 2H), 1.79-1.95 (m, 2H), 2.10-2.26 (m, 2H), 2.69-2.95 (m, 3H), 3.09-3.24 (m, 1H), 3.55 (s, 2H), 3.72-3.90 (m, 1H), 5.27 (d, J =7.8Hz, 1H), 5.47 (d, J =8.6Hz, 1H), 6.76-6.96 (m, 2H), 7.18-7.43 (m, 4H) (Example 36)
Synthesis of (−)-trans-2- (4-chlorophenyl) -5-oxo-N- [1- (2,3,5-trifluorobenzyl) piperidin-4-yl] tetrahydrofuran-3-carboxamide maleate (1) Synthesis of trans-2- (4-chlorophenyl) -5-oxo-N- [1- (2,3,5-trifluorobenzyl) piperidin-4-yl] tetrahydrofuran-3-carboxamide In Reference Example 4 To the obtained compound (23.0 g) was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1- (2,3,5-trifluorobenzyl) piperidin-4-amine (20.0 g) as a colorless oil.
To a solution of the compound obtained here (20.0 g), the compound obtained in Reference Example 1 (5) (18.0 g), and 1-hydroxybenzotriazole (13.0 g) in chloroform (100 mL), 1-ethyl- 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (16.0 g) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted twice with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol-chloroform), and trans-2- (4-chlorophenyl) -5-oxo-N- [1 -(2,3,5-trifluorobenzyl) piperidin-4-yl] tetrahydrofuran-3-carboxamide (22.0 g) was obtained as a colorless oil.
1 HNMR (300 MHz, CDCl 3 ) δ 1.23-1.49 (m, 2H), 1.79-1.95 (m, 2H), 2.10-2.26 (m, 2H), 2.69-2.95 (m, 3H), 3.09-3.24 ( m, 1H), 3.55 (s, 2H), 3.72-3.90 (m, 1H), 5.27 (d, J = 7.8Hz, 1H), 5.47 (d, J = 8.6Hz, 1H), 6.76-6.96 (m , 2H), 7.18-7.43 (m, 4H)

（２）（−）−トランス−２−（４−クロロフェニル）−５−オキソ−Ｎ−［１−（２，３，５−トリフルオロベンジル）ピペリジン−４−イル］テトラヒドロフラン−３−カルボキサミド マレイン酸塩の合成
実施例３６（１）で得られた化合物（２２．０ｇ）の酢酸エチル（３５０ｍＬ）溶液にマレイン酸（５．５ｇ）の酢酸エチル（１８８ｍＬ）溶液を加え、室温下３０分間攪拌後、氷冷下で１時間攪拌した。析出した結晶を減圧乾燥し、トランス−２−（４−クロロフェニル）−５−オキソ−Ｎ−［１−（２，３，５−トリフルオロベンジル）ピペリジン−４−イル］テトラヒドロフラン−３−カルボキサミド マレイン酸塩（２１．０ｇ）を無色粉末として得た。
［α］D 20 = -28.6 (c 1.00, MeOH) (2) (−)-trans-2- (4-chlorophenyl) -5-oxo-N- [1- (2,3,5-trifluorobenzyl) piperidin-4-yl] tetrahydrofuran-3-carboxamide maleic acid Synthesis of salt To a solution of the compound obtained in Example 36 (1) (22.0 g) in ethyl acetate (350 mL) was added maleic acid (5.5 g) in ethyl acetate (188 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was stirred for 1 hour under ice cooling. The precipitated crystals were dried under reduced pressure, and trans-2- (4-chlorophenyl) -5-oxo-N- [1- (2,3,5-trifluorobenzyl) piperidin-4-yl] tetrahydrofuran-3-carboxamide malein The acid salt (21.0 g) was obtained as a colorless powder.
[Α] D 20 = -28.6 (c 1.00, MeOH)

実施例３７〜４６の化合物は、参考例１（５）で得られた化合物を原料として、実施例３６に示した方法により対応するアミン化合物と縮合し得た。   The compounds of Examples 37 to 46 could be condensed with the corresponding amine compounds by the method shown in Example 36 using the compound obtained in Reference Example 1 (5) as a raw material.

実施例４７〜５３の化合物は、参考例２で得られた化合物を原料として、実施例３６に示した方法により対応するアミン化合物と縮合し得た。   The compounds of Examples 47 to 53 could be condensed with the corresponding amine compounds by the method shown in Example 36 using the compound obtained in Reference Example 2 as a raw material.

実施例５４〜６１の化合物は、参考例３で得られた化合物を原料として、実施例３６に示した方法により対応するアミン化合物と縮合し得た。   The compounds of Examples 54 to 61 could be condensed with the corresponding amine compounds by the method shown in Example 36 using the compound obtained in Reference Example 3 as a starting material.

（実施例６２）トランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボキサミド、及び（実施例６３）シス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボキサミドの合成
参考例１（１）で得られた化合物（１．５０ｇ）のＮ，Ｎ−ジメチルホルムアミド（１５ｍＬ）溶液に４−アミノ−１−ベンジルピペリジン（１．２０ｇ）、１−ヒドロキシベンゾトリアゾール（２．００ｇ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（２．５０ｇ）を加え、室温下１８時間攪拌した。反応液に飽和重曹水を加え、酢酸エチルを用いて抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（１３％酢酸エチル−ヘキサン〜１０％メタノール−クロロホルム）で分離精製し、１３％酢酸エチル−ヘキサン溶出部より実施例６２のトランス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボキサミド（０．７７ｇ）を無色粉末として得、また１０％メタノール−クロロホルム溶出部より実施例６３のシス−Ｎ−（１−ベンジルピペリジン−４−イル）−２−（４−クロロフェニル）−５−オキソテトラヒドロフラン−３−カルボキサミド（０．９４ｇ）を淡黄色粉末として得た。
実施例１〜６３の化合物の構造とＮＭＲデータを下記表１に示す。
実施例６４〜３９９の化合物は、参考例１（１）で得られた化合物、あるいは参考例１（１）において対応する置換ベンズアルデヒドを原料として参考例１（１）に示した方法により得られた化合物から、実施例６２及び実施例６３に示した方法により合成した。
実施例６４〜３２７の化合物の構造とＮＭＲデータも下記表１に示す。
実施例３２８〜３９２の化合物に対しては、マイクロマス（Micromass）社製のPlatformLC型質量分析計を用いて大気圧化学イオン化（APCI：Atmospheric pressure chemical ionization）を測定した。実施例３２８〜３９２の化合物の構造とAPCIの測定値を下記表２に示す。また、実施例３９３〜３９９の化合物に対しては、同質量分析計を用いてエレクトロスプレーイオン化（ESI：Electrospray ionization) を測定した。実施例３９３〜３９９の化合物の構造とESIの測定値を下記表３に示す。 Example 62 trans-N- (1-Benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxamide, and (Example 63) cis-N- (1- Synthesis of benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxamide N, N-dimethylformamide of the compound (1.50 g) obtained in Reference Example 1 (1) ( 15 mL) in solution 4-amino-1-benzylpiperidine (1.20 g), 1-hydroxybenzotriazole (2.00 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.50 g) And stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (13% ethyl acetate-hexane-10% methanol-chloroform), and trans-N- (1-benzyl) of Example 62 was eluted from the 13% ethyl acetate-hexane eluate. Piperidin-4-yl) -2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxamide (0.77 g) was obtained as a colorless powder. From the eluate of 10% methanol-chloroform, the cis-N of Example 63 was obtained. -(1-Benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxamide (0.94 g) was obtained as a pale yellow powder.
The structures and NMR data of the compounds of Examples 1 to 63 are shown in Table 1 below.
The compounds of Examples 64-399 were obtained by the method shown in Reference Example 1 (1) using the compound obtained in Reference Example 1 (1) or the corresponding substituted benzaldehyde in Reference Example 1 (1) as a raw material. The compound was synthesized from the compound by the method shown in Example 62 and Example 63.
The structures and NMR data of the compounds of Examples 64-327 are also shown in Table 1 below.
For the compounds of Examples 328 to 392, atmospheric pressure chemical ionization (APCI) was measured using a PlatformLC mass spectrometer manufactured by Micromass. The structures of the compounds of Examples 328 to 392 and the measured values of APCI are shown in Table 2 below. For the compounds of Examples 393 to 399, electrospray ionization (ESI) was measured using the same mass spectrometer. The structures of the compounds of Examples 393 to 399 and the measured values of ESI are shown in Table 3 below.

（試験例１）
ヒト由来ＦＡＴＰ４に対する脂肪酸吸収機能阻害作用（アンタゴニスト作用）
試験化合物のＦＡＴＰ４脂肪酸吸収阻害試験は、Ａｎｄｒｅａｓ Ｓｔａｈｌらの方法（Ｍｏｌｅｃｕｌａｒ ｃｅｌｌ １９９９ Ｓｅｐ；４：２９９−３０８）を一部改変して実施した。
ヒト由来ＦＡＴＰ４に対する脂肪酸吸収機能調節作用（アンタゴニスト作用）の決定には、ヒト由来ＦＡＴＰ４を安定発現したＨＥＫ２９３細胞株を用いた。特に記載がない限り、これらのＨＥＫ２９３細胞は１０％ＦＢＳ、１％非必須アミノ酸（ＮＥＡＡ；大日本製薬)を含むＭＥＭ培地（Ｇｉｂｃｏ）を用いて培養した。
試験は平底の９６ウェルＰｏｌｙ−Ｄ−Ｌｙｓｉｎｅ Ｃｏａｔｅｄ Ｍｉｃｒｏｐｌａｔｅｓ（Ｃｏｒｎｉｎｇ）を用いて行った。アッセイ２日前に、ほぼコンフルエントになるまで培養した細胞をＰＢＳを用いてリンスした後、トリプシン（Ｇｉｂｃｏ）を用いて剥がし、遠心操作にて回収した。得られた細胞の数を測定し、３×１０4 cells / wellとなるようにプレートの各ウェルに細胞を播種した。ＣＯ2培養器にて２日間培養後、細胞試験化合物のジメチルスルホキシド（ＤＭＳＯ）溶液ならびに、コントロールとしてＤＭＳＯを、ＤＭＳＯ終濃度０．５％になるように添加した。さらに、それぞれ終濃度２０μＭになるようにＢＯＤＩＰＹ（４，４−ｄｉｆｌｕｏｒｏ−５−ｍｅｔｈｙｌ−４−ｂｏｒａ−３ａ，４ａ− ｄｉａｚａ−s−ｉｎｄａｃｅｎｅ−３−ｄｏｄｅｃａｎｏｉｃ ａｃｉｄ；Ｆｕｎａｋｏｓｈｉ）を、０．１％となるようにＢＳＡ（Ｓｉｇｍａ）を添加して、取り込み反応開始した。反応は室温で行った。
３５分後、０．１％ＢＳＡを含んだＰＢＳで各ウェルを３回洗浄した。その後、各ウェルに０．１％ＳＤＳを含んだ０．５Ｎ ＮａＯＨを添加して１時間振とうして細胞を溶解した。この際の細胞内脂肪酸濃度をＡＲＶＯで測定(Ｅｘ＝４８５ｎｍ，Ｅｍ５１０ｎｍ)した。この結果により、各化合物のアンタゴニスト活性を、ＤＭＳＯのみを添加したウェル（対照群）の脂肪酸取り込み量を１００％として、細胞試験化合物存在化で５０％取り込み量が阻害される化合物濃度（ＩＣ50値）として算出した。
本発明の化合物のＩＣ50値は１００μＭから１０ｎＭであり、下記表４に代表例を示す。
(Test Example 1)
Fatty acid absorption function inhibitory action (antagonist action) on human FATP4
The FATP4 fatty acid absorption inhibition test of the test compound was performed by partially modifying the method of Andrew Stahl et al. (Molecular cell 1999 Sep; 4: 299-308).
HEK293 cell line stably expressing human-derived FATP4 was used for determination of fatty acid absorption function regulating action (antagonist action) on human-derived FATP4. Unless otherwise stated, these HEK293 cells were cultured in MEM medium (Gibco) containing 10% FBS, 1% non-essential amino acids (NEAA; Dainippon Pharmaceutical).
The test was conducted using a flat-bottom 96-well Poly-D-Lysine Coated Microplates (Corning). Two days before the assay, the cells cultured until they became almost confluent were rinsed with PBS, then detached with trypsin (Gibco), and collected by centrifugation. The number of the obtained cells was measured, and the cells were seeded in each well of the plate so as to be 3 × 10 4 cells / well. After culturing in a CO 2 incubator for 2 days, a dimethyl sulfoxide (DMSO) solution of a cell test compound and DMSO as a control were added to a final DMSO concentration of 0.5%. Further, BODIPY (4,4-difluoro-5-methyl-4-bora-3a, 4a-diaza-s-indacene-3-dodecanoic acid; Funakoshi) was adjusted to 0.1% to a final concentration of 20 μM. BSA (Sigma) was added so that the uptake reaction was started. The reaction was performed at room temperature.
After 35 minutes, each well was washed three times with PBS containing 0.1% BSA. Thereafter, 0.5N NaOH containing 0.1% SDS was added to each well and shaken for 1 hour to lyse the cells. The intracellular fatty acid concentration at this time was measured by ARVO (Ex = 485 nm, Em510 nm). Based on this result, the antagonist activity of each compound was determined based on the compound concentration (IC 50 value) at which 50% uptake was inhibited by the presence of the cell test compound, with the fatty acid uptake in the well (control group) added with DMSO alone being 100%. ).
IC 50 values of the compounds of the present invention are 100 μM to 10 nM, and typical examples are shown in Table 4 below.

（試験例２）
脂肪酸吸収阻害作用
本発明化合物の脂肪酸吸収阻害作用を、Ｃ５７/ＢＬ ６Ｎマウスを用いて検討した。雄性Ｃ５７/ＢＬ ６Ｎマウス（８週齢、日本チャールスリバー）に化合物（１５ｍｇ／ｋｇ）と14Ｃ標識脂肪酸（ステアリン酸：室町薬品）を終濃度６０μＭとなるように含んだ２０ｍＭ グリコケノデオキシコール酸ナトリウム（ＧＣＤＣ）溶液を連続的に強制経口投与（５ｍｌ／ｋｇ）した。投与３０分後にイソプロパノール麻酔下にて大腿部を切断し、血液を３００μＬ採取した後、セラクイック（アルフレッサ ファーマ）を用いて遠心分離後、血清を回収した。血清中の脂肪酸濃度を液体シンチレーションカウンターによって測定した。２０ｍＭ ＧＣＤＣ溶液投与群（コントロール群）に対する脂肪酸濃度低下率を算出して、脂肪酸吸収阻害活性とした。実施例３６の化合物は、３７．４％の脂肪吸収阻害活性を示した。 (Test Example 2)
Fatty Acid Absorption Inhibitory Action The fatty acid absorption inhibitory action of the compound of the present invention was examined using C57 / BL 6N mice. Male C57 / BL 6N mice (8 weeks old, Charles River, Japan) containing 20 mM sodium glycochenodeoxycholate containing compound (15 mg / kg) and 14 C-labeled fatty acid (stearic acid: Muromachi Yakuhin) to a final concentration of 60 μM GCDC) solution was continuously administered by oral gavage (5 ml / kg). Thirty minutes after administration, the thigh was cut under anesthesia with isopropanol, and 300 μL of blood was collected, followed by centrifugation using Ceraquik (Alfresa Pharma), and serum was collected. Serum fatty acid concentration was measured with a liquid scintillation counter. The fatty acid concentration decrease rate relative to the 20 mM GCDC solution administration group (control group) was calculated and used as the fatty acid absorption inhibitory activity. The compound of Example 36 showed 37.4% fat absorption inhibitory activity.

本発明の化合物は、優れたＦＡＴＰ４阻害作用を有し、肥満、肥満症、高脂血症、抗ＴＧ血症、脂質代謝異常疾患、糖尿病、動脈硬化症、又は、肥満に起因する高脂血症、抗ＴＧ血症、脂質代謝異常疾患、糖尿病、動脈硬化症、もしくは、高血圧症の治療剤もしくは予防剤として有用である。   The compound of the present invention has an excellent FATP4 inhibitory action, and obesity, obesity, hyperlipidemia, anti-TGemia, dyslipidemia, diabetes, arteriosclerosis, or hyperlipidemia caused by obesity It is useful as a therapeutic or prophylactic agent for symptom, anti-TG disease, dyslipidemia, diabetes, arteriosclerosis, or hypertension.

Claims (3)

下記式（Ｉ）で表されるヘテロ５員環化合物又はその製薬学的に許容される塩。
ただし、式（Ｉ）中、
Ａは−ＣＯ−又は−ＣＨ2−を示し、
Ｘは−ＣＨ2−、−Ｏ−又は−ＮＨ−を示し、
Ｙ及びＷは同一又は異なって、
又は
を示し、
Ｚは−ＣＨ2−、−Ｏ−又は−ＮＨ−を示し、
Ａｒは
又は
を示し、
Ｒ2、Ｒ3及びＲ4は同一又は異なって水素原子、ハロゲン原子で置換されても良い炭素数１〜１２のアルキル基、ハロゲン原子で置換されても良い炭素数１〜１０のアルコキシ基、炭素数１〜６のアルキルチオ基、ハロゲン原子、ニトロ基、シアノ基、メトキシカルボニル基、メチルスルフィニル基、メチルスルホニル基、ジメチルアミノスルホニル基又はトリフルオロメチルスルホニルオキシ基を示し、
Ｒ5はハロゲン原子、ニトロ基又はシアノ基を示し、
Ｒ1は−ＣＯ−ＮＲ6Ｒ7、−ＣＯ2−Ｒ8、−ＮＨＣＯ−Ｒ9、
又は
を示し、
Ｒ6は−（ＣＨ2）ｎ−Ｒ14、炭素数３〜８のシクロアルキル基、炭素数２〜１８のアルケニル基、
又は
を示し、
Ｒ7は水素原子、−（ＣＨ2）ｎ−Ｒ19又はアリル基を示し、
Ｒ8は
又は
を示し、
Ｒ9は
又は
を示し、
Ｒ10、Ｒ11及びＲ12は同一又は異なって、水素原子、塩素原子、メチル基又はメトキシ基を示し、
Ｒ13は炭素数１〜１２のアルキル基、ベンジルオキシカルボニル基、
又は
を示し、
Ｒ14は水素原子、ハロゲン原子、炭素数１〜１０のアルコキシ基、炭素数１〜６のアルキルチオ基、炭素数３〜８のシクロアルキル基、炭素数４〜８のシクロアルケニル基、メトキシカルボニル基、ベンジルオキシカルボニル基、
又は
を示し、
Ｒ15、Ｒ16及びＲ17は同一又は異なって、水素原子、ハロゲン原子、炭素数１〜１２のアルキル基、炭素数１〜１０のアルコキシ基又は炭素数１〜６のアルキルチオ基を示し、
Ｒ18はフェニル基、エトキシカルボニル基、フェネチル基、
又は
を示し、
Ｒ19は水素原子、水酸基、カルバモイル基、メチルアミノカルボニル基、シアノ基、カルボキシル基、メトキシカルボニル基又はアリル基を示し、
Ｒ20、Ｒ21及びＲ22は同一又は異なって、水素原子、ハロゲン原子、ハロゲン原子で置換されても良い炭素数１〜１２のアルキル基、ハロゲン原子で置換されても良い炭素数１〜１０のアルコキシ基、炭素数１〜６のアルキルチオ基、フェニル基又はジメチルアミノ基を示し、
Ｒ23はハロゲン原子、炭素数１〜１２のアルキル基又は炭素数１〜６のアルキルチオ基を示し、
Ｒ24、Ｒ25及びＲ26は同一又は異なって、ハロゲン原子、炭素数１〜１２のアルキル基、炭素数１〜１０のアルコキシ基又はニトロ基を示し、
Ｒ27、Ｒ28及びＲ29は同一又は異なって、水素原子、ハロゲン原子、炭素数１〜１０のアルキル基、炭素数１〜１０のアルコキシ基又はシアノ基を示し、
ｎは１〜２０の整数を示す。 A hetero 5-membered ring compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
However, in formula (I),
A represents —CO— or —CH 2 —;
X represents —CH 2 —, —O— or —NH—;
Y and W are the same or different,
Or
Indicate
Z represents —CH 2 —, —O— or —NH—;
Ar is
Or
Indicate
R 2 , R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom, An alkylthio group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a methoxycarbonyl group, a methylsulfinyl group, a methylsulfonyl group, a dimethylaminosulfonyl group or a trifluoromethylsulfonyloxy group;
R 5 represents a halogen atom, a nitro group or a cyano group,
R 1 is —CO—NR 6 R 7 , —CO 2 —R 8 , —NHCO—R 9 ,
Or
Indicate
R 6 is — (CH 2 ) n—R 14 , a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 18 carbon atoms,
Or
Indicate
R 7 represents a hydrogen atom, — (CH 2 ) n—R 19 or an allyl group,
R 8 is
Or
Indicate
R 9 is
Or
Indicate
R 10 , R 11 and R 12 are the same or different and each represents a hydrogen atom, a chlorine atom, a methyl group or a methoxy group,
R 13 represents an alkyl group having 1 to 12 carbon atoms, a benzyloxycarbonyl group,
Or
Indicate
R 14 is a hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkenyl group having 4 to 8 carbon atoms, or a methoxycarbonyl group. Benzyloxycarbonyl group,
Or
Indicate
R 15 , R 16 and R 17 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or an alkylthio group having 1 to 6 carbon atoms,
R 18 is a phenyl group, an ethoxycarbonyl group, a phenethyl group,
Or
Indicate
R 19 represents a hydrogen atom, a hydroxyl group, a carbamoyl group, a methylaminocarbonyl group, a cyano group, a carboxyl group, a methoxycarbonyl group or an allyl group,
R 20 , R 21 and R 22 are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms which may be substituted with a halogen atom, or 1 to 10 carbon atoms which may be substituted with a halogen atom. An alkoxy group, an alkylthio group having 1 to 6 carbon atoms, a phenyl group or a dimethylamino group,
R 23 represents a halogen atom, an alkyl group having 1 to 12 carbon atoms or an alkylthio group having 1 to 6 carbon atoms,
R 24 , R 25 and R 26 are the same or different and each represents a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a nitro group,
R 27 , R 28 and R 29 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a cyano group,
n shows the integer of 1-20. 下記式（II）で表されるヘテロ５員環化合物又はその製薬学的に許容される塩。

ただし、式（II）中、
Ｒ18は前記請求項１のＲ18と同意義である。Ａｒは
を示す。
ただし、Ｒ2、Ｒ3及びＲ4は前記請求項１のＲ2、Ｒ3及びＲ4とそれぞれ同意義である。 A hetero 5-membered ring compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.

However, in formula (II),
R 18 has the same meaning as R 18 in claim 1. Ar is
Indicates.
However, R 2, R 3 and R 4 are as defined respectively R 2, R 3 and R 4 of claim 1. 下記式（III）で表されるヘテロ５員環化合物又はその製薬学的に許容される塩。

式（III）中、Ｒ13及びＡｒは前記請求項１のＲ13及びＡｒとそれぞれ同意義である。 A hetero 5-membered ring compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof.

In formula (III), R 13 and Ar have the same meanings as R 13 and Ar in claim 1, respectively.
JP2009095659A 2009-04-10 2009-04-10 Heterocyclic 5-membered ring compound Pending JP2012136437A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2009095659A JP2012136437A (en) 2009-04-10 2009-04-10 Heterocyclic 5-membered ring compound
PCT/JP2010/056379 WO2010117040A1 (en) 2009-04-10 2010-04-08 Five-membered heterocyclic compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2009095659A JP2012136437A (en) 2009-04-10 2009-04-10 Heterocyclic 5-membered ring compound

Publications (1)

Publication Number Publication Date
JP2012136437A true JP2012136437A (en) 2012-07-19

Family

ID=42936321

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2009095659A Pending JP2012136437A (en) 2009-04-10 2009-04-10 Heterocyclic 5-membered ring compound

Country Status (2)

Country Link
JP (1) JP2012136437A (en)
WO (1) WO2010117040A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY38184A (en) * 2018-04-17 2019-10-31 Bayer Ag HETEROARYL-TRIAZOLE AND HETEROARYL-TETRAZOLE COMPOUNDS NOVELTY AS PESTICIDES

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1278651A (en) * 1968-03-20 1972-06-21 Mobil Oil Corp Preparation of lactones
JPS5461936A (en) * 1977-10-26 1979-05-18 Ricoh Co Ltd Photoreceptor for electrophotography
JPS62180363A (en) * 1986-02-04 1987-08-07 Konishiroku Photo Ind Co Ltd Method for processing silver halide color photographic sensitive material
JP2006076963A (en) * 2004-09-10 2006-03-23 Fuji Photo Film Co Ltd Compound containing pyrazolidone, silver halide photosensitive material using the same, heat developable photosensitive material and image forming method
CN1807421A (en) * 2006-01-25 2006-07-26 中国科学院上海有机化学研究所 High optical activity chiral phthalide analog compound and synthesis method
WO2008006187A2 (en) * 2006-07-12 2008-01-17 Legeev, Yury V. Protein complexes for prevention and treatment of diseases with angiogenesis disorders
JP2011507910A (en) * 2007-12-21 2011-03-10 ユニバーシティー オブ ロチェスター Methods for changing the lifetime of eukaryotes
CN101284815B (en) * 2008-05-16 2011-04-13 南京工业大学 Pyrazoleoxy acetic acid compounds, preparation method and use

Also Published As

Publication number Publication date
WO2010117040A1 (en) 2010-10-14

Similar Documents

Publication Publication Date Title
CN105764904B (en) Aza-pyridone compounds and uses thereof
RU2709207C2 (en) 1,3,4-oxadiazole derivatives of compound as inhibitor of histone deacetylase 6 and pharmaceutical composition containing same
US7550481B2 (en) Phenylamide and pyridylamide beta-secretase inhibitors for the treatment of Alzheimer's disease
US9643927B1 (en) Process for the preparation of kinase inhibitors and intermediates thereof
EP2739615B1 (en) Phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones and the use thereof as medicament
US10550087B2 (en) Process for the preparation of kinase inhibitors and intermediates thereof
WO2007091396A1 (en) Novel amidopropionic acid derivative and pharmaceutical product containing same
WO2008061109A2 (en) Indazole derivatives useful as melanin concentrating receptor ligands
NO337013B1 (en) New azaibicyclic compounds, processes for their preparation and pharmaceutical compositions containing them
EP1713778A1 (en) Benzazepine derivatives as histamine h3 antagonists
JP6141428B2 (en) Antiproliferative benzo [B] azepin-2-one
JP2013513569A (en) Spiroindole-cyclopropaneindolinone useful as an AMPK modulator
CA2761658C (en) 5-membered heterocyclic compound cyclopenta[c]pyrrolylalkylcarbamate derivatives, preparation thereof, and therapeutic use thereof
JP2001500850A (en) Non-peptide bombesin receptor antagonist
KR100793095B1 (en) Novel Sulfone Amide Derivatives Capable Of Inhibiting BACE
CN101801918A (en) Monoamide derivatives as orexin receptor antagonists
JP5947724B2 (en) New inhibitors of cyclophilin and their use
JP2023516102A (en) 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitors, and pharmaceutical compositions containing the same
WO1997009066A1 (en) Fas LIGAND SOLUBILIZATION INHIBITOR
JP2012136437A (en) Heterocyclic 5-membered ring compound
JP2005179281A (en) Biphenyl compound
WO2006030931A1 (en) N-substituted n-(4-piperidinyl)amide derivative
FR2941947A1 (en) 3-BENZOFURANYL-INDOL-2-ONE 3-DERIVED DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
WO2015163604A1 (en) Oxazolidine-based compound and selective androgen receptor agonist comprising same
FR2941946A1 (en) SUBSTITUTED 3-BENZOFURANYL-INDOL-2-ONE-3-ACETAMIDOPIPERAZINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE