JPWO2005030722A1 - N-substituted-N- (4-piperidinyl) amide derivatives - Google Patents

Abstract

The present invention is represented by the following general formula (I), wherein R1 represents an alkyl group having 1 to 6 carbon atoms, R2 represents a phenyl group or the like, R3 represents a hydrogen atom, an alkoxy having 2 to 8 carbon atoms. Represents a carbonyl group or a methyl group substituted with an alkoxy group having 1 to 6 carbon atoms, R4 represents a phenyl group which may have a substituent, and R5 represents a hydrogen atom or an alkyl having 1 to 6 carbon atoms. R6 represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, a phenyl group, a 5- or 6-membered heterocyclic group, an aralkyl group, or a heterocyclic ring. Represents an alkyl group, R7 represents a hydrogen atom or a methyl group, and m represents 1 or 2.) or a salt thereof, and an analgesic containing this as an active ingredient.

Description

  The present invention relates to an N-substituted-N- (4-piperidinyl) amide derivative or a salt thereof, and an analgesic containing this as an active ingredient.

特許文献４には、次式（Ｂ）、

で表されるＮ−置換−Ｎ−（４−ピペリジニル）アミド誘導体が鎮痛活性を有する薬物として記載されている。
一方、非特許文献１には、次式（Ｃ）、

で表されるＮ−置換−Ｎ−（４−ピペリジニル）アミド誘導体について麻酔作用への応用が検討された旨、記載されている。
また、Ｎ−置換−Ｎ−（４−ピペリジニル）アミド誘導体の代表的化合物であるフェンタニルは麻酔補助薬及び鎮痛薬として臨床上使用されている。これらＮ−置換−Ｎ−（４−ピペリジニル）アミド誘導体の鎮痛作用は、オピオイド受容体の一つであるμ−受容体に対するアゴニスト作用によるものと考えられている。
μ−受容体アゴニストとしては、フェンタニル等のＮ−置換−Ｎ−（４−ピペリジニル）アミド誘導体のほかにモルヒネがよく知られている。しかしながら、これらの薬物は依存性、徐脈、呼吸抑制、消化管運動抑制等の副作用があり、副作用を軽減した新たな鎮痛剤の提供が求められている。
かかる副作用の軽減を目的として、本発明者らは先にＮ−置換−Ｎ−（４−ピペリジニル）アミド誘導体に関する特許出願（ＷＯ ０３／０８２８１９（以下、特許文献５という。））を行っている。
本発明化合物のＮ−置換−Ｎ−（４−ピペリジニル）アミド誘導体は、ピペリジンの１位はアルキル基で置換されているが、このアルキル基の末端の炭素原子にはフェニル基及びカルバモイル基が結合している。一方、ピペリジンの１位のアルキル基に関し、上記式（Ａ）では末端の炭素原子はフェニル基のみで置換されており、式（Ｂ）ではメトキシカルボニル基のみで置換されており、上記式（Ｃ）では末端の炭素原子はフェニル基とカルボキシル基（又はエトキシカルボニル基）で置換されており、従って、本発明化合物とこれらの化合物とは構造上、明確に相違する。尚、上記特許文献５では、本発明化合物のＮＲ^５Ｒ^６（アミン）に相当する部分がアミノ酸残基である。N-substituted-N- (4-piperidinyl) amide derivatives are disclosed in JP-A No. 51-115478 (hereinafter referred to as Patent Document 1), JP-A No. 53-149980 (hereinafter referred to as Patent Document 2), and the like. Japanese Laid-Open Patent Publication No. 2-292279 (hereinafter referred to as Patent Document 3), Japanese Patent Laid-Open No. 2-330017 (hereinafter referred to as Patent Document 4), or Zhonggu Yaoke Daxue Xuebao 1993, 24, p257-263 (hereinafter referred to as Non-patent). Many compounds have been reported in the literature 1), etc., and it is known that they have analgesic action and anesthetic action.
For example, Patent Document 1 includes the following formula (A),

In Patent Document 4, the following formula (B),

N-substituted-N- (4-piperidinyl) amide derivatives represented by the formula are described as drugs having analgesic activity.
On the other hand, Non-Patent Document 1 includes the following formula (C),

The N-substituted-N- (4-piperidinyl) amide derivative represented by the formula is described as having been studied for anesthetic action.
In addition, fentanyl, which is a representative compound of N-substituted-N- (4-piperidinyl) amide derivatives, is clinically used as an anesthetic aid and analgesic. The analgesic action of these N-substituted-N- (4-piperidinyl) amide derivatives is considered to be due to an agonistic action on μ-receptor, which is one of opioid receptors.
In addition to N-substituted-N- (4-piperidinyl) amide derivatives such as fentanyl, morphine is well known as a μ-receptor agonist. However, these drugs have side effects such as dependence, bradycardia, respiratory depression, and gastrointestinal motility inhibition, and there is a need to provide new analgesics with reduced side effects.
In order to reduce such side effects, the present inventors have previously filed a patent application (WO 03/082819 (hereinafter referred to as Patent Document 5)) relating to an N-substituted-N- (4-piperidinyl) amide derivative. .
In the N-substituted-N- (4-piperidinyl) amide derivative of the compound of the present invention, the 1-position of piperidine is substituted with an alkyl group, and a phenyl group and a carbamoyl group are bonded to the terminal carbon atom of the alkyl group. is doing. On the other hand, regarding the alkyl group at the 1-position of piperidine, in the above formula (A), the terminal carbon atom is substituted only with a phenyl group, and in formula (B), only the methoxycarbonyl group is substituted. ), The terminal carbon atom is substituted with a phenyl group and a carboxyl group (or ethoxycarbonyl group). Therefore, the compound of the present invention and these compounds are clearly different in structure. In Patent Document 5, the moiety corresponding to NR ⁵ R ⁶ (amine) of the compound of the present invention is an amino acid residue.

（式中、Ｒ^１は炭素数１〜６のアルキル基、３〜７員環のシクロアルキル基、炭素数１〜６のアルコキシ基で置換された炭素数１〜６のアルキル基、又は５若しくは６員環の複素環基を表し、
Ｒ^２は置換基としてハロゲン原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシ基、又はハロゲン原子で置換された炭素数１〜６のアルキル基から選択された基若しくは原子を１〜３個有していても良いフェニル基又は５若しくは６員環の複素環基を表し、
Ｒ^３は水素原子、フェニル基、炭素数２〜８のアルコキシカルボニル基、又は炭素数１〜６のアルコキシ基で置換されたメチル基を表し、
Ｒ^４は置換基としてハロゲン原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシ基、ハロゲン原子で置換された炭素数１〜６のアルキル基、ニトロ基、シアノ基、又はアミノ基から選択された基若しくは原子を１〜３個有していても良いフェニル基を表し、
Ｒ^５は水素原子、炭素数１〜６のアルキル基又はアラルキル基（アルキル部分の炭素数は１〜６で、アリール部分の炭素数は６〜１０）を表し、
Ｒ^６は水素原子、炭素数１〜６のアルキル基、フェニル基、５若しくは６員環の複素環基、アラルキル基（アルキル部分の炭素数は１〜６で、アリール部分の炭素数は６〜１０）、又は複素環アルキル基（アルキル部分の炭素数は１〜６で、複素環は５若しくは６員環で、ベンゼン環と縮環していても良い。）を表す。
ここで、炭素数１〜６のアルキル基は、ハロゲン原子、３〜７員環のシクロアルキル基、炭素数１〜６のアルコキシ基、アミノ基、アルキルアミノ基（アルキル部分の炭素数は１〜６）、ジアルキルアミノ基（各アルキル部分の炭素数は１〜６）、炭素数２〜６のアシルアミノ基、カルバモイル基、アルキルカルバモイル基（アルキル部分の炭素数１〜６）、ジアルキルカルバモイル（各アルキル部分の炭素数は１〜６）、ヒドロキシル基、ニトロ基、又はシアノ基から選ばれる基若しくは原子を置換基として１〜５個有していても良い。
またフェニル基、複素環基、アラルキル基のアリール部分及び複素環アルキルの複素環部分（複素環がベンゼン環と縮環している場合にはそのベンゼン環を含む）は、ハロゲン原子、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシ基、ハロゲン原子で置換された炭素数１〜６のアルキル基、アミノ基、アルキルアミノ基（アルキル部分の炭素数は１〜６）、ジアルキルアミノ基（各アルキル部分の炭素数は１〜６）、炭素数２〜６のアシルアミノ基、カルバモイル基、アルキルカルバモイル基（アルキル部分の炭素数１〜６）、ジアルキルカルバモイル（各アルキル部分の炭素数は１〜６）、ヒドロキシル基、ヒドロキシメチル基、ニトロ基、又はシアノ基から選ばれる基若しくは原子を置換基として１〜５個有していても良い。
さらにＲ^６は、Ｒ^５並びにＲ^５及びＲ^６が結合している窒素原子と共に５〜７員環の複素環（環構成原子として、Ｒ^５及びＲ^６が結合している窒素原子以外に更に別の窒素原子、酸素原子、又は硫黄原子を含んでいても良い。またこの複素環は炭素数１〜６のアルキル基、アラルキル基（アルキル部分の炭素数は１〜６で、アリール部分の炭素数は６〜１０）又は炭素数２〜６のアシル基で置換されていても良い。）を形成しても良く、
Ｒ^７は水素原子又はメチル基を表し、
そして、ｍは１又は２を表す。）
また、本発明は上記一般式（Ｉ）で表される化合物、又はその塩を有効成分として含有する鎮痛剤に関する。An object of the present invention is to provide a novel N-substituted-N- (4-piperidinyl) amide derivative or a salt thereof having analgesic action.
That is, the present invention relates to a compound represented by the following general formula (I) or a salt thereof.

(In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 members, a C ¹ to C 6 alkyl group substituted with an alkoxy group having 1 to 6 carbon atoms, or 5 or Represents a 6-membered heterocyclic group,
R ² represents a substituent or a group or atom selected from a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. Represents a phenyl group or a 5- or 6-membered heterocyclic group which may have 1 to 3,
R ³ represents a hydrogen atom, a phenyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, or a methyl group substituted with an alkoxy group having 1 to 6 carbon atoms,
R ⁴ is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group substituted with a halogen atom, a nitro group, a cyano group, or amino as a substituent. Represents a phenyl group optionally having 1 to 3 groups or atoms selected from the group;
R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aralkyl group (the alkyl portion has 1 to 6 carbon atoms and the aryl portion has 6 to 10 carbon atoms);
R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a 5- or 6-membered heterocyclic group, and an aralkyl group (the alkyl portion has 1 to 6 carbon atoms and the aryl portion has 6 to 6 carbon atoms). 10), or a heterocyclic alkyl group (the alkyl moiety has 1 to 6 carbon atoms, the heterocyclic ring is a 5- or 6-membered ring, and may be condensed with a benzene ring).
Here, the alkyl group having 1 to 6 carbon atoms is a halogen atom, a 3- to 7-membered cycloalkyl group, an alkoxy group having 1 to 6 carbon atoms, an amino group, or an alkylamino group (the carbon number of the alkyl moiety is 1 to 6). 6), a dialkylamino group (wherein each alkyl moiety has 1 to 6 carbon atoms), an acylamino group having 2 to 6 carbon atoms, a carbamoyl group, an alkylcarbamoyl group (wherein the alkyl moiety has 1 to 6 carbon atoms), a dialkylcarbamoyl (each alkyl The portion may have 1 to 5 carbon atoms as a substituent, or a group or atom selected from 1 to 6), a hydroxyl group, a nitro group, or a cyano group.
In addition, a phenyl group, a heterocyclic group, an aryl part of an aralkyl group, and a heterocyclic part of a heterocyclic alkyl (including a benzene ring when the heterocyclic ring is condensed with a benzene ring) are a halogen atom, carbon number 1 Alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, amino group, alkylamino group (the alkyl moiety has 1 to 6 carbon atoms), dialkylamino Group (carbon number of each alkyl part is 1-6), acylamino group having 2-6 carbon atoms, carbamoyl group, alkylcarbamoyl group (carbon number of 1-6 of alkyl part), dialkylcarbamoyl (carbon number of each alkyl part is 1 to 6), 1 to 5 groups or atoms selected from hydroxyl group, hydroxymethyl group, nitro group, or cyano group may be substituted.
Further ^{R 6} are the heterocyclic (ring constituting atoms 5- to 7-membered ring together with the nitrogen atom ^{to which R 5} and ^{R 5} and ^{R 6} are attached, further in addition to the nitrogen atom ^{to which R 5} and ^{R 6} are attached This heterocycle may contain an alkyl group having 1 to 6 carbon atoms or an aralkyl group (the alkyl portion has 1 to 6 carbon atoms, and the carbon of the aryl portion). The number may be substituted with 6 to 10) or an acyl group having 2 to 6 carbon atoms).
R ⁷ represents a hydrogen atom or a methyl group,
And m represents 1 or 2. )
Moreover, this invention relates to the analgesic containing the compound represented by the said general formula (I), or its salt as an active ingredient.

（式中、Ｒ^８はベンジル基、又は炭素数１〜６のアルキル基（分枝可）を表し、Ｚは塩素原子、臭素原子、ヨウ素原子、メシルオキシ基、又はトシルオキシ基等の脱離基を表し、そしてＲ^１，Ｒ^２，Ｒ^３，Ｒ^４，Ｒ^５，Ｒ^６，Ｒ^７及びｍは前記と同じ。）
１）出発原料（ａ）は、公知の方法（Ｐ．Ｇ．Ｈ．Ｖａｎ Ｄａｅｌｅ ｅｔ ａｌ．，Ａｒｚｎｅｕｍ．−Ｆｏｒｓｃｈ．Ｄｒｕｇ Ｒｅｓ．，１９７６，２６，１５２１、Ｄ．Ｌ．Ｆｅｌｄｍａｎ ａｎｄ Ｍ．Ｆ．Ｊ．Ｂｒａｃｋｅｅｎ，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９０，５５，４２０７、Ｌ．Ｖ．Ｋｕｄｚｍａ ｅｔ ａｌ．，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９８９，３２，２５３４など）、及びそれらに準じる方法により合成することができる。
２）第１工程
（１）アセトニトリル等の反応に関与しない溶媒中、室温〜８０℃で、出発原料（ａ）とα、β−不飽和エステル（ｂ）とのＭｉｃｈａｅｌ反応により一般式（ｄ）の化合物を合成できる（ｍ＝１の場合）。
（２）アセトニトリル、４−メチル−２−ペンタノン、Ｎ，Ｎ−ジメチルホルムアミド等の反応に関与しない溶媒中、炭酸ナトリウム、炭酸カリウム又はトリエチルアミン等の塩基存在下、出発原料（ａ）と一般式（ｃ）で表される化合物との反応により一般式（ｄ）の化合物を合成できる（ｍ＝１，２の場合）。反応温度は室温〜１５０℃である。なお、一般式（ｃ）で表される化合物で、Ｚが塩素原子または臭素原子である場合には、ヨウ化ナトリウムまたはヨウ化カリウムを共存させることが好ましい。
３）第２工程
脱保護（−Ｒ^８）は、Ｒ^８がベンジル基の場合にはメタノール、エタノール等の溶媒中パラジウム−炭素等を触媒とした接触還元により行われ、Ｒ^８がｔ−ブチル基の場合にはトリフルオロ酢酸等による酸処理により行われる。Ｒ^８がｔ−ブチル基以外の炭素数１〜６のアルキル基の場合には、メタノール、エタノール、テトラヒドロフラン等の水と混和する有機溶媒と水との混合溶媒中、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の強塩基を作用させることにより脱保護（−Ｒ^８）が行われる。この場合の反応温度は０〜６０℃である。また、脱保護（−Ｒ^８）には塩酸等による通常の酸加水分解反応を適用することもできる。この場合の反応温度は、２０〜１２０℃である。
４）第３工程
一般式（ｅ）の化合物とアミン（ｆ）との縮合反応は、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド等の反応に関与しない溶媒中、１−ヒドロキシベンゾトリアゾール、Ｎ−ヒドロキシコハク酸イミド等の添加剤存在下、または非存在下に、Ｎ，Ｎ′−ジシクロヘキシルカルボジイミド、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩等の縮合剤を用いて行われる。反応温度は０〜６０℃である。縮合剤が１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩の場合やアミン（ｆ）が塩酸塩等の塩である場合には、トリエチルアミン、Ｎ−メチルモルホリン等の塩基を共存させる。
また、本発明化合物の中間原料である化合物（ｄ）は下記のＢ法によっても製造することができる。

（式中、Ｒ^１，Ｒ^２，Ｒ^３，Ｒ^４，Ｒ^５，Ｒ^６，Ｒ^７、Ｒ^８、ｍ及びＺは前記と同じ。）
１）出発原料（ｈ）は、公知の方法（Ｚ−Ｘ．Ｗａｎｇ ｅｔ ａｌ，Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９５，３８，３６５２など）及びそれらに準じる方法により合成することができる。
２）第１工程
出発原料（ｈ）を一般式（ｂ）または（ｃ）で表される化合物と上記Ａ法における第１工程と同様にして反応させることにより、一般式（ｉ）の化合物を合成できる。
３）第２工程
一般式（ｉ）のアシル化反応は、ジクロロメタン、クロロホルム、トルエン等の反応に関与しない溶媒中、トリエチルアミン、Ｎ−メチルモルホリン等の塩基存在下に、一般式（ｊ）で表される酸クロリドを反応させることにより行われる。この場合、反応温度は室温〜溶媒の還流温度である。また、一般式（ｉ）のアシル化反応は、一般式（ｋ）で表される酸無水物を用いて、トルエン等の反応に関与しない溶媒の存在下または非存在下に、５０〜１５０℃の温度で行うこともできる。
かくして得られた本発明化合物の代表化合物例を次に示す。
本発明の代表化合物例
（１）上記一般式（Ｉ）で、Ｒ^２＝フェニル基（置換基はＹ）、Ｒ^３＝メトキシカルボニル基、Ｒ^４＝フェニル基（置換基はＷ）及びＲ^７＝Ｈである次式で表される本発明化合物。

（２）上記一般式（Ｉ）で、Ｒ^３＝メトキシカルボニル基、Ｒ^４＝フェニル基及びＲ^７＝Ｈである次式で表される本発明化合物。

（３）上記一般式（Ｉ）で、Ｒ^２＝フェニル基（置換基はＹ）、Ｒ^３＝メトキシカルボニル基、Ｒ^４＝フェニル基及びＲ^７＝Ｈである次式で表される本発明化合物。

（４）上記一般式（Ｉ）で、Ｒ^２＝フェニル基（置換基はＹ）、Ｒ^４＝フェニル基、Ｒ^６＝（ＣＨ_２）ｎ−Ｒ^９、Ｒ^７＝Ｈ及びｍ＝１である次式で表される本発明化合物。

（５）上記一般式（Ｉ）で、Ｒ^３＝メトキシカルボニル基、Ｒ^４＝フェニル基、Ｒ^６＝（ＣＨ_２）ｎ−Ｒ^９及びｍ＝１である次式で表される本発明化合物。

（６）上記一般式（Ｉ）で、Ｒ^３＝Ｈ、Ｒ^４＝フェニル基、Ｒ^６＝（ＣＨ_２）ｎ−Ｒ^９、Ｒ^７＝Ｍｅ及びｍ＝１である次式で表される本発明化合物。

次に本発明の薬理実験について述べる。
本発明化合物について、［^３Ｈ］ＤＡＭＧＯを用いた結合実験によるμ−受容体に対する親和性及び酢酸ライジング試験による鎮痛作用に関する薬理実験を行ったところ、後記実施例５２記載のように本発明化合物はμ−受容体に対する優れた結合親和性並びに優れた鎮痛作用を有することが明らかになった。（表１４，１５参照）
さらに酢酸ライジング試験による鎮痛作用について、末梢性及び中枢（全身）性μ−オピオイド受容体アンタゴニストによる拮抗試験を行ったところ、後記実施例１，１１、３１及び４６記載の本発明化合物の鎮痛作用は末梢性であることが明らかになった。（表１６）
従って、上記一般式（Ｉ）で表される本発明化合物は、優れた鎮痛作用を有することから、鎮痛剤として有用である。
特に本発明化合物のうち末梢のμ−受容体に選択的に作用する薬物は、中枢性の作用に基づく副作用（依存性等）がない鎮痛剤として期待される。
本発明化合物は、ヒトに対して経口投与により、又は非経口投与により投与することができる。
製剤化するためには、製剤の技術分野における錠剤、カプセル剤、散剤、注射剤、坐薬、又は経皮剤等の剤型に製造することができる。
投与量は通常成人においては、本発明化合物を経口剤の場合には１日約０．０１ｍｇ〜１０００ｍｇを、注射剤の場合には約０．００１ｍｇ〜１００ｍｇであるが、年齢、症状等により増減することができる。
次に、参考例及び実施例を挙げ本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。Next, the present invention will be described in detail.
In the general formula (I), R ¹ is an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, or a pentyl group ( Preferably, it is an ethyl group.), A cyclopropyl group, a cyclopentyl group, a cyclohexyl group or other 3- to 7-membered cycloalkyl group (preferably a cyclopropyl group), a methoxy group, an ethoxy group, a propyloxy group, isopropyl Methyl group, ethyl group, propyl group, isopropyl group, butyl group, i, substituted with an alkoxy group having 1 to 6 carbon atoms such as oxy group, butyloxy group, i-butyloxy group, t-butyloxy group or pentyloxy group An alkyl group having 1 to 6 carbon atoms such as a butyl group, a t-butyl group, or a pentyl group (for example, ethoxyethyl group or A methoxymethyl group, preferably a methoxymethyl group), or a 5- or 6-membered heterocyclic group such as a furyl group, a thiazolyl group or a thienyl group (preferably a furyl group or a thienyl group). .
R ² is a phenyl group that may have 1 to 3 substituents, or a 5- or 6-membered heterocyclic group such as a pyridyl group, a pyrazinyl group, a pyrimidyl group, or a pyrazole group (preferably a pyridyl group or Pyrazinyl group.).
Examples of preferred substituents for phenyl group and heterocyclic group include halogen atom such as fluorine atom, chlorine atom or bromine atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl. Group or carbon having 1 to 6 carbon atoms such as pentyl group, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, i-butyloxy group, t-butyloxy group, or pentyloxy group A methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group substituted with an alkoxy group of 1 to 6 or a halogen atom such as 1 to 3 fluorine atoms, bromine atoms or chlorine atoms; C1-C6 alkyl groups such as t-butyl group or pentyl group (trifluoromethyl group, chloromethyl group, 2 Chloroethyl group, 2-bromoethyl group, or 2-fluoroethyl group, etc.) and the like, more preferably a fluorine atom, a chlorine atom, a methyl group, a methoxy group, and a trifluoromethyl group.
R ³ is a hydrogen atom, a phenyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms such as a methoxycarbonyl group or an ethoxycarbonyl group, or a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, or an i-butyloxy group. , A t-butyloxy group, or a methyl group (such as a methoxymethyl group) substituted with an alkoxy group having 1 to 6 carbon atoms such as a pentyl group oxy, more preferably a methoxycarbonyl group or a methoxymethyl group.
R ⁴ includes a phenyl group which may have 1 to 3 substituents.
Examples of such substituents include halogen atoms such as fluorine atom, chlorine atom or bromine atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl group, or pentyl group. Alkoxy groups having 1 to 6 carbon atoms, methoxy groups, ethoxy groups, propyloxy groups, isopropyloxy groups, butyloxy groups, i-butyloxy groups, t-butyloxy groups, pentyloxy groups, and other alkoxy groups having 1 to 6 carbon atoms , A methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, or a pentyl group substituted with 1 to 3 fluorine atoms, a bromine atom or a halogen atom such as a chlorine atom An alkyl group having 1 to 6 carbon atoms such as trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2-bromoe Group, or the like 2-fluoroethyl group), a nitro group, a cyano group, and a amino group.
R ⁵ is a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl group, aralkyl such as a benzyl group or an alkyl group having 1 to 6 carbon atoms such as a pentyl group. Group (the carbon number of the alkyl moiety is 1 to 6 and the carbon number of the aryl moiety is 6 to 10), more preferably a hydrogen atom, a methyl group or an ethyl group.
R ⁶ is a hydrogen atom, or a methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group or hexyl group which may have 1 to 5 substituents. A C1-C6 alkyl group such as a group, a phenyl group, a furyl group, a thienyl group, a pyrrolyl group, a pyridyl group or a tetrahydropyranyl group such as a 5- or 6-membered heterocyclic group, a benzyl group, a phenethyl group, 3- Aralkyl groups such as phenylpropyl group or 2-naphthylethyl group (the alkyl moiety has 1 to 6 carbon atoms and the aryl moiety has 6 to 10 carbon atoms), or a 2- (2-pyridyl) ethyl group, (3- Thienyl) methyl group, 2- (2-thienyl) ethyl group, 3- (2-thienyl) propyl group, 2- (1H-pyrrol-1-yl) ethyl group, 2- (1H-imidazole) -4-yl) ethyl group, (1H-indol-2-yl) methyl group, 2- (1H-indol-2-yl) ethyl group, 2- (1H-indol-3-yl) ethyl group, 3- Heterocyclic alkyl groups such as (1H-indol-3-yl) propyl group, 2- (1H-benzimidazol-2-yl) ethyl group, 2- (benzo [b] thiophen-3-yl) ethyl group (alkyl The number of carbons in the moiety is 1 to 6, and the heterocyclic ring is a 5- or 6-membered ring, which may be condensed with a benzene ring.), Preferably an aralkyl group which may have a substituent or Heterocyclic alkyl groups are exemplified.
Here, examples of the substituent that the alkyl group having 1 to 6 carbon atoms may have include a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom, and a 3- to 7-membered cyclohexane such as a cyclopropyl group. C1-C6 alkoxy group such as alkyl group, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, i-butyloxy group, t-butyloxy group, or pentyloxy group, amino group, methylamino An alkylamino group such as a group (the carbon number of the alkyl portion is 1 to 6), a dialkylamino group such as a dimethylamino group (the carbon number of each alkyl portion is 1 to 6), and a carbon number of 2 to 6 such as an acetylamino group Alkylcarbamoyl groups such as acylamino group, carbamoyl group, N-methylcarbamoyl group (C1-C6 of alkyl portion), N, N-dimethyl Rubamoiru dialkylcarbamoyl groups such as (number of carbon atoms in each alkyl moiety 1-6), a hydroxyl group, a nitro group, or a cyano group.
On the other hand, a phenyl group, a heterocyclic group, an aryl part of an aralkyl group, and a heterocyclic part of a heterocyclic alkyl (including a benzene ring when the heterocyclic ring is condensed with a benzene ring) may be included. Examples of substituents include halogen atoms such as fluorine atom, chlorine atom or bromine atom, carbon such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl group or pentyl group. An alkoxy group having 1 to 6 carbon atoms such as an alkyl group having 1 to 6 carbon atoms, a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an i-butyloxy group, a t-butyloxy group, or a pentyloxy group; Methyl, ethyl, propyl, isopropyl substituted with 1 to 3 fluorine atoms, bromine atoms or halogen atoms such as chlorine atoms , A butyl group, an i-butyl group, a t-butyl group, or a pentyl group, such as an alkyl group having 1 to 6 carbon atoms (trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2-bromoethyl group, or 2- A fluoroethyl group, etc.), an amino group, an alkylamino group such as a methylamino group (the carbon number of the alkyl moiety is 1-6), a dialkylamino group such as a dimethylamino group (the carbon number of each alkyl moiety is 1-6), C2-C6 acylamino group such as acetylamino group, carbamoyl group, alkylcarbamoyl group such as N-methylcarbamoyl group (C1-C6 of alkyl moiety), dialkylcarbamoyl group such as N, N-dimethylcarbamoyl group (The number of carbon atoms in each alkyl moiety is 1 to 6), a hydroxyl group, a hydroxymethyl group, a nitro group, or a cyano group.
The R ⁶ may piperidine ring together with the nitrogen atom to which R ⁵ and R ⁵ and R ⁶ are attached, a morpholine ring, may form a heterocyclic ring of 5 to 7-membered ring such as thiomorpholine ring or piperazine ring.
This heterocyclic ring is an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, or a pentyl group, and an aralkyl group such as a benzyl group. (The carbon number of the alkyl part is 1-6, the carbon number of the aryl part is 6-10), or may be substituted with an acyl group having 2-6 carbon atoms such as an acetyl group.
R ⁷ includes a hydrogen atom or a methyl group.
And m is 1 or 2, and is preferably 1.
(1) As the present compound represented by the general formula R ³ is a methyl group substituted with an alkoxycarbonyl group or an alkoxy group having 1 to 6 carbon atoms having 2 to 8 carbon atoms (I) A compound or a salt thereof is preferred.
(2) As the present invention compounds, R ⁷ is a compound or a salt thereof represented by the general formula and R ³ a methyl group is an alkoxycarbonyl group of which a hydrogen atom or 2 to 8 carbon atoms (I) preferable.
(3) As the present invention compounds, R ² is a halogen atom as a substituent, an alkyl group having 1 to 6 carbon atoms, carbon atoms substituted alkoxy group having 1 to 6 carbon atoms, or a halogen atom 1-6 A compound represented by the above general formula (I) or a compound represented by the above (1) or (2), which is a phenyl group optionally having 1 to 3 atoms or a group selected from alkyl groups Or its salt is preferable.
(4) As the compound of the present invention, R ² is a halogen atom as a substituent, an alkyl group having 1 to 6 carbon atoms, carbon atoms substituted alkoxy group having 1 to 6 carbon atoms, or a halogen atom 1-6 A compound represented by the above general formula (I), which is a 5- or 6-membered heterocyclic group optionally having 1 to 3 groups or atoms selected from the above alkyl group, or (1) or ( The compound represented by 2) or a salt thereof is preferred.
(5) As the present invention compounds is a group heterocyclic group R ² is selected pyridyl group, pyrazinyl group, pyrimidyl group, pyrazole group, the substituent of the heterocyclic ring a halogen atom, a carbon number 1 to 6 A compound represented by the above general formula (I), a compound represented by the above (1) or (2) or a salt thereof, which is a group or atom selected from the above alkyl groups, is preferable.
(6) As the present invention compounds, R ⁶ is an aralkyl group (the number of carbon atoms in the alkyl moiety is 1 to 6, carbon atoms 6-10 aryl moiety) carbon atoms or a heterocyclic alkyl group (the alkyl moiety 1 to 6 and the heterocyclic ring is a 5- or 6-membered ring and may be condensed with a benzene ring.) Or a compound represented by the above general formula (I) or (1) to (5) A compound represented by any of the above or a salt thereof is preferable.
Here, the aryl part of the aralkyl group and the heterocyclic part of the heterocyclic alkyl (including the benzene ring when the heterocyclic ring is condensed with the benzene ring) are a halogen atom, an alkyl group having 1 to 6 carbon atoms. , An alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, an amino group, an alkylamino group (the alkyl moiety has 1 to 6 carbon atoms), a dialkylamino group (each alkyl moiety) 1-6), an acylamino group having 2-6 carbon atoms, a carbamoyl group, an alkylcarbamoyl group (1-6 carbon atoms in the alkyl moiety), a dialkylcarbamoyl (1-6 carbon atoms in each alkyl moiety), It may have 1 to 5 groups or atoms selected from a hydroxyl group, a hydroxymethyl group, a nitro group, or a cyano group as a substituent.
(7) Moreover, as this invention compound, the compound represented by the said general formula (I) whose m is 1, the compound represented by either of said (1)-(6), or its salt is preferable.
The compound of the present invention represented by the general formula (I) may have diastereomers, optical isomers and the like, and these isomers are also included in the present invention.
Furthermore, the compounds of the present invention include pharmaceutically acceptable salts such as salts with inorganic acids such as hydrochloric acid or sulfuric acid, or organic acids such as oxalic acid, citric acid or tartaric acid.
Next, the manufacturing method of general formula (I) which is this invention compound is described. The inventive compound of the general formula (I) is produced by the following method A.

(In the formula, R ⁸ represents a benzyl group or an alkyl group having 1 to 6 carbon atoms (branched), and Z represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a mesyloxy group, or a tosyloxy group. And R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and m are the same as above.)
1) The starting material (a) is prepared according to a known method (PGH Van Daele et al., Arzneum.-Forsch. Drug Res., 1976, 26, 1521, DL Feldman and MF. J. Brackenen, J. Org. Chem., 1990, 55, 4207, LV Kudzma et al., J. Med. Chem., 1989, 32, 2534 and the like, and the like. Can do.
2) First step (1) The reaction is carried out by the Michael reaction of the starting material (a) with the α, β-unsaturated ester (b) at room temperature to 80 ° C. in a solvent not involved in the reaction such as acetonitrile. Can be synthesized (when m = 1).
(2) The starting material (a) and the general formula (a) in the presence of a base such as sodium carbonate, potassium carbonate or triethylamine in a solvent not involved in the reaction such as acetonitrile, 4-methyl-2-pentanone, N, N-dimethylformamide The compound of the general formula (d) can be synthesized by the reaction with the compound represented by c) (when m = 1, 2). The reaction temperature is from room temperature to 150 ° C. In the compound represented by the general formula (c), when Z is a chlorine atom or a bromine atom, it is preferable that sodium iodide or potassium iodide coexist.
3) The second step deprotection (-R ⁸ ) is carried out by catalytic reduction using palladium-carbon as a catalyst in a solvent such as methanol and ethanol when R ⁸ is a benzyl group, and R ⁸ is t-butyl. In the case of a group, it is carried out by acid treatment with trifluoroacetic acid or the like. When R ⁸ is an alkyl group having 1 to 6 carbon atoms other than the t-butyl group, lithium hydroxide, sodium hydroxide in a mixed solvent of water and an organic solvent miscible with water such as methanol, ethanol, tetrahydrofuran and the like. Deprotection (-R ⁸ ) is performed by the action of a strong base such as potassium hydroxide. The reaction temperature in this case is 0-60 ° C. Also, the deprotection (-R ⁸⁾ may be applied conventional acid hydrolysis with hydrochloric acid or the like. The reaction temperature in this case is 20 to 120 ° C.
4) Third step The condensation reaction of the compound of the general formula (e) and the amine (f) is carried out by using 1-hydroxybenzotriazole, N-hydroxysuccinate in a solvent not involved in the reaction such as dichloromethane and N, N-dimethylformamide. The reaction is carried out using a condensing agent such as N, N′-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in the presence or absence of an additive such as acid imide. The reaction temperature is 0-60 ° C. When the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or when amine (f) is a salt such as hydrochloride, a base such as triethylamine or N-methylmorpholine is allowed to coexist. .
Moreover, the compound (d) which is an intermediate raw material of this invention compound can be manufactured also by the following B method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , m and Z are the same as above.)
1) The starting material (h) can be synthesized by a known method (ZX Wang et al, J. Med. Chem., 1995, 38, 3652, etc.) and a method analogous thereto.
2) The first step starting material (h) is reacted with the compound represented by the general formula (b) or (c) in the same manner as in the first step in the above-mentioned method A, thereby converting the compound of the general formula (i) Can be synthesized.
3) Step 2 The acylation reaction of the general formula (i) is represented by the general formula (j) in the presence of a base such as triethylamine or N-methylmorpholine in a solvent not involved in the reaction such as dichloromethane, chloroform and toluene. By reacting the acid chloride. In this case, the reaction temperature is from room temperature to the reflux temperature of the solvent. In addition, the acylation reaction of the general formula (i) is carried out using an acid anhydride represented by the general formula (k) in the presence or absence of a solvent that does not participate in the reaction, such as toluene, at 50 to 150 ° C. It can also be carried out at a temperature of
Examples of representative compounds of the compound of the present invention thus obtained are shown below.
Representative compound examples of the present invention (1) In the above general formula (I), R ² = phenyl group (substituent is Y), R ³ = methoxycarbonyl group, R ⁴ = phenyl group (substituent is W) and R ⁷ The compound of the present invention represented by the following formula:

(2) The compound of the present invention represented by the following formula in which R ³ = methoxycarbonyl group, R ⁴ = phenyl group and R ⁷ = H in the above general formula (I).

(3) The present invention represented by the following formula where R ² = phenyl group (substituent is Y), R ³ = methoxycarbonyl group, R ⁴ = phenyl group and R ⁷ = H in the above general formula (I) Compound.

(4) In the above general formula (I), R ² = phenyl group (substituent is Y), R ⁴ = phenyl group, R ⁶ = (CH ₂ ) n-R ⁹ , R ⁷ = H and m = 1 A compound of the present invention represented by the following formula:

(5) The compound of the present invention represented by the following formula in which R ³ = methoxycarbonyl group, R ⁴ = phenyl group, R ⁶ = (CH ₂ ) n-R ⁹ and m = 1 in the above general formula (I) .

(6) In the above general formula (I), R ³ = H, R ⁴ = phenyl group, R ⁶ = (CH ₂ ) n-R ⁹ , R ⁷ = Me and m = 1 The compound of the present invention.

Next, the pharmacological experiment of the present invention will be described.
When the compound of the present invention was subjected to a pharmacological experiment on the affinity to μ-receptor by the binding experiment using [ ³ H] DAMGO and the analgesic action by the acetic acid rising test, the compound of the present invention was as described in Example 52 below. It has been shown that it has an excellent binding affinity for the μ-receptor as well as an excellent analgesic action. (See Tables 14 and 15)
Further, as for the analgesic action by the acetic acid rising test, an antagonistic test using peripheral and central (systemic) μ-opioid receptor antagonists was conducted, and the analgesic action of the compounds of the present invention described in Examples 1, 11, 31 and 46 described later was It was revealed to be peripheral. (Table 16)
Therefore, the compound of the present invention represented by the above general formula (I) is useful as an analgesic agent because it has an excellent analgesic action.
In particular, among the compounds of the present invention, a drug that selectively acts on the peripheral μ-receptor is expected as an analgesic having no side effects (dependence, etc.) based on a central action.
The compound of the present invention can be administered to humans by oral administration or parenteral administration.
In order to formulate, it can be manufactured into a dosage form such as a tablet, capsule, powder, injection, suppository, or transdermal preparation in the technical field of preparation.
The dose is usually about 0.01 mg to 1000 mg per day in the case of an oral preparation of the compound of the present invention and about 0.001 mg to 100 mg in the case of an injection, but the dose may be increased or decreased depending on age, symptoms, etc. can do.
Next, although a reference example and an Example are given and this invention is demonstrated still in detail, this invention is not limited to these.

実施例番号は前述の合成実施例で得られた化合物を示し、実施例２３を除き全てシュウ酸塩を用いた（表１５，１６も同じ）。
（２）鎮痛作用

（３）末梢性および中枢（全身）性μ−オピオイド受容体アンタゴニストによる拮抗試験

上記の表１４及び１５から本発明化合物はμ−受容体に対する優れた結合親和性を有し、優れた鎮痛作用を有することが明らかになった。また、表１６から、本発明化合物の鎮痛作用は末梢性であることが明らかとなった（すなわち、末梢性μ−オピオイド受容体アンタゴニストを前処置すると、発明化合物の鎮痛作用はほぼ消失した）。
尚、上記（３）の拮抗試験において、比較薬物として用いたフェンタニルの鎮痛作用は末梢性アンタゴニストの前処置で何ら影響を受けなかったが、全身性アンタゴニストの前処置により完全に消失した。一方、もう一つの比較薬物として用いたロペラミドの鎮痛作用は末梢性アンタゴニストによってほぼ完全に拮抗された。以上の結果より、フェンタニルの鎮痛作用は末梢のμ−オピオイド受容体に起因するのではなく、中枢のμ−オピオイド受容体を介して発現することが確認された。また、ロペラミドの鎮痛作用は末梢のμ−オピオイド受容体を介して発現することが確認された。Reference example 1
3- [4-Methoxycarbonyl-4- (phenylpropionylamino) piperidi N-1-yl] -2-phenylpropionic acid
(1)Benzyl 2-phenylpropenoate
  To a solution of 2-phenylpropenoic acid (398 mg, 2.69 mmol), benzyl alcohol (349 mg, 3.23 mmol) and 4-dimethylaminopyridine (66 mg, 0.54 mmol) in anhydrous dichloromethane (12 mL) was added N, under ice-cooling. N'-dicyclohexylcarbodiimide (610 mg, 2.96 mmol) was added. After stirring for 0.5 hour under ice-cooling and 15 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and 5% aqueous citric acid solution were added to the residue, and the mixture was stirred for 0.5 hour. Insoluble matters were filtered off, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 6/1) to obtain 567 mg (yield 88%) of the title compound as a colorless oil.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 5.28 (2H, s), 5.92 (1H, d, J = 1 Hz), 6.39 (1H, d, J = 1 Hz), 7.3-7.5 (10H, m)
(2)3- [4-Methoxycarbonyl-4- (phenylpropionylamino) pi Peridin-1-yl] -2-phenylpropionate benzyl
To a solution of methyl 4- (phenylpropionylamino) piperidine-4-carboxylate (393 mg, 1.35 mmol) in acetonitrile (2 mL) was added benzyl 2-phenylpropenoate (320 mg, 1.34 mmol), and the mixture was stirred at room temperature for 17 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1) to obtain 407 mg (yield 79%) of the title compound as white crystals.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.6 (2H, m), 1.86 (2H, q, J = 7 Hz), 2.1-2. 2 (1H, m), 2.2-2.3 (1H, m), 2.40 (1H, dt, J = 2, 11 Hz), 2.5-2.6 (3H, m), 2. 7-2.8 (1H, m), 3.15 (1H, dd, J = 11, 13 Hz), 3.77 (3H, s), 3.81 (1H, dd, J = 4, 11 Hz), 5.05 (1H, d, J = 13Hz), 5.08 (1H, d, J = 13Hz), 7.2-7.3 (12H, m), 7.4-7.5 (3H, m )
(3)3- [4-Methoxycarbonyl-4- (phenylpropionylamino) pi Peridin-1-yl] -2-phenylpropionic acid
  To a solution of benzyl 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionate (479 mg, 0.906 mmol) in ethanol (10 mL) was added 10% palladium-carbon ( 48 mg), and catalytic hydrogenation was carried out at room temperature for 1 hour at 1 atmosphere. After the catalyst was filtered off, the filtrate was dried under reduced pressure under reduced pressure to obtain 398 mg (yield 100%) of the title compound as pale yellow crystals.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.85 (2H, q, J = 7 Hz), 1.8-1.9 (2H, m), 2.2-2. 3 (1H, m), 2.4-2.5 (1H, m), 2.63 (1H, dd, J = 4, 13 Hz), 2.82 (1H, dt, J = 3, 12 Hz), 2.90 (1H, dt, J = 2, 12 Hz), 3.0-3.1 (1 H, m), 3.31 (1 H, t, J = 13 Hz), 3.3-3.4 (1 H M), 3.72 (1H, dd, J = 4, 13 Hz), 3.78 (3H, s), 7.1-7.4 (10H, m)
Reference example 2
3- [4-[(2-Furoyl) phenylamino] -4-methoxycarbonylpipe Lysine-1-yl] -2-phenylpropionic acid
(1)1-Benzyl-4-[(2-furoyl) phenylamino] piperidine-4 -Methyl carboxylate
  To a solution of methyl 1-benzyl-4-phenylaminopiperidine-4-carboxylate (1.50 g, 4.62 mmol) and triethylamine (1.5 mL) in chloroform (12 mL) was added 2-furoyl chloride (0.55 mL, 5 .55 mmol) was added. After stirring at room temperature for 1 hour, the mixture was heated to reflux for 6 hours. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with chloroform, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 99/1 and n-hexane / ethyl acetate = 1/2) to give 1.29 g (yield 67%) of the title compound. )Obtained.
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.6-1.8 (2H, m), 2.3-2.5 (4H, m), 2.6-2.7 (2H, m), 3.47 (2H, s), 3.81 (3H, s), 5.22 (1H, d, J = 4 Hz), 6.11 (1H, dd, J = 1, 4 Hz), 7.1-7.5 (10H, m), 8.02 (1H, s).
(2)4-[(2-Furoyl) phenylamino] piperidine-4-carboxylic acid Chill
  To a solution of methyl 1-benzyl-4-[(2-furoyl) phenylamino] piperidine-4-carboxylate (1.29 g, 3.08 mmol) obtained above in dichloroethane (20 mL) was added chloroformate 1 under ice-cooling. -Chloroethyl (0.43 mL, 4.01 mmol) was added. The mixture was stirred for 0.5 hours under ice-cooling, heated to reflux for 2 hours, returned to room temperature, and concentrated under reduced pressure. Methanol (20 mL) was added to the reaction mixture, heated under reflux for 2 hours, returned to room temperature, the reaction mixture was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol / aqueous ammonia = 93/7 / 0.2) to obtain 464 mg (yield 46%) of the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.5-1.7 (2H, m), 2.3-2.4 (2H, m), 2.8-3.0 (2H, m), 3.0-3. 1 (2H, m), 3.83 (3H, s), 5.25 (1H, d, J = 3 Hz), 6.12 (1H, dd, J = 1, 3 Hz), 7.1-7. 5 (6H, m).
(3)3- [4-[(2-Furoyl) phenylamino] -4-methoxycarbonyl Lupiperidin-1-yl] -2-phenylpropionate benzyl
  To a solution of methyl 4-[(2-furoyl) phenylamino] piperidine-4-carboxylate (377 mg, 1.15 mmol) obtained above in acetonitrile (4 mL), benzyl 2-phenylpropenoate (301 mg, 1.26 mmol) And stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to obtain 455 mg (yield 70%) of the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.6-1.7 (2H, m), 2.2-2.6 (6H, m), 2.7-2.9 (1H, m), 3.18 (1H, dd, J = 11, 13 Hz), 3.79 (3H, s), 3.83 (1 H, dd, J = 4.11 Hz), 5.07 (2 H, s), 5.21 (1 H, d, J = 3 Hz), 6.12 (1H, dd, J = 1, 3 Hz), 7.1-7.6 (16H, m).
(4)3- [4-[(2-Furoyl) phenylamino] -4-methoxycarbonyl Lupiperidin-1-yl] -2-phenylpropionic acid
  To a solution of benzyl 3- [4-[(2-furoyl) phenylamino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionate (453 mg, 0.799 mmol) obtained above in methanol (7 mL). 10% Palladium-carbon (50 mg) was added and catalytic hydrogenation was performed at room temperature for 1 hour at 1 atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure and recrystallized from methanol-ether to obtain 351 mg (yield 92%) of the title compound as white crystals.
¹H NMR (CD₃OD, 400 MHz) δ: 2.0-2.2 (2H, m), 2.4-2.6 (2H, m), 3.0-3.1 (1H, m), 3.2-3 .6 (5H, m), 3.83 (3H, s), 3.8-3.9 (1H, m), 5.37 (1H, t, J = 3 Hz), 6.2-6.3 (1H, m), 7.2-7.6 (11H, m).
Reference example 3
2-Phenyl-3- [4-phenyl-4- (phenylpropionylamino) pipe Lysine-1-yl] propionic acid
(1)2-Phenyl-3- [4-phenyl-4- (phenylpropionylamino) ) Piperidin-1-yl] benzyl propionate
  The title compound was obtained in the same manner as in Reference Example 1 (2) using 4-phenyl-4- (phenylpropionylamino) piperidine and benzyl 2-phenylpropenoate.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.83 (3H, t, J = 7 Hz), 1.72 (2H, q, J = 7 Hz), 1.9-2.1 (3H, m), 2.1-2. 3 (1H, m), 2.38 (1 H, dd, J = 4, 13 Hz), 2.5-2.8 (4 H, m), 3.07 (1 H, dd, J = 11, 13 Hz), 3.80 (1H, dd, J = 4, 11 Hz), 5.06 (1H, d, J = 13 Hz), 5.11 (1H, d, J = 13 Hz), 7.1-7.4 (18H , M), 7.5-7.6 (2H, m).
(2)2-Phenyl-3- [4-phenyl-4- (phenylpropionylamino) ) Piperidin-1-yl] propionic acid
  The title compound was obtained in the same manner as in Reference Example 1 (3) using the above-mentioned 2-phenyl-3- [4-phenyl-4- (phenylpropionylamino) piperidin-1-yl] propionate benzyl.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.79 (3H, t, J = 7 Hz), 1.66 (2H, q, J = 7 Hz), 2.3-2.7 (5H, m), 2.7-2. 8 (1H, m), 2.9-3.1 (1H, m), 3.2-3.4 (1H, m), 3.5-3.6 (1H, m), 3.57 ( 1H, t, J = 12 Hz), 3.77 (1H, dd, J = 3, 12 Hz), 6.9-7.6 (15H, m).
Reference example 4
cis-3- [3-Methyl-4- (phenylpropionylamino) piperidine- 1-yl] -2-phenylpropionic acid
(1)cis-3- [3-Methyl-4- (phenylamino) piperidine-1-y L] -2-Phenylpropionate benzyl
  The title compound was obtained as a diastereomeric mixture in the same manner as in Reference Example 1 (2) using cis-3-methyl-4- (phenylamino) piperidine and benzyl 2-phenylpropenoate.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.88 (1.5 H, d, J = 7 Hz), 0.89 (1.5 H, d, J = 7 Hz), 1.5-1.7 (2 H, m), 2. 0-2.2 (1H, m), 2.2-2.8 (5H, m), 3.16 (0.5H, dd, J = 11, 13 Hz), 3.19 (0.5H, dd) , J = 11, 13 Hz), 3.4-3.5 (1 H, m), 3.55 (1 H, brs), 3.89 (0.5 H, dd, J = 4, 11 Hz), 3. 90 (0.5 H, dd, J = 5, 11 Hz), 5.06 (0.5 H, d, J = 13 Hz), 5.12 (0.5 H, d, J = 13 Hz), 5.16 (0 .5H, d, J = 13 Hz), 5.21 (0.5 H, d, J = 13 Hz), 6.5-6.7 (3H, m), 7.1-7.4 (12H, m) .
(2)cis-3- [3-Methyl-4- (phenylpropionylamino) piperi Gin-1-yl] -2-phenylpropionate benzyl
  Dichloromethane of cis-3- [3-methyl-4- (phenylamino) piperidin-1-yl] -2-phenylpropionate (1.16 g, 2.71 mmol) and triethylamine (0.53 mL) obtained above. To the (12 mL) solution, propionyl chloride (0.30 mL, 3.44 mmol) was added dropwise under ice cooling. After stirring at room temperature for 6 days, sodium bicarbonate water was added to the reaction mixture, the organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / acetonitrile = 50/1), and 136 mg (yield 10%) of diastereomer A (elution first) of the title compound was obtained. 133 mg (yield 10%) of stereomer B (later eluted) was obtained.
Diastereomer A
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (3H, d, J = 7 Hz), 0.99 (3H, t, J = 7 Hz), 1.1-1.4 (2H, m), 1.8-2. 1 (2H, m), 2.14 (1H, dt, J = 2, 11 Hz), 2.24 (1H, dd, J = 3, 11 Hz), 2.38 (1H, dd, J = 4, 12 Hz) ), 2.5-2.9 (3H, m), 3.07 (1H, t, J = 12 Hz), 3.82 (1H, dd, J = 4, 12 Hz), 4.35 (1H, dt) , J = 13, 4 Hz), 5.04 (1 H, d, J = 12 Hz), 5.12 (1 H, d, J = 12 Hz), 6.9-7.5 (15 H, m).
Diastereomer B
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, d, J = 7 Hz), 0.99 (3H, t, J = 7 Hz), 1.1-1.4 (2H, m), 1.8-2. 0 (3H, m), 2.4-2.5 (2H, m), 2.6-2.7 (2H, m), 2.8-2.9 (1H, m), 3.04 ( 1H, dd, J = 11, 12 Hz), 3.79 (1H, dd, J = 5, 11 Hz), 4.36 (1H, dt, J = 13, 4 Hz), 4.97 (1H, d, J = 13 Hz), 5.16 (1 H, d, J = 13 Hz), 6.9-7.5 (15 H, m).
(3)cis-3- [3-Methyl-4- (phenylpropionylamino) piperi Gin-1-yl] -2-phenylpropionic acid
  Reference Example 1 using diastereomer A and diastereomer B of benzyl cis-3- [3-methyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionate obtained above The title compound was obtained in the same manner as (3).
Diastereomer A
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.00 (3H, t, J = 7 Hz), 1.18 (3H, d, J = 7 Hz), 1.3-1.7 (2H, m), 1.8-2. 1 (2H, m), 2.46 (1H, dt, J = 3, 12 Hz), 2.57 (1H, dd, J = 3, 12 Hz), 2.65 (1H, dd, J = 5, 13 Hz) ), 2.8-3.0 (2H, m), 2.99 (1H, t, J = 13 Hz), 3.1-3.2 (1H, m), 3.71 (1H, dd, J = 5,13 Hz), 4.50 (1 H, dt, J = 12, 4 Hz), 6.9-7.5 (10 H, m).
Diastereomer B
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 1.01 (3H, t, J = 7 Hz), 1.19 (3H, d, J = 7 Hz), 1.4-1.6 (2H, m), 1.8-2. 0 (2H, m), 2.24 (1H, dt, J = 3, 12 Hz), 2.67 (1H, dd, J = 5, 13 Hz), 2.7-2.9 (2H, m), 2.9-3.0 (1H, m), 2.95 (1H, t, J = 13 Hz), 3.2-3.4 (1H, m), 3.64 (1H, dd, J = 5) , 13 Hz), 4.52 (1 H, dt, J = 13,4 Hz), 7.0-7.5 (10 H, m).
Reference Example 5
trans-3- [3-Methyl-4- (phenylpropionylamino) piperidi N-1-yl] -2-phenylpropionic acid
(1)trans-3- [3-Methyl-4- (phenylamino) piperidine- 1-yl] -2-phenylpropionic acid benzyl ester
  The title compound was obtained as a diastereomeric mixture in the same manner as in Reference Example 1 (2) using trans-3-methyl-4- (phenylamino) piperidine and benzyl 2-phenylpropenoate.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.93 (1.5 H, d, J = 7 Hz), 0.94 (1.5 H, d, J = 7 Hz), 1.2-1.3 (1 H, m), 1. 4-1.6 (1H, m), 1.80 (0.5 H, t, J = 11 Hz), 1.9-2.1 (2H, m), 2.1-2.3 (0.5 H) M), 2.5-2.6 (1H, m), 2.7-2.9 (2H, m), 2.9-3.1 (1H, m), 3.1-3.4. (2H, m), 3.8-4.0 (1 H, m), 5.07 (0.5 H, d, J = 13 Hz), 5.08 (0.5 H, d, J = 13 Hz), 5 .20 (0.5H, d, J = 13 Hz), 5.22 (0.5H, d, J = 13 Hz), 6.5-6.7 (3H, m), 7.1-7.4 ( 12H, m).
(2)trans-3- [3-Methyl-4- (phenylpropionylamino) pi Peridin-1-yl] -2-phenylpropionate benzyl
  Using benzyl-3- [3-methyl-4- (phenylamino) piperidin-1-yl] -2-phenylpropionate and propionyl chloride obtained above, in the same manner as in Reference Example 4 (2), the title The compound was obtained as a diastereomeric mixture.
(3)trans-3- [3-Methyl-4- (phenylpropionylamino) pi Peridin-1-yl] -2-phenylpropionic acid
  Using the above obtained trans-3- [3-methyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionate benzyl, the title compound was dia- sed in the same manner as in Reference Example 1 (3). Obtained as a stereomeric mixture.
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.02 (3H, t, J = 7 Hz), 1.06 (1.5 H, d, J = 6 Hz), 1.11 (1.5 H, d, J = 7 Hz), 1. 4-1.7 (1H, m), 1.7-1.9 (2H, m), 1.96 (2H, q, J = 7 Hz), 2.10 (0.5 H, t, J = 12 Hz) ), 2.2-2.4 (1H, m), 2.54 (0.5H, dt, J = 2, 12 Hz), 2.66 (1H, dd, J = 5, 13 Hz), 2.9 -3.1 (2H, m), 3.3-3.5 (1H, m), 3.65 (0.5H, dd, J = 5, 13 Hz), 3.68 (0.5H, dd, J = 5, 13 Hz), 4.5-4.8 (1 H, m), 7.0-7.5 (10 H, m).
Reference Example 6
3- [4-Methoxymethyl-4- (phenylpropionylamino) piperidine- 1-yl] -2-phenylpropionic acid
(1)3- [4-Methoxymethyl-4- (phenylpropionylamino) piperi Gin-1-yl] -2-phenylpropionate benzyl
The title compound was obtained as a colorless oil in the same manner as in Reference Example 1 (2) using N- (4-methoxymethylpiperidin-4-yl) -N-phenylpropionamide and benzyl 2-phenylpropenoate.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.93 (3H, t, J = 7 Hz), 1.6-1.7 (2H, m), 1.81 (2H, q, J = 7 Hz), 2.1-2. 2 (3H, m), 2.2-2.3 (1H, m), 2.5-2.6 (2H, m), 2.6-2.7 (1H, m) 3.15 (1H , Dd, J = 10, 12 Hz), 3.40 (3H, s), 3.82 (1H, dd, J = 4, 10 Hz), 4.0-4.1 (2H, m), 5.06 (1H, d, J = 12 Hz), 5.12 (1H, d, J = 12 Hz), 7.2-7.4 (15H, m)
(2)3- [4-Methoxymethyl-4- (phenylpropionylamino) piperi Gin-1-yl] -2-phenylpropionic acid
Using the benzyl 3- [4-methoxymethyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionate obtained above in the same manner as in Reference Example 1 (3), the title compound was converted into a white powder. Obtained.
mp: 120-125 ° C
  ¹1 H NMR (DMSO-d₆, 400 MHz) δ: 0.80 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.71 (2H, q, J = 7 Hz), 1.9-2. 1 (2H, m), 2.2-2.6 (4H, m), 2.7-2.8 (1H, m), 2.99 (1H, dd, J = 10, 12 Hz), 3. 33 (3H, s), 3.71 (1H, dd, J = 5, 10 Hz), 3.9-4.0 (2H, m), 7.2-7.4 (10H, m)
Reference Example 7
4- [4-Methoxycarbonyl-4- (phenylpropionylamino) piperidi N-1-yl] -2-phenylbutyric acid
(1)Benzyl 4-chloro-2-phenylbutyrate
  3-Phenyl-γ-butyrolactone (1.30 g, 8.0 mmol), benzyl alcohol (8 mL) and 4M hydrogen chloride-ether (8 mL) were mixed and heated to reflux at 120 ° C. for 44 hours. After cooling to room temperature, cold water was added and extracted with ether. The ether layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1) to obtain 0.15 g (yield 6%) of the title compound.
(2)4- [4-Methoxycarbonyl-4- (phenylpropionylamino) pi Peridin-1-yl] -2-phenylbutyrate benzyl
  Benzyl 4-chloro-2-phenylbutyrate (0.15 g, 0.52 mmol), methyl 4- (phenylpropionylamino) piperidine-4-carboxylate (174 mg, 0.60 mmol), sodium carbonate (106 mg, 1.0 mmol) , A mixture of sodium iodide (7 mg) and acetonitrile (10 mL) was heated to reflux for 48 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 160 mg of the title compound as a crude product. This crude product was further purified by silica gel column chromatography (methanol / chloroform = 1/200) to obtain 105 mg (yield 31%) of the title compound as a colorless oil.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.6 (2H, m), 1.8-1.9 (1H, m), 1.86 (2H, q, J = 7 Hz), 2.2-2.4 (7H, m), 2.5-2.6 (2H, m), 3.6-3.7 (1H, m,), 3.77. (3H, s), 5.01 (1H, d, J = 12 Hz), 5.06 (1H, d, J = 12 Hz), 7.2-7.4 (15H, m)
(3)4- [4-Methoxycarbonyl-4- (phenylpropionylamino) pi Peridin-1-yl] -2-phenylbutyric acid
  The title compound was obtained in the same manner as in Reference Example 1 (3) using benzyl 4- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylbutyrate.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.96 (3H, t, J = 7 Hz), 1.4-3.1 (12H, m), 1.89 (2H, q, J = 7 Hz), 3.80 (3H, s), 3.9-4.0 (1H, m), 7.2-7.5 (10H, m)
Reference Example 8
3- [4-[(2-Furoyl) pyridin-2-ylamino] -4-methoxycal Bonylpiperidin-1-yl] -2-phenylpropionic acid
(1)8-Benzyl-1,3,8-triazaspiro [4.5] decane-2,4- Dione
  To a solution of 1-benzyl-4-piperidone (20.0 g, 0.106 mol) in ethanol (250 mL) -water (250 mL) was added ammonium carbonate (47.8 g) and sodium cyanide (10.4 g, 0.211 mol). In addition, the mixture was stirred at 50 ° C. for 10 hours. The reaction mixture was returned to room temperature, ethanol was distilled off under reduced pressure, and the mixture was stirred for 1 hour under ice cooling. The precipitated crystals were collected by filtration, washed successively with water and ether, and dried under reduced pressure to give 26.1 g (yield 96%) of the title compound as white crystals.
¹1 H NMR (DMSO-d₆, 400 MHz) δ: 1.4-1.5 (2H, m), 1.7-1.9 (2H, m), 2.2-2.3 (2H, m), 2.6-2. 8 (2H, m), 3.48 (2H, s), 7.2-7.4 (5H, m), 8.40 (1H, s), 10.58 (1H, s).
(2)4-amino-1-benzylpiperidine-4-carboxylic acid
  To a solution of sodium hydroxide (4.17 g, 0.104 mol) in water (24 mL) was added the above 8-benzyl-1,3,8-triazaspiro [4,5] decane-2,4-dione (6.00 g, 23 0.1 mmol), and the mixture was stirred in a sealed tube container at 180 ° C. for 24 hours. Water (30 mL) was added to the reaction mixture, and neutralized with concentrated hydrochloric acid under ice cooling. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 4.52 g (yield 83%) of the title compound as white crystals.
¹1 H NMR (DMSO-d₆, 400 MHz) δ: 1.7-2.0 (2H, m), 2.0-2.2 (2H, m), 2.7-3.2 (4H, m), 3.90 (2H, br s), 7.2-7.5 (5H, m).
(3)4-Amino-1-benzylpiperidine-4-carboxylate methyl ester
  Methanol (20 mL) was cooled to −10 ° C., and thionyl chloride (5.1 mL, 69.3 mmol) was added dropwise over 30 minutes under a nitrogen stream, and the above 4-amino-1-benzylpiperidine-4-carboxylic acid was then added. (4.51 g, 19.2 mmol) was added and stirred at room temperature for 4 days. Under ice-cooling, aqueous ammonia was added for neutralization, followed by extraction with chloroform three times. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.29 g (yield 90%) of the title compound as a pale yellow oil.
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.5-1.6 (2H, m), 2.0-2.2 (2H, m), 2.4-2.6 (4H, m), 3.51 (2H, s), 3.72 (3H, s), 7.2-7.4 (5H, m).
(4)1-Benzyl-4- (pyridin-2-ylamino) piperidine-4-cal Methyl borate
  Under a nitrogen stream, palladium acetate (181 mg, 0.805 mmol), sodium tert-butoxide (1.16 g, 12.1 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phos A solution of fabicyclo [3.3.3] undecane (411 mg, 1.61 mmol) and 2-chloropyridine (915 mg, 8.05 mmol) in dry toluene (25 mL) was stirred at room temperature for 1.5 hours, and then the above 4- A solution of methyl amino-1-benzylpiperidine-4-carboxylate (2.80 g, 11.3 mmol) in dry toluene (25 mL) was added. After stirring at 80 ° C. for 5 hours, the temperature was returned to room temperature, the reaction mixture was poured into 1N hydrochloric acid, and the aqueous layer was separated. The aqueous layer was neutralized with potassium carbonate, extracted with chloroform, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol = 97/3). The obtained mixture (290 mg) was dissolved in a methanol solution (5 mL) saturated with hydrogen chloride and stirred overnight at room temperature. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with chloroform, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 271 mg (yield 10%) of the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 2.0-2.2 (2H, m), 2.2-2.4 (4H, m), 2.6-2.8 (2H, m), 3.51 (2H, s), 3.64 (3H, s), 4.56 (1H, s), 6.41 (1H, d, J = 8 Hz), 6.5-6.6 (1H, m), 7.2 −7.4 (6H, m), 8.03 (1H, dd, J = 1, 5 Hz).
(5)4- (Pyridin-2-ylamino) piperidine-4-carboxylate
  To a solution of methyl 1-benzyl-4- (pyridin-2-ylamino) piperidine-4-carboxylate (263 mg, 0.808 mmol) obtained above in methanol (10 mL) was added 10% palladium-carbon (130 mg), Catalytic hydrogenation was carried out for 2 hours under reflux with heating at 1 atm. The reaction mixture was returned to room temperature, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain 229 mg of the title compound.
(6)3- [4-Methoxycarbonyl-4- (pyridin-2-ylamino) pipe Lysine-1-yl] -2-phenylpropionate benzyl
  To a solution of methyl 4- (pyridin-2-ylamino) piperidine-4-carboxylate (229 mg) obtained above in acetonitrile (6.5 mL) was added benzyl 2-phenylpropenoate (1.07 mg, 1.26 mmol). Stir at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/2) to obtain 239 mg (yield 62%, 2 steps) of the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 2.0-2.2 (4H, m), 2.32 (1H, dt, J = 3, 11 Hz), 2.48 (1H, dt, J = 3, 11 Hz), 2. 56 (1H, dd, J = 5, 13 Hz), 2.6-2.7 (1H, m), 2.7-2.9 (1H, m), 3.21 (1H, dd, J = 11 , 13 Hz), 3.64 (3 H, s), 3.91 (1 H, dd, J = 5, 11 Hz), 4.51 (1 H, s), 5.07 (1 H, d, J = 12 Hz), 5.22 (1H, d, J = 12Hz), 6.39 (1H, d, J = 8Hz), 6.5-6.6 (1H, m), 7.2-7.4 (11H, m ), 8.0-8.1 (1H, m).
(7)3- [4-[(2-Furoyl) pyridin-2-ylamino] -4-methoxy Cycarbonylpiperidin-1-yl] -2-phenylpropionate benzyl
  Chloroform of 3- [4-methoxycarbonyl-4- (pyridin-2-ylamino) piperidin-1-yl] -2-phenylpropionate (88 mg, 0.186 mmol) and triethylamine (0.09 mL) obtained above. To the (1 mL) solution, 2-furoyl chloride (22 μL, 0.223 mmol) was added. After stirring at room temperature for 1 hour, the mixture was stirred at 60 ° C. for 30 minutes. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with chloroform, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/3) to obtain 101 mg (yield 96%) of the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.8-2.0 (2H, m), 2.1-2.4 (2H, m), 2.4-2.7 (3H, m), 2.54 (1H, dd, J = 5, 12 Hz), 2.7-2.9 (1H, m), 3.18 (1H, dd, J = 11, 12 Hz), 3.81 (3H, s), 3.85 ( 1H, dd, J = 5, 11 Hz), 5.07 (1H, d, J = 13 Hz), 5.12 (1H, d, J = 13 Hz), 5.88 (1H, d, J = 3 Hz), 6.17 (1H, dd, J = 2, 3 Hz), 7.1-7.5 (13H, m), 7.7-7.8 (1H, m), 8.6-8.7 (1H , M).
(8)3- [4-[(2-Furoyl) pyridin-2-ylamino] -4-methoxy Cycarbonylpiperidin-1-yl] -2-phenylpropionic acid
  A solution of benzyl 3- [4-[(2-furoyl) pyridin-2-ylamino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionate (101 mg, 0.178 mmol) in methanol (10 mL) 10% palladium-carbon (10 mg) was added thereto, and catalytic hydrogenation was carried out at room temperature for 1 hour at 1 atm. After the catalyst was filtered off, the filtrate was concentrated to dryness under reduced pressure to obtain 78 mg (yield 92%) of the title compound.
¹H NMR (CD₃OD, 400 MHz) δ: 2.1-2.3 (2H, m), 2.4-2.6 (2H, m), 3.09 (1H, dd, J = 4, 13 Hz), 3.2 -3.6 (4H, m), 3.57 (1H, dd, J = 11, 13 Hz), 3.8-3.9 (1H, m), 3.83 (3H, s), 5.9 -6.1 (1H, m), 6.31 (1H, dd, J = 2, 3 Hz), 7.2-7.4 (6H, m), 7.4-7.6 (2H, m) 7.8-8.0 (1H, m), 8.60 (1H, dd, J = 2, 5 Hz).
Reference Example 9
3- [4-Methoxycarbonyl-4- [propionyl (pyridin-2-yl) a Mino] piperidin-1-yl] -2-phenylpropionic acid
(1)3- [4-Methoxycarbonyl-4- [propionyl (pyridin-2-yl L) amino] piperidin-1-yl] -2-phenylpropionate benzyl
  A solution of benzyl 3- [4-methoxycarbonyl-4- (pyridin-2-ylamino) piperidin-1-yl] -2-phenylpropionate (115 mg, 0.243 mmol) and triethylamine (0.1 mL) in chloroform (1 mL). To which was added propionyl chloride (25 μL, 0.291 mmol). After stirring at room temperature for 2.5 hours, the reaction mixture was poured into aqueous sodium bicarbonate, extracted with chloroform, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/3) to obtain 115 mg (yield 90%) of the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.97 (3H, t, J = 8 Hz), 1.2-3.1 (10H, br), 2.50 (1H, dd, J = 4, 12 Hz), 3.14 ( 1H, dd, J = 11, 12 Hz), 3.79 (3 H, s), 3.83 (1 H, dd, J = 4, 11 Hz), 5.06 (1 H, d, J = 13 Hz), 5. 10 (1 H, d, J = 13 Hz), 7.2-7.4 (11 H, m), 7.43 (1 H, d, J = 8 Hz), 7.80 (1 H, dt, J = 2, 7 Hz) ), 8.60 (1H, dd, J = 2, 5 Hz).
(2)3- [4-Methoxycarbonyl-4- [propionyl (pyridin-2-yl L) amino] piperidin-1-yl] -2-phenylpropionic acid
  Using the above benzyl 3- [4-methoxycarbonyl-4- [propionyl (pyridin-2-yl) amino] piperidin-1-yl] -2-phenylpropionate in the same manner as in Reference Example 8 (8) A compound was obtained.
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.6-3.6 (8H, br), 1.86 (2H, q, J = 7 Hz), 3.03 (1H , Dd, J = 4, 13 Hz), 3.5-3.7 (1H, m), 3.80 (3H, s), 3.7-3.9 (1H, m), 7.2-7 .4 (5H, m), 7.4-7.6 (2H, m), 7.8-8.0 (1H, m), 8.5-8.6 (1H, m).
Reference Example 10
3- [4- [Cyclopropylcarbonyl (pyridin-2-yl) amino] -4- Methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid
(1)3- [4- [Cyclopropylcarbonyl (pyridin-2-yl) amino] -4-Methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid Benzyl
  A solution of benzyl 3- [4-methoxycarbonyl-4- (pyridin-2-ylamino) piperidin-1-yl] -2-phenylpropionate (119 mg, 0.251 mmol) and triethylamine (0.1 mL) in chloroform (1 mL). Was added cyclopropanecarbonyl chloride (27 μL, 0.302 mmol). After stirring at room temperature for 2 hours, the reaction mixture was poured into aqueous sodium bicarbonate, extracted with chloroform, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/3) to obtain 135 mg (99% yield) of the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.54 (2H, dd, J = 3, 8 Hz), 0.8-1.0 (3H, m), 1.6-2.8 (8H, br), 2.51 ( 1H, dd, J = 5, 13 Hz), 3.15 (1H, dd, J = 11, 13 Hz), 3.76 (3H, s), 3.83 (1H, dd, J = 5, 11 Hz), 5.06 (1H, d, J = 13Hz), 5.11 (1H, d, J = 13Hz), 7.2-7.4 (11H, m), 7.51 (1H, d, J = 8Hz) ), 7.82 (1H, dt, J = 2, 7 Hz), 8.6-8.7 (1H, m).
(2)3- [4- [Cyclopropylcarbonyl (pyridin-2-yl) amino] -4-Methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid
  Using benzyl 3- [4- [cyclopropylcarbonyl (pyridin-2-yl) amino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionate as described in Reference Example 8 (8). To give the title compound.
¹H NMR (CD₃OD, 400 MHz) δ: 0.63 (2H, dd, J = 3, 8 Hz), 0.8-1.0 (3H, m), 1.9-2.2 (2H, br), 2.3 -2.6 (2H, br), 3.0-3.1 (1H, m), 3.1-3.5 (4H, m), 3.5-3.6 (1H, m), 3 .78 (3H, s), 3.83 (1H, dd, J = 4, 11 Hz), 7.2-7.4 (5H, m), 7.4-7.6 (1H, m), 7 .60 (1H, dd, J = 2, 8 Hz), 7.9-8.0 (1H, m), 8.5-8.7 (1H, m).
Reference Example 11
3- [4-[(2-Furoyl) pyrazinylamino] -4-methoxycarbonylpi Peridin-1-yl] -2-phenylpropionic acid
(1)1-benzyl-4- (pyrazinylamino) piperidine-4-carboxylic acid Chill
  The title compound was obtained in the same manner as in Reference Example 8 (4) using methyl 4-amino-1-benzylpiperidine-4-carboxylate and chloropyrazine.
¹1 H NMR (CDCl₃, 400 MHz) δ: 2.0-2.2 (2H, m), 2.2-2.4 (4H, m), 2.6-2.8 (2H, m), 3.52 (2H, s), 3.64 (3H, s), 4.69 (1H, s), 7.2-7.4 (5H, m), 7.81 (1H, d, J = 3 Hz), 7.92 (1H, dd, J = 1, 3 Hz), 7.95 (1H, d, J = 1 Hz).
(2)4- (Pyrazinylamino) piperidine-4-carboxylic acid methyl ester
  The title compound was obtained in the same manner as in Reference Example 8 (5) using methyl 1-benzyl-4- (pyrazinylamino) piperidine-4-carboxylate.
(3)3- [4-Methoxycarbonyl-4- (pyrazinylamino) piperidine- 1-yl] -2-phenylpropionic acid benzyl ester
  The title compound was obtained in the same manner as in Reference Example 8 (6) using methyl 4- (pyrazinylamino) piperidine-4-carboxylate.
¹1 H NMR (CDCl₃, 400 MHz) δ: 2.0-2.1 (2H, m), 2.1-2.2 (2H, m), 2.29 (1H, dt, J = 3, 11 Hz), 2.45 ( 1H, dt, J = 3, 11 Hz), 2.57 (1H, dd, J = 5, 13 Hz), 2.6-2.7 (1H, m), 2.8-2.9 (1H, m ), 3.21 (1H, dd, J = 11, 13 Hz), 3.64 (3H, s), 3.90 (1H, dd, J = 5, 11 Hz), 4.75 (1H, s), 5.07 (1H, d, J = 13Hz), 5.23 (1H, d, J = 13Hz), 7.2-7.4 (10H, m), 7.80 (1H, d, J = 3Hz) ), 7.9-8.0 (2H, m).
(4)3- [4-[(2-Furoyl) pyrazinylamino] -4-methoxycarbo Nilpiperidin-1-yl] -2-phenylpropionate benzyl
  The title compound was obtained in the same manner as in Reference Example 8 (7) using benzyl 3- [4-methoxycarbonyl-4- (pyrazinylamino) piperidin-1-yl] -2-phenylpropionate.
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.8-2.0 (2H, m), 2.1-2.4 (2H, m), 2.4-2.7 (3H, m), 2.55 (1H, dd, J = 5, 13 Hz), 2.8-2.9 (1H, m), 3.19 (1H, dd, J = 11, 13 Hz), 3.82 (3H, s), 3.85 ( 1H, dd, J = 5, 11 Hz), 5.07 (1H, d, J = 13 Hz), 5.13 (1H, d, J = 13 Hz), 6.24 (1H, dd, J = 2, 3 Hz) ), 6.43 (1H, dd, J = 1, 3 Hz), 7.09 (1H, dd, J = 1, 2 Hz), 7.2-7.4 (10H, m), 8.57 (1H , Dd, J = 1, 2 Hz), 8.60 (1H, d, J = 2 Hz), 8.63 (1H, d, J = 1 Hz).
(5)3- [4-[(2-Furoyl) pyrazinylamino] -4-methoxycarbo Nilpiperidin-1-yl] -2-phenylpropionic acid
  The title compound was obtained in the same manner as in Reference Example 8 (8) using benzyl 3- [4-[(2-furoyl) pyrazinylamino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionate.
¹1 H NMR (CDCl₃/ CD₃OD = 30/1, 400 MHz) δ: 2.2-2.6 (4H, m), 2.67 (1H, dd, J = 3, 13 Hz), 2.7-3.3 (4H, m) 3.3-3.4 (1H, m), 3.5-3.7 (2H, m), 3.7-3.8 (1H, m), 3.81 (3H, s), 6 .25 (1H, dd, J = 1, 3 Hz), 6.40 (1 H, d, J = 3 Hz), 7.09 (1 H, s), 7.2-7.4 (5 H, m), 8 .08 (1H, br s), 8.43 (1H, d, J = 2 Hz), 8.52 (1H, s).
[Example 1]
(1)1- [2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4 -Methyl carboxylate
  3- [4-Methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid (141 mg, 0.32 mmol) obtained in Reference Example 1 (3), 1-hydroxybenzotriazole water To a solution of Japanese product (58 mg, 0.38 mmol) and tryptamine (61 mg, 0.38 mmol) in dichloromethane (6 mL) under ice-cooling, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (73 mg, 0 .38 mmol) and N-methylmorpholine (42 μL, 0.38 mmol) were added. After stirring for 0.5 hour under ice-cooling and 17 hours at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 175 mg (yield 94%) of the title compound as a colorless oil.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.2-1.5 (2H, m), 1.83 (2H, q, J = 7 Hz), 2.0-2. 5 (6H, m), 2.5-2.6 (1H, m), 2.8-3.0 (3H, m), 3.4-3.7 (3H, m), 3.75 ( 3H, s), 6.88 (1H, d, J = 2 Hz), 7.1-7.5 (14H, m), 7.57 (1H, d, J = 8 Hz), 8.06 (1H, br s).
(2)1- [2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4 -Methyl carboxylate oxalate
  Methyl 1- [2- [2- (1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate (175 mg,. To a solution of 301 mmol) in ethyl acetate (4 mL), oxalic acid (30 mg, 0.33 mmol) was added. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate. Drying under reduced pressure gave 181 mg (yield 90%) of the title compound as white crystals.
mp: 158-160 ° C.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.7-1.9 (2H, m), 1.92 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 2.7-2.9 (2H, m), 3.1-3.4 (5H, m), 3.4-3.6 (2H, m), 3.73 (1H, dd, J = 9, 13 Hz), 3.80 (3H, s), 3.90 (1H, dd, J = 4, 9 Hz), 6.78 (1H, s), 6.97 (1H , T, J = 7 Hz), 7.06 (1H, t, J = 7 Hz), 7.2-7.4 (8H, m), 7.4-7.6 (4H, m).
IR (cm^-1, KBr): 3350, 3057, 1736, 1672, 1632, 1595, 1518, 1491, 1456, 1402, 1385, 1338, 1300, 1228, 1146, 1103, 1074, 1007, 999, 951, 744, 702.
[Example 2]
(1)1- (2-carbamoyl-2-phenylethyl) -4- (phenylpropyl Onylamino) methyl piperidine-4-carboxylate
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 28% aqueous ammonia, the title compound was obtained in the same manner as in Example 1 (1). .
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.87 (2H, q, J = 7 Hz), 2.2-2. 4 (2H, m), 2.43 (1H, dt, J = 2, 11 Hz), 2.49 (1H, dd, J = 4, 13 Hz), 2.5-2.7 (2H, m), 2.7-2.8 (1H, m), 3.05 (1H, dd, J = 10, 13 Hz), 3.59 (1H, dd, J = 4, 10 Hz), 3.77 (3H, s ), 5.74 (1H, brs), 7.1-7.5 (11H, m).
(2)1- (2-carbamoyl-2-phenylethyl) -4- (phenylpropyl Onylamino) piperidine-4-carboxylate methyl oxalate
  Using the methyl 1- (2-carbamoyl-2-phenylethyl) -4- (phenylpropionylamino) piperidine-4-carboxylate obtained above and oxalic acid, the title compound was prepared in the same manner as in Example 1 (2). Obtained as a white powder.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.4-2 .5 (2H, m), 3.21 (1H, dd, J = 4, 13 Hz), 3.3-3.5 (4H, m), 3.81 (3H, s), 3.82 (1H , Dd, J = 10, 13 Hz), 4.04 (1H, dd, J = 4, 10 Hz), 7.2-7.6 (10H, m).
[Example 3]
(1)1- (2-Methylcarbamoyl-2-phenylethyl) -4- (phenyl Propionylamino) piperidine-4-carboxylate
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 40% aqueous methylamine solution, the title compound was obtained in the same manner as in Example 1 (1). It was.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.87 (2H, q, J = 7 Hz), 2.2-2. 4 (2H, m), 2.45 (1H, dt, J = 2,11 Hz), 2.5-2.6 (3H, m), 2.6-2.7 (1H, m), 2. 72 (3H, d, J = 5 Hz), 3.09 (1H, dd, J = 10, 13 Hz), 3.54 (1H, dd, J = 5, 10 Hz), 3.77 (3H, s), 7.02 (1H, br q), 7.1-7.5 (10H, m).
(2)1- (2-Methylcarbamoyl-2-phenylethyl) -4- (phenyl Propionylamino) piperidine-4-carboxylate methyl oxalate
  Using the methyl 1- (2-methylcarbamoyl-2-phenylethyl) -4- (phenylpropionylamino) piperidine-4-carboxylate obtained above and oxalic acid, the title compound was obtained in the same manner as in Example 1 (2). Was obtained as a white powder.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.93 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.4-2 .5 (2H, m), 2.67 (3H, s), 3.2-3.5 (5H, m), 3.81 (3H, s), 3.86 (1H, dd, J = 10) .13 Hz), 3.9-4.1 (1 H, m), 7.2-7.6 (10 H, m).
[Example 4]
(1)1- (2-Dimethylcarbamoyl-2-phenylethyl) -4- (pheny Lupropionylamino) piperidine-4-carboxylic acid methyl ester
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 50% aqueous dimethylamine solution, the title compound was obtained in the same manner as in Example 1 (1). It was.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.85 (2H, q, J = 7 Hz), 2.1-2. 2 (1H, m), 2.2-2.3 (1H, m) 2.4-2.6 (5H, m), 2.91 (3H, s), 2.93 (3H, s), 3.30 (1H, dd, J = 8, 13 Hz), 3.77 (3H, s), 3.91 (1H, dd, J = 4, 8 Hz), 7.2-7.6 (11H, m ).
(2)1- (2-Dimethylcarbamoyl-2-phenylethyl) -4- (pheny Lupropionylamino) piperidine-4-carboxylic acid methyl oxalate
  The title compound was obtained in the same manner as in Example 1 (2) using methyl 1- (2-dimethylcarbamoyl-2-phenylethyl) -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above. Was obtained as white crystals.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.9-2.0 (2H, m), 1.94 (2H, q, J = 7 Hz), 2.4-2 .6 (2H, m), 2.84 (3H, s), 2.94 (3H, s), 3.14 (1H, dd, J = 3, 13 Hz), 3.3-3.6 (4H) , M), 3.82 (3H, s), 3.8-3.9 (1H, m), 4.43 (1H, br d, J = 10 Hz), 7.2-7.6 (10H, m).
[Example 5]
(1)1- (3-Dimethylcarbamoyl-3-phenylpropyl) -4- (phen Nylpropionylamino) piperidine-4-carboxylate
  Using 4- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylbutyric acid and 50% aqueous dimethylamine solution obtained in Reference Example 7 (3), Example 1 (1) To give the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.7-1.8 (1H, m), 1.86 (2H, q, J = 7 Hz), 2.2-2.4 (7H, m), 2.5-2.6 (2H, m), 2.89 (6H, s), 3.77 (1H, dd, J = 6,15Hz), 3.78 (3H, s), 7.2-7.5 (10H, m)
(2)1- (3-Dimethylcarbamoyl-3-phenylpropyl) -4- (phen Nylpropionylamino) piperidine-4-carboxylic acid methyl oxalate
The title compound was obtained in the same manner as in Example 1 (2) using methyl 1- (3-dimethylcarbamoyl-3-phenylpropyl) -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above. Was obtained as a white powder.
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.7-2.1 (3H, m), 1.94 (2H, q, J = 7 Hz), 2.2-2 .4 (1H, m), 2.4-2.6 (2H, m), 2.87 (3H, s), 2.93 (3H, s), 2.9-3.1 (2H, m ), 3.2-3.4 (4H, m), 3.81 (3H, s), 4.0-4.1 (1H, m), 7.2-7.6 (10H, m)
[Example 6]
(1)1- [2- (Ethylmethylcarbamoyl) -2-phenylethyl] -4- (Phenylpropionylamino) piperidine-4-carboxylic acid methyl ester
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and N-ethylmethylamine, the title compound was obtained in the same manner as in Example 1 (1). It was.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 0.9-1.0 (3H, m), 1.5-1.7 (2H, m), 1.85 (2H, q, J = 7 Hz), 2.1-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.6 (5H, m), 2.87 ( 1.5H, s), 2.89 ((1.5H, s)), 3.1-3.4 (3H, m), 3.77 (1.5H, s), 3.78 (1. 5H, s), 3.8-3.9 (1H, m), 7.2-7.5 (10H, m)
(2)1- [2- (Ethylmethylcarbamoyl) -2-phenylethyl] -4- (Phenylpropionylamino) piperidine-4-carboxylic acid methyl oxalic acid salt
  Using methyl 1- [2- (ethylmethylcarbamoyl) -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above and in the same manner as in Example 1 (2). To give the title compound as white crystals.
mp: 173-176 ° C.
¹H NMR (CD₃OD, 400 MHz) δ: 0.71 (1.2 H, t, J = 7 Hz), 0.94 (3 H, t, J = 7 Hz), 1.02 (1.8 H, t, J = 7 Hz), 1 .93 (2H, q, J = 7 Hz), 1.9-2.1 (2H, m), 2.4-2.5 (2H, m), 2.80 (1.8H, s), 2 .88 (1.2H, s), 3.1-3.2 (2H, m), 3.3-3.6 (5H, m), 3.81 (3H, s), 3.8-3 .9 (1H, m), 4.4-4.5 (1H, m), 7.2-7.6 (10H, m).
IR (cm^-1, KBr): 3429, 2941, 1728, 1651, 1647, 1597, 1491, 1452, 1389, 1379, 1302, 1255, 1213, 1146, 1074, 1072, 1030, 1003, 958, 710, 706, 687.
[Example 7]
(1)1- [2-Phenyl-2- (phenylcarbamoyl) ethyl] -4- (fluoro Enylpropionylamino) piperidine-4-carboxylate
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and aniline.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.98 (3H, t, J = 7 Hz), 1.6-1.8 (2H, m), 1.90 (2H, q, J = 7 Hz), 2.3-2. 4 (1H, m), 2.4-2.7 (5H, m), 3.0-3.2 (2H, m), 3.74 (1H, dd, J = 4, 11 Hz), 3. 80 (3H, s), 7.0-7.6 (15H, m), 10.9 (1H, br s).
(2)1- [2-Phenyl-2- (phenylcarbamoyl) ethyl] -4- (fluoro Enylpropionylamino) piperidine-4-carboxylic acid methyl oxalate
  Using methyl 1- [2-phenyl-2- (phenylcarbamoyl) ethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above and in the same manner as in Example 1 (2). The title compound was obtained as white crystals.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.93 (3H, t, J = 8 Hz), 1.8-2.0 (2H, m), 1.92 (2H, q, J = 8 Hz), 2.4-2 .5 (2H, m), 3.2-3.5 (5H, m), 3.79 (3H, s), 3.90 (1H, dd, J = 10, 13 Hz), 4.17 (1H , Dd, J = 4, 10 Hz), 7.0-7.6 (15H, m).
IR (cm^-1, KBr): 3450, 1735, 1691, 1624, 1597, 1552, 1493, 1446, 1406, 1385, 1298, 1257, 1225, 1178, 1147, 1113, 1074, 995, 956, 757, 721, 702, 501.
[Example 8]
(1)1- (2-Benzylcarbamoyl-2-phenylethyl) -4- (pheny Lupropionylamino) piperidine-4-carboxylic acid methyl ester
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and benzylamine.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.84 (2H, q, J = 7 Hz), 2.1-2. 2 (1H, m), 2.2-2.3 (1H, m), 2.3-2.6 (4H, m), 2.7-2.8 (1H, m), 3.06 ( 1H, dd, J = 10, 13 Hz), 3.58 (1H, dd, J = 4, 10 Hz), 3.76 (3H, s), 4.37 (1H, dd, J = 5, 15 Hz), 4.41 (1H, dd, J = 5, 15 Hz), 7.1-7.5 (15H, m), 7.87 (1H, br t).
(2)1- (2-Benzylcarbamoyl-2-phenylethyl) -4- (pheny Lupropionylamino) piperidine-4-carboxylic acid methyl oxalate
  The title compound was obtained in the same manner as in Example 1 (2) using methyl 1- (2-benzylcarbamoyl-2-phenylethyl) -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above. Was obtained as white crystals.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 3.2-3.4 (5H, m), 3.81 (3H, s), 3.8-3.9 (1H, m), 4.03 (1H, dd) , J = 3, 9 Hz), 4.25 (1 H, d, J = 15 Hz), 4.38 (1 H, d, J = 15 Hz), 7.0-7.6 (15 H, m).
IR (cm^-1, KBr): 3427, 3290, 3061, 1734, 1682, 1632, 1593, 1560, 1525, 1491, 1454, 1404, 1383, 1298, 1255, 1227, 1146, 1072, 1028, 997, 955, 762, 702 594,498.
[Example 9]
(1)1- [2- (Benzylmethylcarbamoyl) -2-phenylethyl] -4 -(Phenylpropionylamino) piperidine-4-carboxylic acid methyl ester
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and N-benzylmethylamine, the title compound was obtained in the same manner as in Example 1 (1). It was.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.4-1.7 (2H, m), 1.8-1.9 (2H, m), 2.0-2. 7 (7H, m), 2.85 (1.5 H, s), 2.93 (1.5 H, s), 3.3-3.5 (1 H, m), 3.76 (1.5 H, s), 3.77 (1.5 H, s), 3.82 (0.5 H, J = dd, 4, 9 Hz), 3.98 (0.5 H, dd, J = 4, 9 Hz), 4. 16 (0.5 H, d, J = 17 Hz), 4.42 (0.5 H, d, J = 15 Hz), 4.70 (0.5 H, d, J = 17 Hz), 4.71 (0.5 H) , D, J = 15 Hz), 7.0-7.5 (15H, m).
(2)1- [2- (Benzylmethylcarbamoyl) -2-phenylethyl] -4 -(Phenylpropionylamino) piperidine-4-carboxylate methyl ester Acid salt
  Using methyl 1- [2- (benzylmethylcarbamoyl) -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above and in the same manner as in Example 1 (2). To give the title compound as white crystals.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.9-2.1 (2H, m), 1.96 (2H, q, J = 7 Hz), 2.4-2 .6 (2H, m), 2.80 (2.25H, s), 2.85 (0.75H, s), 3.1-3.6 (5H, m), 3.81 (0.75H) , S), 3.82 (2.25H, s), 3.91 (1H, dd, J = 10, 13 Hz), 4.21 (0.75H, d, J = 15 Hz), 4.36 (0 .25H, d, J = 16Hz), 4.4-4.5 (1H, m), 4.64 (0.25H, d, J = 16Hz), 4.94 (0.75H, d, J = 15 Hz), 6.7-6.8 (0.5 H, m), 7.0-7.6 (14.5 H, m).
[Example 10]
(1)1- [2- (phenethylcarbamoyl) -2-phenylethyl] -4- ( Phenylpropionylamino) piperidine-4-carboxylate methyl
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and phenethylamine.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.86 (2H, q, J = 7 Hz), 2.0-2. 2 (1H, m), 2.2-2.5 (5H, m), 2.6-2.7 (1H, m), 2.72 (2H, t, J = 7 Hz), 2.97 ( 1H, dd, J = 10, 13 Hz), 3.3-3.6 (3H, m), 3.77 (3H, s), 7.0-7.5 (16H, m).
(2)1- [2- (phenethylcarbamoyl) -2-phenylethyl] -4- ( Phenylpropionylamino) piperidine-4-carboxylic acid methyl oxalate
  Using methyl 1- [2- (phenethylcarbamoyl) -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above and in the same manner as in Example 1 (2) The title compound was obtained as white crystals.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.94 (2H, q, J = 7 Hz), 2.4-2 .5 (2H, m), 2.6-2.8 (2H, m), 3.2-3.6 (7H, m), 3.83 (3H, s), 3.8-3.9 (1H, m), 3.95 (1H, dd, J = 4, 9 Hz), 6.9-7.6 (15 H, m).
IR (cm^-1, KBr): 3363, 2956, 1722, 1680, 1659, 1593, 1543, 1491, 1452, 1400, 1375, 1242, 1213, 1147, 1074, 1032, 1007, 949, 748, 729, 721, 704, 694 499.
[Example 11]
(1)1- [2- (Methylphenethylcarbamoyl) -2-phenylethyl]- 4- (Phenylpropionylamino) piperidine-4-carboxylic acid methyl ester
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and N-methylphenethylamine. .
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (1.2 H, t, J = 7 Hz), 0.95 (1.8 H, t, J = 7 Hz), 1.5-1.7 (2 H, m), 1. 84 (0.8 H, q, J = 7 Hz), 1.85 (1.2 H, q, J = 7 Hz), 2.1-2.8 (9 H, m), 2.76 (1.8 H, s ), 2.86 (1.2H, s), 3.21 (0.4H, dd, J = 9, 13 Hz), 3.2-3.4 (1H, m), 3.4-3.7 (1.6H, m), 3.76 (1.2H, s), 3.77 (1.8H, s), 3.7-3.9 (1H, m), 7.0-7.5 (15H, m).
(2)1- [2- (Methylphenethylcarbamoyl) -2-phenylethyl]- 4- (Phenylpropionylamino) piperidine-4-carboxylate methyl ester Oxalate
  Using methyl 1- [2- (methylphenethylcarbamoyl) -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above and in the same manner as in Example 1 (2). To give the title compound as white crystals.
mp: 88-90 ° C
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.1-2 .2 (0.3H, m), 2.3-2.5 (2H, m), 2.73 (2.1H, s), 2.6-2.8 (1.7H, m), 2 .95 (0.9 H, s), 3.0-3.5 (6.3 H, m), 3.69 (0.3 H, dd, J = 10, 13 Hz), 3.81 (3 H, s) 3.8-4.0 (1.4 H, m), 4.27 (0.3 H, dd, J = 3, 10 Hz), 4.36 (0.7 H, dd, J = 3, 10 Hz), 6.9-7.6 (15H, m).
IR (cm^-1, KBr): 3446, 2947, 1741, 1655, 1635, 1493, 1454, 1383, 1257, 1219, 1142, 1078, 1016, 962, 754, 701, 469.
[Example 12]
(1)4-[(2-Furoyl) phenylamino] -1- [2- (methylphenethyl) Rucarbamoyl) -2-phenylethyl] piperidine-4-carboxylate
  Using 3- [4-[(2-furoyl) phenylamino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid and N-methylphenethylamine obtained in Reference Example 2 (4) The title compound was obtained in the same manner as 1 (1).
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.6-1.8 (2H, m), 2.2-2.9 (9H, m), 2.78 (1.5H, s), 2.87 (1.5H, s), 3.2-3.7 (3H, m), 3.7-3.9 (0.5H, m), 3.78 (1.5H, s), 3.80 (1.5H, s), 3.88 (0.5H, dd, J = 4, 9 Hz), 5.20 (1H, d, J = 3 Hz), 6.0-6.2 (1H, m), 7.0- 7.5 (16H, m).
(2)4-[(2-Furoyl) phenylamino] -1- [2- (methylphenethyl) Rucarbamoyl) -2-phenylethyl] piperidine-4-carboxylate Oxalate
  Using the methyl 4-[(2-furoyl) phenylamino] -1- [2- (methylphenethylcarbamoyl) -2-phenylethyl] piperidine-4-carboxylate obtained above and oxalic acid, Example 1 (2 ) To give the title compound as a white powder.
  ¹H NMR (CD₃OD, 400 MHz) δ: 2.0-2.2 (2.3 H, m), 2.4-2.6 (2 H, m), 2.74 (2.1 H, s), 2.6-2 .8 (1.7 H, m), 2.96 (0.9 H, s), 3.13 (1 H, dd, J = 3, 13 Hz), 3.2-3.6 (5.3 H, m) 3.74 (0.3 H, dd, J = 10, 13 Hz), 3.84 (3 H, s), 3.8-4.0 (1.4 H, m), 4.31 (0.3 H, dd, J = 3, 10 Hz), 4.39 (0.7 H, dd, J = 3, 10 Hz), 5.42 (1 H, d, J = 3 Hz), 6.25 (1 H, dd, J = 1) , 3 Hz), 6.9-7.6 (16H, m).
IR (cm^-1, KBr): 3433, 3027, 2951, 1730, 1641, 1560, 1493, 1470, 1468, 1402, 1354, 1286, 1215, 1190, 1146, 1074, 1012, 951, 775, 756, 702.
[Example 13]
(1)3- [4-Methoxymethyl-4- (phenylpropionylamino) piperi Gin-1-yl] -N-methyl-N-phenethyl-2-phenylpropionami Do
Using 3- [4-methoxymethyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and N-methylphenethylamine obtained in Reference Example 6 (2), Example 1 (1) To give the title compound.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.91 (1.2 H, t, J = 7 Hz), 0.92 (1.8 H, t, J = 7 Hz), 1.5-1.7 (2 H, m), 1. 80 (0.8 H, q, J = 7 Hz), 1.81 (1.2 H, q, J = 7 Hz), 2.1-2.8 (8 H, m), 2.76 (1.8 H, s ), 2.87 (1.2H, s), 3.1-3.9 (5H, m), 3.39 (1.2H, s), 3.40 (1.8H, s), 3. 9-4.1 (2H, m), 7.0-7.6 (15H, m).
(2)3- [4-Methoxymethyl-4- (phenylpropionylamino) piperi Gin-1-yl] -N-methyl-N-phenethyl-2-phenylpropionami Oxalate
  Using 3- [4-methoxymethyl-4- (phenylpropionylamino) piperidin-1-yl] -N-methyl-N-phenethyl-2-phenylpropionamide and oxalic acid obtained above, Example 1 (2 ) To give the title compound as a white powder.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.90 (2H, q, J = 7 Hz), 1.9-3.5 (12H, m), 2.76 (2 .1H, s), 3.01 (0.9H, s), 3.45 (3H, s), 3.6-4.5 (5H, m), 7.0-7.6 (15H, m ).
IR (cm^-1, KBr): 3427, 2935, 1728, 1649, 1491, 1454, 1375, 1250, 1201, 1111, 1076, 1030, 750, 702.
[Example 14]
(1)N-methyl-N-phenethyl-2-phenyl-3- [4-phenyl-4- (Phenylpropionylamino) piperidin-1-yl] propionic acid amide
  Using 2-phenyl-3- [4-phenyl-4- (phenylpropionylamino) piperidin-1-yl] propionic acid and N-methylphenethylamine obtained in Reference Example 3 (2), Example 1 (1) and The title compound was obtained in the same manner.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.81 (1.2 H, t, J = 7 Hz), 0.82 (1.8 H, t, J = 7 Hz), 1.70 (0.8 H, q, J = 7 Hz), 1.71 (1.2H, q, J = 7 Hz), 1.8-2.3 (4H, m), 2.33 (0.4H, dd, J = 4, 13 Hz), 2.37 (0 .6H, dd, J = 4, 13 Hz), 2.4-2.8 (6H, m), 2.72 (1.8 H, s), 2.86 (1.2 H, s), 3.13 (0.4H, dd, J = 9, 13 Hz), 3.2-3.4 (1H, m), 3.4-3.6 (1.6 H, m), 3.7-3.9 ( 1H, m), 7.0-7.4 (18H, m), 7.5-7.6 (2H, m).
(2)N-methyl-N-phenethyl-2-phenyl-3- [4-phenyl-4- (Phenylpropionylamino) piperidin-1-yl] propionic acid amide Oxalate
  Using the N-methyl-N-phenethyl-2-phenyl-3- [4-phenyl-4- (phenylpropionylamino) piperidin-1-yl] propionic acid amide and oxalic acid obtained above, Example 1 (2 ) To give the title compound as white crystals.
mp: 130-133 ° C
¹H NMR (CD₃OD, 400 MHz) δ: 0.81 (3H, t, J = 7 Hz), 1.81 (2H, q, J = 7 Hz), 2.1-2.6 (2H, m), 2.6-3 .2 (7H, m), 2.72 (1.8H, s), 2.97 (1.2H, s), 3.2-3.6 (3.8H, m), 3.6-3 .8 (0.6H, m), 3.8-3.9 (0.6H, m), 4.1-4.2 (0.4H, m), 4.3-4.4 (0. 6H, m), 6.9-7.7 (20H, m).
IR (cm^-1, KBr): 3420, 3020, 2930, 1710, 1650, 1640, 1590, 1490, 1440, 1410, 1360, 1280, 1230, 750, 690.
[Example 15]
(1)1- [2- [N-methyl-N- (3-phenylpropyl) carbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4 -Methyl carboxylate
  3- [4-Methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and N-methyl-3-phenylpropylamine were used in the same manner as in Example 1 (1). A compound was obtained.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (1.5 H, t, J = 7 Hz), 0.95 (1.5 H, t, J = 7 Hz), 1.5-1.9 (7 H, m), 2. 0-2.6 (8H, m), 2.87 (1.5H, s), 2.89 (1.5H, s), 3.0-3.4 (3H, m), 3.6- 3.7 (0.5 H, m), 3.76 (1.5 H, s), 3.77 (1.5 H, s), 3.9-4.0 (0.5 H, m), 7. 0-7.5 (15H, m).
(2)1- [2- [N-methyl-N- (3-phenylpropyl) carbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4 -Methyl carboxylate oxalate
  Using methyl 1- [2- [N-methyl-N- (3-phenylpropyl) carbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as a white powder in the same manner as in Example 1 (2).
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.93 (1.5 H, t, J = 7 Hz), 0.94 (1.5 H, t, J = 7 Hz), 1.6-2.5 (10 H, m), 2 .82 (1.5H, s), 2.90 (1.5H, s), 3.0-3.9 (8H, m), 3.80 (1.5H, s), 3.81 (1 .5H, s), 4.2-4.3 (0.5H, m), 4.3-4.5 (0.5H, m), 6.9-7.6 (15H, m).
[Example 16]
(1)1- [2-[(2-hydroxyethyl) methylcarbamoyl] -2-fe Nylethyl] -4- (phenylpropionylamino) piperidine-4-carvone Methyl acid
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (methylamino) ethanol in the same manner as in Example 1 (1), the title compound Got.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.9 (2H, m), 1.87 (2H, q, J = 7 Hz), 2.0-2. 4 (1.5H, m), 2.4-3.1 (6H, m), 2.91 (1.5H, s), 3.01 (1.5H, s), 3.1-3. 6 (2.5H, m), 3.6-3.8 (2.5H, m), 3.77 (3H, s), 3.9-4.1 (1H, m), 4.3- 4.4 (0.5H, m), 7.2-7.5 (10H, m).
(2)1- [2-[(2-hydroxyethyl) methylcarbamoyl] -2-fe Nylethyl] -4- (phenylpropionylamino) piperidine-4-carvone Methyl oxalate
Using 1- [2-[(2-hydroxyethyl) methylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above and Example 1 ( The title compound was obtained as white amorphous in the same manner as 2).
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.1 (4H, m), 2.4-2.6 (2H, m), 2.89 (1 .2H, s), 2.94 (1.8H, s), 2.9-3.0 (0.6H, m), 3.0-3.2 (1H, m), 3.2-3 7 (7.4H, m), 3.81 (3H, s), 3.7-3.9 (1H, m), 4.4-4.5 (0.6H, m), 4.6 -4.7 (0.4H, m), 7.2-7.6 (10H, m).
[Example 17]
(1)1- [2- (3-carbamoylpropylcarbamoyl) -2-phenyl ester Methyl] -4- (phenylpropionylamino) piperidine-4-carboxylic acid Le
Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 4-aminobutanamide, the title compound was obtained in the same manner as in Example 1 (1). It was.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.7-1.8 (2H, m), 1.87 (2H, q, J = 7 Hz), 2.0-2.2 (2H, m), 2.2-2.4 (2H, m), 2.4-2.5 (1H, m), 2.50 ( 1H, dd, J = 4, 13 Hz), 2.5-2.7 (2H, m), 2.7-2.8 (1H, m), 3.10 (1H, dd, J = 11, 13 Hz) ), 3.2-3.4 (2H, m), 3.5-3.6 (1H, m), 3.77 (3H, s), 5.28 (1H, br s), 6.47. (1H, brs), 7.2-7.5 (11H, m).
(2)1- [2- (3-carbamoylpropylcarbamoyl) -2-phenyl ester Methyl] -4- (phenylpropionylamino) piperidine-4-carboxylic acid Le oxalate
  1- [2- (3-Carbamoylpropylcarbamoyl) -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid were used in the same manner as in Example 1 (2). The compound was obtained as a white powder.
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.6-1.8 (2H, m), 1.8-2.0 (2H, m), 1.93 (2H , Q, J = 7 Hz), 2.13 (2H, t, J = 7 Hz), 2.4-2.6 (2H, m), 3.0-3.5 (7H, m), 3.7 -3.9 (1H, m), 3.9-4.0 (1H, m), 3.81 (3H, s), 7.2-7.6 (10H, m).
IR (cm^-1, KBr): 3350, 3050, 2930, 1720, 1650, 1590, 1540, 1480, 1440, 1390, 1370, 1270, 1220, 1140, 690.
[Example 18]
(1)1- [2- (morpholinocarbonyl) -2-phenylethyl] -4- (fluoro Enylpropionylamino) piperidine-4-carboxylate
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and morpholine.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.86 (2H, q, J = 7 Hz), 2.1-2. 3 (2H, m), 2.4-2.6 (5H, m), 3.1-3.2 (1H, m), 3.3-3.4 (2H, m), 3.4 3.5 (4H, m), 3.5-3.7 (2H, m), 3.77 (3H, s), 3.8-3.9 (1H, m), 7.2-7. 5 (10H, m)
(2)1- [2- (morpholinocarbonyl) -2-phenylethyl] -4- (fluoro Enylpropionylamino) piperidine-4-carboxylic acid methyl oxalate
  Using methyl 1- [2- (morpholinocarbonyl) -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above and in the same manner as in Example 1 (2). The title compound was obtained as a white powder.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.94 (2H, q, J = 7 Hz), 1.9-2.1 (2H, m), 2.4-2 .6 (2H, m), 2.9-3.0 (1H, m), 3.1-3.3 (2H, m), 3.3-3.8 (10H, m), 3.81 (3H, s), 3.8-3.9 (1H, m), 4.4-4.6 (1H, m), 7.2-7.6 (10H, m)
[Example 19]
(1)1- [2- (Piperidinocarbonyl) -2-phenylethyl] -4- (fluoro Enylpropionylamino) piperidine-4-carboxylate
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and piperidine.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.0-1.1 (1H, m), 1.3-1.7 (7H, m), 1.85 (2H, q, J = 7 Hz), 2.1-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.6 (5H, m), 3.3 3.5 (4H, m), 3.5-3.6 (1H, m), 3.77 (3H, s), 3.9-4.0 (1H, m), 7.2-7. 5 (10H, m)
(2)1- [2- (Piperidinocarbonyl) -2-phenylethyl] -4- (fluoro Enylpropionylamino) piperidine-4-carboxylic acid methyl oxalate
  Using 1- [2- (piperidinocarbonyl) -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above and similar to Example 1 (2) To give the title compound as white crystals.
mp: 154-157 ° C
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.6-0.7 (1H, m), 0.94 (3H, t, J = 7 Hz), 1.2-1.4 (2H, m), 1.4-1. .6 (3H, m), 1.93 (2H, q, J = 7 Hz), 1.9-2.1 (2H, m), 2.4-2.5 (2H, m), 3.1 -3.3 (3H, m), 3.3-3.6 (5H, m), 3.81 (3H, s), 3.8-4.0 (2H, m), 4.4-4 .5 (1H, m), 7.2-7.6 (10H, m)
IR (cm^-1, KBr): 3454, 3061, 2939, 2858, 1740, 1657, 1633, 1493, 1452, 1383, 1298, 1257, 1213, 1146, 1140, 1072, 1007, 949, 852, 702
[Example 20]
(1)1- [2- (4-Acetylpiperazin-1-yl) carbonyl-2-fe Nylethyl] -4- (phenylpropionylamino) piperidine-4-carvone Methyl acid
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 1-acetylpiperazine. .
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.85 (2H, q, J = 7 Hz), 2.0-2. 1 (4H, m), 2.1-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.6 (5H, m), 2.8- 3.0 (1H, m), 3.2-3.5 (6H, m), 3.5-3.6 (1H, m), 3.77 (3H, s), 3.8-3. 9 (1H, m), 7.2-7.5 (10H, m)
(2)1- [2- (4-Acetylpiperazin-1-yl) carbonyl-2-fe Nylethyl] -4- (phenylpropionylamino) piperidine-4-carvone Methyl oxalate
  Example 1 Using methyl 1- [2- (4-acetylpiperazin-1-yl) carbonyl-2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as white amorphous in the same manner as (2).
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.93 (2H, q, J = 7 Hz), 1.9-2.1 (5H, m), 2.4-2 .5 (2H, m), 2.6-2.8 (1H, m), 3.1-3.2 (1H, m), 3.2-3.7 (10H, m), 3.7 -3.8 (1H, m), 3.81 (3H, s), 3.8-3.9 (1H, m), 4.5-4.6 (1H, m), 7.3-7 .6 (10H, m).
IR (cm^-1, KBr): 3454, 3423, 2941, 1736, 1645, 1491, 1448, 1377, 1254, 1228, 1182, 1146, 1072, 999, 949, 706.
[Example 21]
(1)1- [2- (4-Benzylpiperazin-1-yl) carbonyl-2-fe Nylethyl] -4- (phenylpropionylamino) piperidine-4-carvone Methyl acid
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 1-benzylpiperazine. .
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.86 (2H, q, J = 7 Hz), 1.8-2. 0 (2H, m), 2.1-2.2 (1H, m), 2.2-2.3 (3H, m), 2.3-2.6 (6H, m), 3.3 3.6 (5H, m), 3.6-3.7 (1H, m), 3.77 (3H, s), 3.9-4.0 (1H, m), 7.2-7. 5 (15H, m)
(2)1- [2- (4-Benzylpiperazin-1-yl) carbonyl-2-fe Nylethyl] -4- (phenylpropionylamino) piperidine-4-carvone Methyl acid dioxalate
  Example 1 Using methyl 1- [2- (4-benzylpiperazin-1-yl) carbonyl-2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as white amorphous in the same manner as (2).
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.96 (3H, t, J = 7 Hz), 1.90 (2H, q, J = 7 Hz), 1.9-2.1 (1H, m), 2.1-2. 2 (1H, m), 2.3-2.5 (2H, m), 2.8-2.9 (1H, m), 2.9-3.8 (12H, m), 3.80 ( 3H, s), 3.9-4.0 (1H, m), 4.1-4.3 (2H, m), 4.5-4.6 (1H, m), 7.0-7. 1 (2H, m), 7.2-7.5 (13H, m)
IR (cm^-1, KBr): 3446, 2953, 2580, 1736, 1653, 1491, 1452, 1402, 1259, 1221, 1124, 1007, 953, 754, 704
[Example 22]
(1)N-[[3- [4-Methoxycarbonyl-4- (phenylpropionyl) Mino) piperidin-1-yl] -2-phenyl] propionyl] -N-methyl- D-glucamine
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and N-methyl-D-glucamine in the same manner as in Example 1 (1), the title compound Got.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.8-1.0 (3H, m), 1.6-1.8 (2H, m), 1.8-2.0 (2H, m), 2.1-3 .1 (10H, m), 3.2-4.0 (12H, m), 4.10 (0.5H, dd, J = 4, 9 Hz), 4.27 (0.2H, dd, J = 4,9 Hz), 4.38 (0.3 H, dd, J = 4, 9 Hz), 7.2-7.6 (10 H, m).
  FAB-MS m / z: 616 (MH⁺)
(2)N-[[3- [4-Methoxycarbonyl-4- (phenylpropionyl) Mino) piperidin-1-yl] -2-phenyl] propionyl] -N-methyl- D-glucamine oxalate
Using N-[[3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenyl] propionyl] -N-methyl-D-glucamine and oxalic acid, Example 1 ( The title compound was obtained as a white powder in the same manner as 2).
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.1 (4H, m), 2.4-2.6 (2H, m), 2.7-3 .2 (5H, m), 3.2-4.1 (12.3H, m), 3.81 (3H, s), 4.4-4.5 (0.4H, m), 4.6 -4.7 (0.3H, m), 7.2-7.6 (10H, m).
[Example 23]
N-[[3- [4-Methoxycarbonyl-4- (phenylpropionylamino) Piperidin-1-yl] -2-phenyl] propionyl] -D-glucosamine
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and D-glucosamine hydrochloride in the same manner as in Example 1 (1), the title compound was converted to white. Obtained as a powder.
¹H NMR (CD₃OD, 400 MHz) δ: 0.8-1.0 (3H, m), 1.6-1.8 (2H, m), 1.8-2.0 (2H, m), 2.1-2 7 (6H, m), 2.8-3.2 (2H, m), 3.2-3.9 (7H, m), 3.73 (3H, s), 4.47 (0.1H , D, J = 8 Hz), 4.52 (0.1 H, d, J = 8 Hz), 4.97 (0.3 H, d, J = 3 Hz), 5.12 (0.5 H, d, J = 3 Hz), 7.1-7.6 (10 H, m).
FAB-MS m / z: 600 (MH⁺)
[Example 24]
(1)1- [2- [2- (4-Hydroxyphenyl) ethylcarbamoyl] -2 -Phenylethyl] -4- (phenylpropionylamino) piperidine-4-ca Methyl rubonate
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and tyramine.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.87 (2H, q, J = 7 Hz), 2.1-2. 2 (1H, m), 2.2-2.3 (1H, m), 2.3-2.6 (4H, m), 2.61 (2H, t, J = 7 Hz), 2.6- 2.8 (1H, m), 3.03 (1H, dd, J = 10, 13 Hz), 3.3-3.4 (1H, m), 3.4-3.6 (2H, m), 3.76 (3H, s), 6.69 (2H, d, J = 8 Hz), 6.87 (2H, d, J = 8 Hz), 7.1-7.5 (11H, m).
(2)1- [2- [2- (4-Hydroxyphenyl) ethylcarbamoyl] -2 -Phenylethyl] -4- (phenylpropionylamino) piperidine-4-ca Methyl rubonate oxalate
Example 1 (2) using methyl 1- [2- [2- (4-hydroxyphenyl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid To give the title compound as a white powder.
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 2.5-2.7 (2H, m), 3.0-3.5 (7H, m), 3.73 (1H, dd, J = 9, 13 Hz), 3 .80 (3H, s), 3.8-4.0 (1H, m), 6.58 (2H, d, J = 8 Hz), 6.80 (2H, d, J = 8 Hz), 7.2 -7.6 (10H, m).
IR (cm^-1, KBr): 3304, 2951, 2690, 2582, 1738, 1653, 1595, 1558, 1516, 1493, 1452, 1379, 1300, 1236, 1173, 1146, 1109, 1072, 1003, 949, 829, 764, 706 505.
[Example 25]
(1)4- (Phenylpropionylamino) -1- [2-phenyl-2- [2- (2-Pyridyl) ethylcarbamoyl] ethyl] piperidine-4-carboxylate Chill
  3- [4-Methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (2-pyridyl) ethylamine were used in the same manner as in Example 1 (1). A compound was obtained.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.85 (2H, q, J = 7 Hz), 2.1-2. 3 (2H, m), 2.3-2.6 (4H, m), 2.6-2.7 (1H, m), 2.90 (2H, t, J = 6 Hz), 2.9- 3.1 (1H, m), 3.4-3.7 (3H, m), 3.77 (3H, s), 7.0-7.6 (14H, m), 8.42 (1H, d, J = 5 Hz).
(2)4- (Phenylpropionylamino) -1- [2-phenyl-2- [2- (2-Pyridyl) ethylcarbamoyl] ethyl] piperidine-4-carboxylate Chill oxalate
  Example 1 Using methyl 4- (phenylpropionylamino) -1- [2-phenyl-2- [2- (2-pyridyl) ethylcarbamoyl] ethyl] piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as white crystals in the same manner as (2).
mp: 88-90 ° C
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.4-2 .5 (2H, m), 2.8-3.0 (2H, m), 3.1-3.7 (7H, m), 3.8-3.9 (1H, m), 3.81 (3H, s), 3.9-4.0 (1H, m), 7.0-7.7 (13H, m), 8.3-8.4 (1H, m).
IR (cm^-1, KBr): 3050, 2950, 1730, 1660, 1600, 1490, 1450, 1370, 1220, 700.
[Example 26]
(1)4- (Phenylpropionylamino) -1- [2-phenyl-2- [2- (2-Thienyl) ethylcarbamoyl] ethyl] piperidine-4-carboxylate Chill
  3- [4-Methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (2-thienyl) ethylamine were used in the same manner as in Example 1 (1). A compound was obtained.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.96 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.85 (2H, q, J = 7 Hz), 2.1-2. 2 (1H, m), 2.2-2.5 (5H, m), 2.6-2.8 (1H, m), 2.95 (2H, t, J = 6 Hz), 2.9- 3.0 (1H, m), 3.3-3.4 (1H, m) 3.4-3.7 (2H, m), 3.77 (3H, s), 6.69 (1H, d , J = 3 Hz), 6.86 (1H, dd, J = 3, 5 Hz), 7.0-7.5 (11H, m), 7.69 (1H, brt).
(2)4- (Phenylpropionylamino) -1- [2-phenyl-2- [2- (2-Thienyl) ethylcarbamoyl] ethyl] piperidine-4-carboxylate Chill oxalate
  Example 1 Using methyl 4- (phenylpropionylamino) -1- [2-phenyl-2- [2- (2-thienyl) ethylcarbamoyl] ethyl] piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as white crystals in the same manner as (2).
mp: 159-164 ° C.
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.4-2 .5 (2H, m), 2.9-3.0 (2H, m), 3.2-3.6 (7H, m), 3.81 (3H, s), 3.8-3.9 (1H, m), 3.9-4.0 (1H, m), 6.61 (1H, d, J = 3 Hz), 6.79 (1H, dd, J = 3, 5 Hz), 7.09 (1H, d, J = 5 Hz), 7.2-7.6 (10H, m).
IR (cm^-1, KBr): 3350, 2950, 1720, 1680, 1660, 1550, 1500, 1450, 1380, 1260, 1240, 1220, 1150, 690.
[Example 27]
(1)4- (Phenylpropionylamino) -1- [2-phenyl- [2- [2 -(1H-pyrrol-1-yl) ethyl] carbamoyl] ethyl] piperidine- 4-Carboxylic acid methyl ester
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 1- (2-aminoethyl) pyrrole, as in Example 1 (1). The title compound was obtained.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.86 (2H, q, J = 7 Hz), 2.0-2. 2 (1H, m), 2.2-2.5 (5H, m), 2.6-2.8 (1H, m), 2.98 (1H, dd, J = 11.13 Hz), 3. 3-3.4 (1H, m), 3.48 (1 H, dd, J = 4, 11 Hz), 3.5-3.6 (1 H, m), 3.76 (3 H, s), 3. 93 (2H, t, J = 6 Hz), 6.04 (2H, t, J = 2z), 6.49 (2H, t, J = 2 Hz), 7.1-7.5 (10H, m), 7.61 (1H, br t).
(2)4- (Phenylpropionylamino) -1- [2-phenyl- [2- [2 -(1H-pyrrol-1-yl) ethyl] carbamoyl] ethyl] piperidine- 4-Carboxylic acid methyl oxalate
Implementation with methyl 4- (phenylpropionylamino) -1- [2-phenyl- [2- [2- (1H-pyrrol-1-yl) ethyl] carbamoyl] ethyl] piperidine-4-carboxylate and oxalic acid The title compound was obtained as white crystals in the same manner as in Example 1 (2).
mp: 100-103 ° C
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 3.16 (1H, dd, J = 4,13 Hz), 3.2-3.4 (4H, m), 3.4-3.5 (2H, m), 3 .78 (1H, dd, J = 10, 13 Hz), 3.81 (3H, s), 3.8-4.0 (3H, m), 5.87 (2H, t, J = 2z), 6 .41 (2H, t, J = 2 Hz), 7.2-7.6 (10H, m).
IR (cm^-1, KBr): 3429, 3304, 2941, 2771, 1736, 1662, 1655, 1595, 1551, 1493, 1452, 1377, 1242, 1182, 1146, 1093, 1059, 1001, 945, 733, 704, 609, 474.
[Example 28]
(1)1- [2- [2- (1H-imidazol-4-yl) ethylcarbamoyl ] -2-Phenylethyl] -4- (phenylpropionylamino) piperidine- 4-Carboxylic acid methyl ester
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and histamine.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.87 (2H, q, J = 7 Hz), 2.1-2. 3 (2H, m), 2.4-2.7 (5H, m), 2.95 (2H, t, J = 6 Hz), 3.10 (1H, dd, J = 9, 13 Hz), 3. 3-3.6 (3H, m), 3.78 (3H, s), 6.72 (1H, s), 7.1-7.5 (13H, m).
(2)1- [2- [2- (1H-imidazol-4-yl) ethylcarbamoyl ] -2-Phenylethyl] -4- (phenylpropionylamino) piperidine- 4-Carboxylic acid methyl oxalate
  Using methyl 1- [2- [2- (1H-imidazol-4-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as a white amorphous in the same manner as in Example 1 (2).
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.93 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.92 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 2.7-2.9 (2H, m), 3.1-3.6 (8H, m), 3.80 (3H, s), 3.8-3.9 (1H, m), 6.91 (1H.br s), 7.2-7.6 (10H, m), 8.61 (1H, br s).
[Example 29]
(1)1- [2- [2- (2-Naphtyl) ethylcarbamoyl] -2-phenyl Ethyl] -4- (phenylpropionylamino) piperidine-4-carboxylic acid Chill
  3- [4-Methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (2-naphthyl) ethylamine were used in the same manner as in Example 1 (1). A compound was obtained.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.2-1.5 (2H, m), 1.82 (2H, q, J = 7 Hz), 2.0-2. 1 (1H, m), 2.2-2.5 (5H, m), 2.6-2.7 (1H, m), 2.8-3.0 (3H, m), 3.4 3.7 (3H, m), 3.74 (3H, s), 7.1-7.6 (15H, m),
7.72 (2H, d, J = 9 Hz), 7.72 (1H, dd, J = 2, 9 Hz).
(2)1- [2- [2- (2-Naphtyl) ethylcarbamoyl] -2-phenyl Ethyl] -4- (phenylpropionylamino) piperidine-4-carboxylic acid Chill
Oxalate
  Example 1 Using methyl 1- [2- [2- (2-naphthyl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as white crystals in the same manner as (2).
mp: 125-128 ° C
¹H NMR (CD₃OD, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.6-1.8 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.3-2 .4 (2H, m), 2.8-3.0 (2H, m), 3.1-3.4 (5H, m), 3.4-3.5 (1H, m), 3.6 -3.7 (1H, m), 3.80 (3H, s), 3.7-4.0 (2H, m), 7.1-7.6 (14H, m), 7.68 (2H , D, J = 8 Hz), 7.78 (1H, dd, J = 2, 8 Hz).
IR (cm^-1, KBr): 3400, 1740, 1720, 1680, 1660, 1600, 1540, 1490, 1450, 1380, 1230, 1200, 700.
[Example 30]
(1)1- [2- [2- (1H-Indol-2-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4 -Methyl carboxylate
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (1H-indol-2-yl) ethylamine, Example 1 (1) and In the same manner, the title compound was obtained as a white powder.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.83 (2H, q, J = 7 Hz), 2.1-2. 2 (1H, m), 2.2-2.3 (1H, m), 2.3-2.6 (4H, m), 2.6-2.7 (1H, m), 2.87 ( 2H, t, J = 6 Hz), 3.00 (1H, dd, J = 11, 13 Hz), 3.4-3.7 (3H, m), 3.75 (3H, s), 6.12 ( 1H, br s), 7.0-7.6 (15H, m), 8.50 (1H, br s).
(2)1- [2- [2- (1H-Indol-2-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4 -Methyl carboxylate oxalate
  The methyl 1- [2- [2- (1H-indol-2-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino)] piperidine-4-carboxylate and oxalic acid obtained above were used. And the title compound was obtained as in Example 1 (2).
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.7-1.8 (2H, m), 1.92 (2H, q, J = 7 Hz), 2.2-2 .4 (2H, m), 2.8-3.0 (2H, m), 3.1-3.3 (5H, m), 3.4-3.6 (2H, m), 3.7 -3.8 (1H, m), 3.80 (3H, s), 3.9-4.0 (1H, m) 5.99 (1H, s), 6.94 (1H, dt, J = 1, 8 Hz), 7.01 (1H, dt, J = 1, 8 Hz), 7.2-7.6 (12 H, m).
IR (cm^-1, KBr): 3317, 3059, 1736, 1655, 1595, 1547, 1491, 1458, 1377, 1236, 1147, 1072, 1001, 947, 781, 737, 704, 498.
[Example 31]
(1)4-[(2-Furoyl) phenylamino] -1- [2- [2- (1H-i Ndol-3-yl) ethylcarbamoyl] -2-phenylethyl] piperidine -4-Methyl carboxylate
  Using 3- [4-methoxycarbonyl-4-[(2-furoyl) phenylamino] piperidin-1-yl] -2-phenylpropionic acid and tryptamine obtained in Reference Example 2 (4), Example 1 (1 ) To give the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 1.3-1.6 (2H, m), 2.1-2.5 (6H, m), 2.6-2.7 (1H, m), 2.91 (2H, t, J = 7 Hz), 2.97 (1H, dd, J = 11, 13 Hz), 3.4-3.5 (2H, m), 3.5-3.7 (1H, m), 3. 77 (3H, s), 5.19 (1H, d, J = 3 Hz), 6.13 (1H, dd, J = 1, 3 Hz), 6.88 (1H, d, J = 2 Hz), 7. 0-7.6 (15 H, m), 7.56 (1 H, d, J = 8 Hz), 8.22 (1 H, br s).
(2)4-[(2-Furoyl) phenylamino] -1- [2- [2- (1H-i Ndol-3-yl) ethylcarbamoyl] -2-phenylethyl] piperidine -4-Carboxylic acid methyl oxalate
  Methyl 4-[(2-furoyl) phenylamino] -1- [2- [2- (1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] piperidine-4-carboxylate obtained above and Using oxalic acid, the title compound was obtained as a white powder in the same manner as in Example 1 (2).
  ¹H NMR (CD₃OD, 400 MHz) δ: 1.8-2.0 (2H, m), 2.3-2.5 (2H, m), 2.7-3.0 (2H, m), 3.1-3 .4 (5H, m), 3.4-3.6 (2H, m), 3.75 (1H, dd, J = 9, 12 Hz), 3.83 (3H, s), 3.8-4 0.0 (1H, m), 5.41 (1 H, d, J = 3 Hz), 6.25 (1 H, dd, J = 1, 3 Hz), 6.79 (1 H, s), 6.97 (1 H , T, J = 8 Hz), 7.04 (1H, t, J = 8 Hz), 7.2-7.6 (13H, m).
IR (cm^-1, KBr): 3388, 3059, 2950, 1736, 1641, 1558, 1492, 1471, 1396, 1354, 1286, 1232, 1146, 1075, 1011, 949, 887, 746, 710, 594.
[Example 32]
(1)N- [2- (1H-Indol-3-yl) ethyl] -3- [4-methoxy Cymethyl-4- (phenylpropionylamino) piperidin-1-yl] -2- Phenylpropionic acid amide
The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxymethyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and tryptamine.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.93 (3H, t, J = 7 Hz), 1.4-1.5 (2H, m), 1.79 (2H, q, J = 7 Hz), 1.9-2. 3 (5H, m), 2.38 (1H, dd, J = 4, 13 Hz), 2.5-2.6 (1H, m), 2.9-3.0 (3H, m), 3. 37 (3H, s), 3.47 (1H, dd, J = 4, 10 Hz), 3.4-3.7 (2H, m), 3.89 (1H, d, J = 10 Hz), 3. 92 (1H, d, J = 10 Hz), 6.86 (1H, br s), 7.0-7.4 (13 H, m), 7.58 (1 H, d, J = 8 Hz), 7.62 (1H, br t), 8.18 (1H, br s).
(2)N- [2- (1H-Indol-3-yl) ethyl] -3- [4-methoxy Cymethyl-4- (phenylpropionylamino) piperidin-1-yl] -2- Phenylpropionamide oxalate
  N- [2- (1H-indol-3-yl) ethyl] -3- [4-methoxymethyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid amide obtained above and Using oxalic acid, the title compound was obtained as a white powder in the same manner as in Example 1 (2).
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.89 (2H, q, J = 7 Hz), 1.9-2.4 (3H, m), 2.8-3 0.0 (2H, m), 3.0-3.3 (5H, m), 3.43 (3H, s), 3.4-3.7 (3H, m), 3.8-3.9 (1H, m), 3.9-4.1 (3H, m), 6.79 (1H, s), 6.98 (1H, dt, J = 1, 8 Hz), 7.08 (1H, dt , J = 1, 8 Hz), 7.3-7.6 (12H, m).
IR (cm^-1, KBr): 3398, 2935, 1724, 1655, 1491, 1456, 1375, 1250, 1109, 744, 704.
[Example 33]
(1)N- [2- (1H-indol-3-yl) ethyl] -2-phenyl-3- [4-Phenyl-4- (phenylpropionylamino) piperidin-1-yl] Propionamide
  Using 2-phenyl-3- [4-phenyl-4- (phenylpropionylamino) piperidin-1-yl] propionic acid and tryptamine obtained in Reference Example 3 (2), in the same manner as in Example 1 (1). The title compound was obtained.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.84 (3H, t, J = 7 Hz), 1.69 (2H, q, J = 7 Hz), 1.7-2.2 (4H, m), 2.27 (1H, dd, J = 4, 13 Hz), 2.3-2.7 (4H, m), 2.85 (1H, dd, J = 11, 13 Hz), 2.95 (2H, t, J = 6 Hz), 3.44 (1H, dd, J = 4, 11 Hz), 3.5-3.7 (2H, m), 6.90 (1H, d, J = 2 Hz), 6.9-7.6 (19H) , M), 7.72 (1H, br t), 8.05 (1H, br s).
(2)N- [2- (1H-indol-3-yl) ethyl] -2-phenyl-3- [4-Phenyl-4- (phenylpropionylamino) piperidin-1-yl] Propionamide oxalate
N- [2- (1H-Indol-3-yl) ethyl] -2-phenyl-3- [4-phenyl-4- (phenylpropionylamino) piperidin-1-yl] propionic acid amide and shu obtained above The title compound was obtained as white crystals in the same manner as in Example 1 (2) using an acid.
¹H NMR (CD₃OD, 400 MHz) δ: 0.81 (3H, t, J = 7 Hz), 1.80 (2H, q, J = 7 Hz), 2.2-2.5 (2H, m), 2.6-3 0.0 (5H, m), 3.0-3.4 (4H, m), 3.4-3.5 (2H, m), 3.5-3.7 (1H, m), 3.8 -3.9 (1H, m), 6.80 (1H, s), 6.9-7.1 (2H, m), 7.1-7.6 (17H, m).
IR (cm^-1, KBr): 3340, 3060, 2950, 1720, 1660, 1600, 1540, 1500, 1460, 1360, 1280, 1230, 1080, 740, 700.
[Example 34]
(1)1- [2-[[2- (1H-Indol-3-yl) ethyl] methylcal Vamoyl] -2-phenylethyl] -4- (phenylpropionylamino) pipe Methyl lysine-4-carboxylate
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and Nω-methyltryptamine. .
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (1.5 H, t, J = 7 Hz), 0.95 (1.5 H, t, J = 7 Hz), 1.4-1.7 (2 H, m), 1. 84 (1H, q, J = 7 Hz), 1.85 (1H, q, J = 7 Hz), 2.1-2.6 (7H, m), 2.7-3.0 (2H, m), 2.82 (1.5H, s), 2.92 (1.5H, s), 3.2-3.4 (1H, m), 3.4-3.8 (2.5H, m), 3.75 (1.5 H, s), 3.77 (1.5 H, s), 3.8-3.9 (0.5 H, m), 6.86 (0.5 H, s), 6. 89 (0.5H, s), 7.0-7.6 (14H, m), 8.0-8.2 (1H, m).
(2)1- [2-[[2- (1H-Indol-3-yl) ethyl] methylcal Vamoyl] -2-phenylethyl] -4- (phenylpropionylamino) pipe Lysine-4-carboxylate methyl oxalate
  1- [2-[[2- (1H-Indol-3-yl) ethyl] methylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and sulphate obtained above The title compound was obtained as a white powder in the same manner as in Example 1 (2) using an acid.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (1.5 H, t, J = 7 Hz), 0.95 (1.5 H, t, J = 7 Hz), 1.6-1.8 (1 H, m), 1 .8-2.0 (1H, m), 1.92 (1H, q, J = 7 Hz), 1.93 (1H, q, J = 7 Hz), 2.2-4.0 (12.5H, m), 2.75 (1.5 H, s), 3.00 (1.5 H, s), 3.80 (1.5 H, s), 3.83 (1.5 H, s), 4.3 -4.4 (0.5H, m), 6.8-7.6 (15H, m).
IR (cm^-1, KBr): 3398, 2941, 1736, 1643, 1491, 1454, 1400, 1377, 1298, 1257, 1219, 1146, 1109, 1072, 1009, 947, 744, 706.
[Example 35]
(1)cis-N- [2- (1H-Indol-3-yl) ethyl] -3- [3- Methyl-4- (phenylpropionylamino) piperidin-1-yl] -2-fur Enylpropionic acid amide
  Diastereomer A and diastereomer B of cis-3- [3-methyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid obtained in Reference Example 4 (3) were respectively carried out. Reaction with tryptamine in the same manner as in Example 1 (1) gave the title compound.
  Diastereomer A
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.8-1.2 (2H, m), 0.87 (3H, d, J = 7 Hz), 0.99 (3H, t, J = 7 Hz), 1.7-2. 2 (5H, m), 2.24 (1H, dd, J = 4,13 Hz), 2.5-3.1 (5H, m), 3.3-3.4 (1H, m), 3. 46 (1H, dd, J = 5, 13 Hz), 3.7-3.9 (1H, m), 4.24 (1H, dt, J = 13, 4 Hz), 6.84 (1H, d, J = 2Hz), 7.0-7.5 (13H, m), 7.53 (1H, d, J = 8Hz), 7.83 (1H, br t), 8.08 (1H, br s).
  Diastereomer B
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.85 (3H, d, J = 7 Hz), 0.99 (3H, t, J = 7 Hz), 1.0-1.2 (2H, m), 1.7-2. 0 (3H, m), 2.2-2.5 (3H, m), 2.5-2.7 (2H, m), 2.83 (1H, dd, J = 11, 13 Hz), 2. 9-3.1 (2H, m), 3.3-3.5 (2H, m), 3.5-3.7 (1H, m), 4.25 (1H, dt, J = 13, 4 Hz) ), 6.87 (1H, d, J = 2Hz), 7.0-7.5 (13H, m), 7.55 (1H, d, J = 8Hz), 7.8-7.9 (2H) , Br).
(2)cis-N- [2- (1H-Indol-3-yl) ethyl] -3- [3- Methyl-4- (phenylpropionylamino) piperidin-1-yl] -2-fur Enylpropionamide oxalate
Cis-N- [2- (1H-Indol-3-yl) ethyl] -3- [3-methyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid amide obtained above Each of diastereomer A and diastereomer B was converted to an oxalate salt in the same manner as in Example 1 (2) to give the title compounds as white powders.
Diastereomer A
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.97 (3H, t, J = 7 Hz), 1.03 (3H, d, J = 7 Hz), 1.4-1.6 (2H, m), 1.8-2 0.0 (2H, m), 2.5-3.1 (8H, m), 3.3-3.6 (3H, m), 3.7-3.9 (1H, m), 4.3 -4.5 (1H, m), 6.87 (1H, s), 6.97 (1H, t, J = 7Hz), 7.06 (1H, t, J = 7Hz), 7.1-7 .6 (12H, m).
Diastereomer B
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.98 (3H, t, J = 7 Hz), 1.08 (3H, d, J = 7 Hz), 1.5-1.8 (2H, m), 1.9-2 .1 (2H, m), 2.7-3.0 (4H, m), 3.0-3.4 (4H, m), 3.4-3.6 (2H, m), 3.63 (1H, dd, J = 10, 13 Hz), 3.8-4.0 (1H, m), 4.4-4.5 (1H, m), 6.85 (1H, s), 6.98 (1H, t, J = 7 Hz), 7.07 (1H, t, J = 7 Hz), 7.1-7.6 (12H, m).
[Example 36]
(1)trans-N- [2- (1H-indol-3-yl) ethyl] -3- [ 3-methyl-4- (phenylpropionylamino) piperidin-1-yl] -2 -Phenylpropionic acid amide
  Using trans-3- [3-methyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid (a mixture of diastereomers) and tryptamine obtained in Reference Example 5 (3) The title compound was obtained in the same manner as 1 (1).
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.93 (1.5 H, d, J = 6 Hz), 0.97 (1.5 H, d, J = 6 Hz), 1.04 (1.5 H, t, J = 7 Hz), 1.05 (1.5H, t, J = 7 Hz), 1.5-1.7 (2H, m), 1.8-2.1 (4H, m), 2.3-2.4 (1H , M), 2.5-2.7 (1H, m), 2.8-3.0 (4H, m), 3.0-3.2 (1H, m), 3.4-3.5 (2H, m), 3.5-3.7 (1H, m), 4.2-4.5 (1H, br), 6.8-7.6 (16H, m).
(2)trans-N- [2- (1H-indol-3-yl) ethyl] -3- [ 3-methyl-4- (phenylpropionylamino) piperidin-1-yl] -2 -Phenylpropionic acid amide oxalate
Trans-N- [2- (1H-Indol-3-yl) ethyl] -3- [3-methyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid amide obtained above The (diastereomer mixture) was oxalated in the same manner as in Example 1 (2), and the diastereomers were separated by fractional crystals to obtain white crystals.
Diastereomer A (crystallized from ethyl acetate)
  ¹H NMR (CD₃OD, 400 MHz) δ: 1.00 (3H, t, J = 7 Hz), 1.06 (3H, d, J = 6 Hz), 1.3-2.0 (2H, m), 2.00 (2H , Q, J = 7 Hz), 2.7-3.0 (4H, m), 3.0-3.2 (1H, m), 3.2-3.6 (5H, m), 3.74 (1H, dd, J = 9, 13 Hz), 3.8-4.0 (1H, m), 4.4-4.7 (1H, br), 6.80 (1H, s), 6.97 (1H, t, J = 7 Hz), 7.07 (1H, t, J = 7 Hz), 7.1-7.6 (12H, m).
Diastereomer B (crystallized from mother liquor after precipitation of diastereomer A)
  ¹H NMR (CD₃OD, 400 MHz) δ: 1.00 (3H, t, J = 7 Hz), 1.07 (3H, d, J = 6 Hz), 1.3-2.0 (2H, m), 2.00 (2H , Q, J = 7 Hz), 2.7-3.0 (4H, m), 3.13 (1H, dd, J = 3, 13 Hz), 3.2-3.6 (5H, m), 3 .76 (1H, dd, J = 10, 13 Hz), 3.8-4.0 (1H, m), 4.4-4.7 (1H, br), 6.78 (1H, s), 6 .96 (1H, t, J = 7 Hz), 7.07 (1H, t, J = 7 Hz), 7.1-7.6 (12H, m).
[Example 37]
1- [2- [2- (4-Benzyloxy-1H-indol-3-yl) ethyl Carbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) Piperidine-4-carboxylate
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (4-benzyloxy-1H-indol-3-yl) ethylamine hydrochloride, The title compound was obtained in the same manner as Example 1 (1).
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.3-1.5 (2H, m), 1.81 (2H, q, J = 7 Hz), 2.0-2. 5 (6H, m), 2.5-2.6 (2H, m), 2.9-3.0 (2H, m), 3.32 (1H, dd, J = 4, 10 Hz), 3. 4-3.5 (2H, m), 3.75 (3H, s), 5.15 (2H, s) 6.58 (1H, d, J = 8 Hz), 6.7-6.8 (2H , M), 7.0-7.5 (17H, m), 8.07 (1H, s).
1- [2- [2- (4-Benzyloxy-1H-indol-3-yl) ethyl Carbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) Piperidine-4-carboxylate methyl oxalate
  Methyl 1- [2- [2- (4-benzyloxy-1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate obtained above The title compound was obtained as white crystals in the same manner as in Example 1 (2) using oxalic acid.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.93 (3H, t, J = 8 Hz), 1.6-1.9 (2H, m), 1.91 (2H, q, J = 8 Hz), 2.3-2 .4 (2H, m), 2.8-3.1 (2H, m), 3.1-3.4 (5H, m), 3.44 (2H, t, J = 7 Hz), 3.67 (1H, dd, J = 10, 11 Hz), 3.78 (3H, s), 3.8-3.9 (1H, m), 5.15 (2H, s), 6.52 (2H, d , J = 7 Hz), 6.9-7.0 (2H, m), 7.2-7.7 (15H, m).
IR (cm^-1, KBr): 3358, 1736, 1672, 1633, 1593, 1508, 1491, 1452, 1379, 1360, 1257, 1228, 1146, 1072, 999, 733, 700.
[Example 38]
1- [2- [2- (4-Hydroxy-1H-indol-3-yl) ethylcal Vamoyl] -2-phenylethyl] -4- (phenylpropionylamino) pipe Lysine-4-carboxylate methyl oxalate
  1- [2- [2- (4-Benzyloxy-1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-obtained in Example 37 (1) To a solution of methyl 4-carboxylate (40 mg, 0.058 mmol) in ethanol (2 mL) was added 10% palladium-carbon (10 mg), and catalytic hydrogenation was carried out at room temperature for 1 hour at 1 atmosphere. The catalyst was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform / methanol = 25/1). The obtained free base of the title compound was oxidized in the same manner as in Example 1 (2) to give the title compound (14 mg, 40% yield).
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.93 (3H, t, J = 7 Hz), 1.6-1.9 (2H, m), 1.92 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 2.9-3.6 (9H, m), 3.7-3.9 (2H, m), 3.79 (3H, s), 6.33 (1H, d , J = 7 Hz), 6.58 (1H, s), 6.76 (1H, d, J = 8 Hz), 6.82 (1H, dd, J = 7, 8 Hz) 7.2-7.6 ( 10H, m).
IR (cm^-1, KBr): 3398, 2941, 1736, 1655, 1647, 1593, 1560, 1508, 1491, 1261, 1146, 1039, 737, 704.
[Example 39]
(1)1- [2- [2- (5-Hydroxy-1H-indol-3-yl) ethyl Rucarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino ) Methyl piperidine-4-carboxylate
  The title compound was obtained in the same manner as in Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and serotonin.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.85 (2H, q, J = 7 Hz), 2.1-2. 2 (2H, m), 2.2-2.6 (5H, m), 2.82 (2H, t, J = 6 Hz), 3.08 (1H, t, J = 11 Hz), 3.2 3.4 (1H, m), 3.4-3.5 (1H, m), 3.5-3.6 (1H, m), 3.75 (3H, s), 6.75 (1H, dd, J = 2, 9 Hz), 6.83 (1 H, br s), 6.94 (1 H, d, J = 2 Hz), 7.1-7.5 (12 H, m), 7.97 (1 H , Br s).
(2)1- [2- [2- (5-Hydroxy-1H-indol-3-yl) ethyl Rucarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino ) Piperidine-4-carboxylate methyl oxalate
  Methyl 1- [2- [2- (5-hydroxy-1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate obtained above and The title compound was obtained as off-white crystals in the same manner as Example 1 (2) using oxalic acid.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.6-1.8 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 2.7-2.9 (2H, m), 3.1-3.5 (7H, m), 3.6-3.8 (1H, m), 3.80 (3H, s), 3.8-3.9 (1H, m), 6.65 (1H, dd, J = 2, 9 Hz), 6.75 (1H, s), 6.89 (1H, d , J = 2 Hz), 7.12 (1H, d, J = 9 Hz), 7.2-7.6 (10H, m).
IR (cm^-1, KBr): 3403, 1736, 1647, 1593, 1491, 1383, 1232, 1146, 1072, 1001, 935, 802, 706.
[Example 40]
(1)1- [2- [2- (1-Methylindol-3-yl) ethylcarbamoy L] -2-Phenylethyl] -4- (phenylpropionylamino) piperidine -4-Methyl carboxylate
  Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (1-methylindol-3-yl) ethylamine To give the title compound.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.3-1.5 (2H, m), 1.83 (2H, q, J = 7 Hz), 2.0-2. 2 (2H, m), 2.2-2.6 (4H, m), 2.6-2.7 (1H, m), 2.88 (2H, t, J = 6 Hz), 2.9- 3.0 (1H, m), 3.4-3.7 (3H, m), 3.70 (3H, s), 3.75 (3H, s), 6.67 (1H, s), 7 .0-7.4 (14H, m), 7.55 (1H, d, J = 8 Hz).
(2)1- [2- [2- (1-Methylindol-3-yl) ethylcarbamoy L] -2-Phenylethyl] -4- (phenylpropionylamino) piperidine -4-Carboxylic acid methyl oxalate
  The methyl 1- [2- [2- (1-methylindol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above were used. The title compound was obtained as white crystals in the same manner as in Example 1 (2).
mp: 131-133 ° C
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.7-1.9 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 2.7-2.9 (2H, m), 3.1-3.3 (5H, m), 3.3-3.6 (2H, m), 3.63 (3H, s), 3.7-3.8 (1H, m), 3.81 (3H, s), 3.9-4.0 (1H, m), 6.62 (1H, s), 6.99 (1 H, t, J = 8 Hz), 7.13 (1 H, t, J = 8 Hz) 7.2-7.6 (12 H, m).
IR (cm^-1, KBr): 3150, 2920, 1710, 1680, 1640, 1580, 1540, 1480, 1440, 1370, 1220, 1200, 1140, 720, 680.
[Example 41]
(1)1- [2- [2- (5-Chloro-1H-indol-3-yl) ethylca Rubamoyl] -2-phenylethyl] -4- (phenylpropionylamino) pi Peridine-4-carboxylate methyl
  Example 1 using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (5-chloro-1H-indol-3-yl) ethylamine The title compound was obtained in the same manner as (1).
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.98 (3H, t, J = 7 Hz), 1.1-1.3 (2H, m), 1.84 (2H, q, J = 7 Hz), 2.0-2. 2 (2H, m), 2.2-2.4 (2H, m), 2.4-2.5 (2H, m), 2.6-2.7 (1H, m), 2.8- 3.0 (3H, m), 3.4-3.7 (3H, m), 3.73 (3H, s), 6.95 (1H, d, J = 2 Hz), 7.0-7. 5 (12H, m), 7.55 (1 H, d, J = 2 Hz), 8.04 (1 H, br t), 9.02 (1 H, br s).
(2)1- [2- [2- (5-Chloro-1H-indol-3-yl) ethylca Rubamoyl] -2-phenylethyl] -4- (phenylpropionylamino) pi Peridine-4-carboxylate methyl oxalate
Methyl 1- [2- [2- (5-chloro-1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate obtained above and The title compound was obtained as pale brown crystals using oxalic acid in the same manner as in Example 1 (2).
mp: 119-123 ° C.
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.7-1.9 (2H, m), 1.92 (2H, q, J = 7 Hz), 2.3-2 .4 (2H, m), 2.7-2.9 (2H, m), 3.1-3.3 (5H, m), 3.3-3.5 (2H, m), 3.76 (1H, dd, J = 9, 13 Hz), 3.80 (3H, s), 3.93 (1H, dd, J = 3, 9 Hz), 6.82 (1H, s), 7.03 (1H , Dd, J = 2, 8 Hz), 7.2-7.4 (8H, m), 7.4-7.6 (4H, m).
IR (cm^-1, KBr): 3290, 2950, 1730, 1660, 1490, 1460, 1380, 1250, 1230, 700.
[Example 42]
(1)1- [2- [2- (Benzimidazol-2-yl) ethylcarbamoyl ] -2-Phenylethyl] -4- (phenylpropionylamino) piperidine- 4-Carboxylic acid methyl ester
  Similar to Example 1 (1) using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (benzimidazol-2-yl) ethylamine To give the title compound.
¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.4-1.6 (2H, m), 1.85 (2H, q, J = 7 Hz), 2.1-2. 3 (2H, m), 2.3-2.6 (4H, m), 2.6-2.8 (1H, m), 3.0-3.2 (3H, m), 3.4 3.7 (2H, m), 3.76 (3H, s), 3.7-3.9 (1H, m), 7.1-7.4 (14H, m), 7.4-7. 5 (1H, br), 7.83 (1H, br s).
(2)1- [2- [2- (Benzimidazol-2-yl) ethylcarbamoyl ] -2-Phenylethyl] -4- (phenylpropionylamino) piperidine- 4-Carboxylic acid methyl oxalate
  Using methyl 1- [2- [2- (benzimidazol-2-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and oxalic acid obtained above, The title compound was obtained as white crystals in the same manner as Example 1 (2).
mp: 148-150 ° C
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.8-2.0 (2H, m), 1.93 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 3.0-3.1 (1H, m), 3.1-3.4 (6H, m), 3.5-3.8 (3H, m), 3.79 (3H, s), 3.9-4.0 (1H, m), 7.1-7.6 (14H, m).
IR (cm^-1, KBr): 1740, 1650, 1500, 1460, 1400, 1280, 1230, 700.
[Example 43]
(1)1- [2- [2- (Benzo [b] thiophen-3-yl) ethylcarba Moyl] -2-phenylethyl] -4- (phenylpropionylamino) piperi Methyl gin-4-carboxylate
  Using 3- [4-methoxycarbonyl-4- (phenylpropionylamino) piperidin-1-yl] -2-phenylpropionic acid and 2- (benzo [b] thiophen-3-yl) ethylamine, Example 1 (1 ) To give the title compound.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (3H, t, J = 7 Hz), 1.3-1.5 (2H, m), 1.84 (2H, q, J = 7 Hz), 2.0-2. 2 (1H, m), 2.2-2.5 (5 H, m), 2.6-2.7 (1 H, m), 2.92 (1 H, dd, J = 9, 13 Hz) 3.00 (2H, t, J = 6 Hz), 3.4-3.7 (3H, m), 3.75 (3H, s), 6.97 (1H, s), 7.1-7.4 (12H M), 7.54 (1H, br-t), 7.75 (1H, dd, J = 2, 8 Hz), 7.85 (1H, dd, J = 2, 8 Hz).
(2)1- [2- [2- (Benzo [b] thiophen-3-yl) ethylcarba Moyl] -2-phenylethyl] -4- (phenylpropionylamino) piperi Gin-4-carboxylate methyl oxalate
  1- [2- [2- (Benzo [b] thiophen) -3-yl) ethylcarbamoyl] -2-phenylethyl] -4- (phenylpropionylamino) piperidine-4-carboxylate and sulphate obtained above The title compound was obtained as white crystals in the same manner as in Example 1 (2) using an acid.
mp: 130-135 ° C
¹H NMR (CD₃OD, 400 MHz) δ: 0.94 (3H, t, J = 7 Hz), 1.7-1.9 (2H, m), 1.92 (2H, q, J = 7 Hz), 2.3-2 .5 (2H, m), 2.9-3.0 (2H, m), 3.1-3.4 (5H, m), 3.4-3.6 (2H, m), 3.7 -3.8 (1H, m), 3.80 (3H, s), 3.8-4.0 (1H, m), 6.93 (1H, s), 7.2-7.9 (14H , M).
IR (cm^-1, KBr): 1740, 1650, 1490, 1450, 1420, 1370, 1240, 1140, 700.
[Example 44]
(1)4-[(2-Furoyl) pyridin-2-ylamino] -1- [2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] Piperidine-4-carboxylate
  Using 3- [4-[(2-furoyl) pyridin-2-ylamino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid and tryptamine obtained in Reference Example 8 (8) The title compound was obtained in the same manner as 1 (1).
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 1.7-1.9 (2H, m), 1.9-2.1 (1H, m), 2.2-2.5 (5H, m), 2.7-2. 8 (1H, m), 2.9-3.1 (3H, m), 3.47 (1H, dd, J = 3, 11 Hz), 3.5-3.6 (1H, m), 3. 7-3.8 (1H, m), 3.80 (3H, s), 6.08 (1H, dd, J = 1, 3 Hz), 6.24 (1 H, dd, J = 2, 3 Hz), 7.0-7.3 (11H, m), 7.3-7.4 (1H, m), 7.45 (1H, d, J = 8Hz), 7.57 (1H, d, J = 8Hz) ), 7.77 (1H, dt, J = 2, 8 Hz), 8.64 (1H, dd, J = 2, 5 Hz), 9.60 (1H, br s).
(2)4-[(2-Furoyl) pyridin-2-ylamino] -1- [2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] Piperidine-4-carboxylate methyl oxalate
  4-[(2-Furoyl) pyridin-2-ylamino] -1- [2- [2- (1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] piperidine-4-carboxylic acid obtained above The title compound was obtained as white crystals in the same manner as in Example 1 (2) using methyl acid and oxalic acid.
  ¹H NMR (CD₃OD, 400 MHz) δ: 1.9-2.2 (2H, m), 2.2-2.5 (2H, m), 2.7-3.0 (2H, m), 3.1-3 .4 (5H, m), 3.4-3.6 (2H, m), 3.6-3.8 (1H, m), 3.82 (3H, s), 3.8-3.9 (1H, m), 6.02 (1H, d, J = 4 Hz), 6.32 (1H, dd, J = 2, 4 Hz), 6.81 (1H, s), 6.96 (1H, dt , J = 1, 7 Hz), 7.05 (1H, dt, J = 1, 7 Hz), 7.2-7.4 (7H, m), 7.4-7.6 (2H, m), 7 .55 (1H, dd, J = 5, 7 Hz), 7.9-8.0 (1H, m), 8.62 (1H, br d).
[Example 45]
(1)4-[(2-Furoyl) pyridin-2-ylamino] -1- [2- (methyl) Ruphenethylcarbamoyl) -2-phenylethyl] piperidine-4-carvone Methyl acid
  Similar to Example 1 (1) using 3- [4-[(2-furoyl) pyridin-2-ylamino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid and N-methylphenethylamine To give the title compound.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 1.8-2.0 (2H, m), 2.1-2.8 (9H, m), 2.79 (1.8H, s), 2.88 (1.2H, s), 3.23 (0.4 H, dd, J = 8, 13 Hz), 3.3-3.4 (1 H, m), 3.4-3.7 (1.6 H, m), 3. 79 (1.2H, s), 3.81 (1.8H, s), 3.7-4.0 (1H, m), 5.8-5.9 (1H, m), 6.1- 6.2 (1H, m), 7.0-7.4 (13H, m), 7.6-7.8 (1H, m), 8.5-8.6 (1H, m).
(2)4-[(2-Furoyl) pyridin-2-ylamino] -1- [2- (methyl) Ruphenethylcarbamoyl) -2-phenylethyl] piperidine-4-carvone Methyl oxalate
  Using methyl 4-[(2-furylcarbonyl) pyridin-2-ylamino] -1- [2- (methylphenethylcarbamoyl) -2-phenylethyl] piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as a white powder in the same manner as Example 1 (2).
  ¹H NMR (CD₃OD, 400 MHz) δ: 2.0-2.3 (2H, m), 2.4-2.6 (2H, m), 2.74 (1.8H, s), 2.7-2.9. (2H, m), 2.99 (1.2H, s), 3.1-3.6 (6.4H, m), 3.6-3.8 (0.4H, m), 3.84 (3H, s), 3.8-4.0 (1.2H, m), 4.2-4.3 (0.4H, m), 4.3-4.4 (0.6H, m) , 6.0-6.1 (1H, m), 6.3-6.4 (1H, m), 6.9-7.7 (13H, m), 7.9-8.0 (1H, m) m), 8.66 (1H, br s).
[Example 46]
(1)1- [2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- [propionyl (pyridin-2-yl) amino] Piperidine-4-carboxylate
  Using 3- [4-methoxycarbonyl-4- [propionyl (pyridin-2-yl) amino] piperidin-1-yl] -2-phenylpropionic acid and tryptamine obtained in Reference Example 9 (2), Example 1 The title compound was obtained in the same manner as (1).
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 1.01 (3H, t, J = 8 Hz), 1.6-2.9 (11H, m), 2.9-3.2 (3H, m), 3.4-3. 6 (2H, m), 3.6-3.8 (1H, m), 3.78 (3H, s), 7.02 (1H, br s), 7.0-7.3 (8H, m) ), 7.3-7.4 (2H, m), 7.48 (1H, d, J = 8 Hz), 7.57 (1H, d, J = 8 Hz), 7.84 (1H, dt, J = 2,8 Hz), 8.58 (1H, br d, J = 2 Hz), 9.0-9.4 (1 H, br).
(2)1- [2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- [propionyl (pyridin-2-yl) amino] Piperidine-4-carboxylate methyl oxalate
  1- [2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] -4- [propionyl (pyridin-2-yl) amino] piperidine-4-carboxylic acid obtained above The title compound was obtained as white crystals in the same manner as Example 1 (2) using methyl and oxalic acid.
mp: 142-147 ° C
  ¹H NMR (CD₃OD, 400 MHz) δ: 1.05 (3H, t, J = 7 Hz), 1.6-2.5 (4H, br), 1.98 (2H, q, J = 7 Hz), 2.8-3 0.0 (2H, m), 3.1-3.6 (7H, m), 3.83 (1H, br t), 3.91 (3H, s), 3.99 (1H, br d), 6.90 (1H, s), 7.08 (1H, t, J = 7 Hz), 7.17 (1H, t, J = 7 Hz), 7.3-7.5 (6H, m), 7. 58 (1H, d, J = 8 Hz), 7.6-7.7 (2H, m), 8.12 (1H, br t), 8.72 (1 H, br d).
IR (cm^-1, KBr): 3336, 1730, 1672, 1635, 1585, 1466, 1435, 1381, 1230, 1149, 999, 951, 746.
[Example 47]
(1)1- [2- (Methylphenethylcarbamoyl) -2-phenylethyl]- 4- [propionyl (pyridin-2-yl) amino] piperidine-4-carvone Methyl acid
  3- [4-Methoxycarbonyl-4- [propionyl (pyridin-2-yl) amino] piperidin-1-yl] -2-phenylpropionic acid and N-methylphenethylamine were used in the same manner as in Example 1 (1). To give the title compound.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.95 (1.2 H, t, J = 7 Hz), 0.96 (1.8 H, t, J = 7 Hz), 1.8-2.1 (4 H, m), 2. 1-2.8 (9H, m), 2.78 (1.8H, s), 2.87 (1.2H, s), 3.1-3.4 (1.4H, m), 3. 4-3.7 (1.6 H, m), 3.77 (1.2 H, s), 3.78 (1.8 H, s), 3.7-3.9 (1 H, m), 7. 0-7.5 (12H, m), 7.7-7.8 (1H, m), 8.5-8.6 (1H, m).
(2)1- [2- (Methylphenethylcarbamoyl) -2-phenylethyl]- 4- [propionyl (pyridin-2-yl) amino] piperidine-4-carvone Methyl oxalate
  Example 1 Using methyl 1- [2- (methylphenethylcarbamoyl) -2-phenylethyl] -4- [propionyl (pyridin-2-yl) amino] piperidine-4-carboxylate and oxalic acid obtained above The title compound was obtained as white crystals in the same manner as (2).
mp: 147-149 ° C
  ¹H NMR (CD₃OD, 400 MHz) δ: 1.06 (3H, t, J = 7 Hz), 1.8-2.6 (4H, m), 1.99 (2H, q, J = 7 Hz), 2.83 (1 .8H, s), 2.7-2.9 (2H, m), 3.08 (1.2H, s), 3.1-3.6 (6.4H, m), 3.78 (0 .4H, dd, J = 10, 13 Hz), 3.92 (3H, s), 3.8-4.1 (1.2 H, m), 4.2-4.4 (0.4 H, m) 4.4-4.5 (0.6 H, m), 7.0-7.8 (12 H, m), 8.1-8.2 (1 H, m), 8.75 (1 H, br d ).
IR (cm^-1, KBr): 3427, 2943, 1741, 1659, 1635, 1585, 1466, 1435, 1377, 1267, 1217, 1146, 1070, 995, 754, 702, 467.
[Example 48]
(1)4- [Cyclopropylcarbonyl (pyridin-2-yl) amino] -1- [2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-fe Nylethyl] methyl piperidine-4-carboxylate
  Using 3- [4- [cyclopropylcarbonyl (pyridin-2-yl) amino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid and tryptamine obtained in Reference Example 10 (2) The title compound was obtained in the same manner as Example 1 (1).
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.60 (2H, br d), 0.8-1.1 (3H, m), 1.6-1.8 (2H, m), 1.9-2.5 (6H) , M), 2.6-2.8 (1H, m), 2.9-3.1 (3H, m), 3.45 (1H, dd, J = 3, 11 Hz), 3.4-3 .6 (1H, m), 3.6-3.8 (1H, m), 3.75 (3H, s), 7.0-7.3 (9H, m), 7.3-7.4 (2H, m), 7.5-7.6 (2H, m), 7.85 (1H, dt, J = 2, 8 Hz), 8.61 (1H, dd, J = 2, 5 Hz), 9 .44 (1H, br s).
(2)4-[(Cyclopropylcarbonyl (pyridin-2-yl) amino] -1 -[2- [2- (1H-Indol-3-yl) ethylcarbamoyl] -2-fur Nenylethyl] piperidine-4-carboxylate methyl oxalate
  4-[(Cyclopropylcarbonyl (pyridin-2-yl) amino] -1- [2- [2- (1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] piperidine-4 obtained above -The title compound was obtained as a white powder in the same manner as in Example 1 (2) using methyl carboxylate and oxalic acid.
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.75 (2H, dd, J = 3, 7 Hz), 0.9-1.1 (3H, m), 2.0-2.6 (4H, br), 2.8 -3.0 (2H, m), 3.2-3.6 (7H, m), 3.8-4.0 (1H, m), 3.89 (3H, s), 4.01 (1H , Br d), 6.90 (1H, s), 7.07 (1H, dt, J = 1, 7 Hz), 7.17 (1H, dt, J = 1, 7 Hz), 7.3-7. 5 (6H, m), 7.58 (1H, d, J = 8 Hz), 7.65 (1H, dd, J = 5, 7 Hz), 7.71 (1H, d, J = 8 Hz), 8. 14 (1H, dt, J = 2, 8 Hz), 8.75 (1H, br d).
IR (cm^-1, KBr): 3365, 1736, 1655, 1583, 1435, 1408, 1300, 1246, 1146, 1101, 958, 742, 700.
[Example 49]
(1)4- [Cyclopropylcarbonyl (pyridin-2-yl) amino] -1- [2- (Methylphenethylcarbamoyl) -2-phenylethyl] piperidine- 4-Carboxylic acid methyl ester
  Using 3- [4- [cyclopropylcarbonyl (pyridin-2-yl) amino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid and N-methylphenethylamine and Example 1 (1) The title compound was obtained in the same manner.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 0.5-0.6 (2H, m), 0.7-1.0 (3H, m), 1.8-1.9 (2H, m), 2.0-2. 8 (9 H, m), 2.79 (1.8 H, s), 2.87 (1.2 H, s), 3.20 (0.4 H, dd, J = 8, 13 Hz), 3.2 3.4 (1H, m), 3.4-3.7 (1.6 H, m), 3.74 (1.2 H, s), 3.76 (1.8 H, s), 3.82 ( 0.4 H, dd, J = 4, 8 Hz), 3.89 (0.6 H, dd, J = 4, 8 Hz), 7.0-7.4 (11 H, m), 7.49 (1 H, dd) , J = 3, 8 Hz), 7.7-7.9 (1H, m), 8.5-8.6 (1H, m).
(2)4- [Cyclopropylcarbonyl (pyridin-2-yl) amino] -1- [2- (Methylphenethylcarbamoyl) -2-phenylethyl] piperidine- 4-Carboxylic acid methyl oxalate
  Using methyl 4- [cyclopropylcarbonyl (pyridin-2-yl) amino] -1- [2- (methylphenethylcarbamoyl) -2-phenylethyl] piperidine-4-carboxylate obtained above and oxalic acid The title compound was obtained as white crystals in the same manner as in Example 1 (2). .
mp: 131-136 ° C
  ¹H NMR (CD₃OD, 400 MHz) δ: 0.6-0.8 (2H, m), 0.9-1.2 (3H, m), 2.0-2.7 (4H, m), 2.84 (1 .8H, s), 2.7-3.0 (2H, m), 3.08 (1.2H, s), 3.1-3.6 (6.4H, m), 3.7-3 .8 (0.4H, m), 3.90 (3H, s), 3.8-4.1 (1.2H, m), 4.3-4.4 (0.4H, m), 4 4-4.5 (0.6H, m), 7.0-7.8 (12H, m), 8.1-8.3 (1H, m), 8.7-8.8 (1H, m).
IR (cm^-1, KBr): 3412, 3028, 1736, 1641, 1585, 1468, 1452, 1408, 1300, 1267, 1217, 1147, 958, 754, 721, 702, 501.
[Example 50]
(1)4-[(2-Furoyl) pyrazinylamino] -1- [2- [2- (1H- Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] piperidi 4-methyl carboxylate
  Using 3- [4-[(2-furoyl) pyrazinylamino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid and tryptamine obtained in Reference Example 11 (5), Example 1 (1) To give the title compound.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 1.7-1.9 (2H, m), 2.0-2.1 (1H, m), 2.2-2.5 (5H, m), 2.7-2. 8 (1 H, m), 2.8-3.0 (2 H, m), 3.06 (1 H, dd, J = 11, 13 Hz), 3.47 (1 H, dd, J = 4, 11 Hz), 3.5-3.6 (1H, m), 3.6-3.8 (1H, m), 3.80 (3H, s), 6.28 (1H, dd, J = 2, 3 Hz), 6.52 (1 H, d, J = 3 Hz), 6.99 (1 H, d, J = 2 Hz), 7.0-7.3 (11 H, m), 7.57 (1 H, d, J = 8 Hz) ), 8.5-8.6 (1H, m), 8.59 (1H, d, J = 2 Hz), 8.69 (1H, d, J = 1 Hz), 8.74 (1H, br s) .
(2)4-[(2-Furoyl) pyrazinylamino] -1- [2- [2- (1H- Indol-3-yl) ethylcarbamoyl] -2-phenylethyl] piperidi 4-Carboxylic acid methyl oxalate
  4-[(2-Furoyl) pyrazinylamino] -1- [2- [2- (1H-indol-3-yl) ethylcarbamoyl] -2-phenylethyl] piperidine-4-carboxylate and sulphate obtained above The title compound was obtained as pale yellow crystals in the same manner as Example 1 (2) using an acid. .
  ¹H NMR (CD₃OD, 400 MHz) δ: 1.9-2.2 (2H, m), 2.3-2.5 (2H, m), 2.7-3.0 (2H, m), 3.1-3 .4 (5H, m), 3.49 (2H, br t, J = 7 Hz), 3.7-3.8 (1H, m), 3.84 (3H, s), 3.9-4. 0 (1 H, m), 6.38 (1 H, dd, J = 1, 3 Hz), 6.51 (1 H, d, J = 3 Hz), 6.81 (1 H, s), 6.95 (1 H, dt, J = 1, 7 Hz), 7.04 (1 H, dt, J = 1, 7 Hz), 7.2-7.4 (7 H, m), 7.47 (1 H, d, J = 7 Hz), 8.65 (1H, s), 8.68 (1 H, br s), 8.71 (1 H, d, J = 2 Hz).
[Example 51]
(1)4-[(2-Furoyl) pyrazinylamino] -1- [2- (methylphene Tylcarbamoyl) -2-phenylethyl] piperidine-4-carboxylate
  Using 3- [4-[(2-furoyl) pyrazinylamino] -4-methoxycarbonylpiperidin-1-yl] -2-phenylpropionic acid and N-methylphenethylamine in the same manner as in Example 1 (1), the title compound Got.
  ¹1 H NMR (CDCl₃, 400 MHz) δ: 1.7-1.9 (2H, m), 2.1-2.9 (9H, m), 2.79 (1.8H, s), 2.89 (1.2H, s), 3.24 (0.4 H, dd, J = 8, 13 Hz), 3.3-3.7 (2.6 H, m), 3.80 (1.2 H, s), 3.82 ( 1.8H, s), 3.7-3.9 (1H, m), 6.2-6.3 (1H, m), 6.42 (1H, br d, J = 3 Hz), 7.0 -7.4 (12H, m), 8.5-8.7 (3H, m).
(2)4-[(2-Furoyl) pyrazinylamino] -1- [2- (methylphene Tylcarbamoyl) -2-phenylethyl] piperidine-4-carboxylate Oxalate
  Example 1 (2) using methyl 4-[(2-furoyl) pyrazinylamino] -1- [2- (methylphenethylcarbamoyl) -2-phenylethyl] piperidine-4-carboxylate and oxalic acid obtained above. In the same manner as described above, the title compound was obtained as a pale yellow powder. .
  ¹H NMR (CD₃OD, 400 MHz) δ: 2.0-2.3 (2H, m), 2.4-2.6 (2H, m), 2.75 (1.8H, s), 2.7-2.9. (2H, m), 2.98 (1.2H, s), 3.1-3.6 (6.4H, m), 3.6-3.8 (0.4H, m), 3.85 (3H, s), 3.8-4.0 (1.2H, m), 4.2-4.3 (0.4H, m), 4.3-4.4 (0.6H, m) , 6.3-6.4 (1H, m), 6.5-6.6 (1H, m), 6.9-7.5 (11H, m), 8.6-8.8 (3H, m).
[Example 52]
(Pharmacological experiment)
I. Measuring method
(1) Binding affinity for human μ opioid receptor
  The binding experiment for μ opioid receptor was performed using a membrane preparation (RECEPTOR BIOLOGY INC.) of human μ opioid receptor (GenBank Accession No. L25119) expressed in CHO-K1 cells by gene transfer. For radioligand [³H] DAMGO was used.
  In the presence of the test substance, the membrane preparation and final concentration of 5 nM [³H] DAMGO was added and incubated at 22 ° C. for 2.5 hours. The reaction was stopped by suction filtration with a GF / B filter using a cell harvester and washed with a Tris-HCl buffer. The radioactivity remaining on the membrane was measured with a liquid scintillation counter. In addition, [³The specific binding amount of H] DAMGO was calculated as the difference between the total binding amount and the binding amount in the presence of 100 nM of non-radioactive naloxone.
  [³H] The binding rate in the presence of each concentration of the test substance with respect to the specific binding of DAMGO was calculated, and the IC was measured using GraphPad Prism.₅₀The value was determined.
(2) Analgesic action (acetic acid rising method)
  ICR male mice were used as 8 to 10 mice per group. Thirty minutes after subcutaneous administration of the test substance, a 0.6% aqueous acetic acid solution (0.1 mL / 10 g body weight) was intraperitoneally administered. Thereafter, the number of rising that developed in 20 minutes was counted. ED from the suppression rate for the number of controls₅₀The value was calculated.
(3) Antagonistic studies with peripheral and central (systemic) μ-opioid receptor antagonists
  ICR male mice were used as 8 to 10 mice per group. 5 mg / kg of naloxone methiodide, which is a peripheral μ-opioid receptor antagonist that does not cross the blood brain barrier, or naloxone hydrochloride, which is a systemic μ-opioid receptor antagonist, is intraperitoneally administered. It was administered subcutaneously. After 20 minutes, a 0.6% acetic acid aqueous solution was intraperitoneally administered (0.1 mL / 10 g body weight), and the number of rising that developed in the subsequent 20 minutes was counted. The rise rate of the test substance alone group was compared with the rate of inhibition of the naloxone methiodide or naloxone hydrochloride pretreatment group.
II. Test results
  Test results
(1) Binding experiment to μ-receptor

Example numbers indicate the compounds obtained in the synthesis examples described above, and all oxalates were used except in Example 23 (the same applies to Tables 15 and 16).
(2) Analgesic action

(3) Antagonistic studies with peripheral and central (systemic) μ-opioid receptor antagonists

From the above Tables 14 and 15, it was revealed that the compound of the present invention has an excellent binding affinity for the μ-receptor and an excellent analgesic action. Table 16 also shows that the analgesic action of the compound of the present invention is peripheral (that is, when the peripheral μ-opioid receptor antagonist was pretreated, the analgesic action of the compound of the present invention almost disappeared).
In the antagonism test of (3) above, the analgesic action of fentanyl used as a comparative drug was not affected at all by the pretreatment with the peripheral antagonist, but disappeared completely by the pretreatment with the systemic antagonist. On the other hand, the analgesic action of loperamide used as another comparative drug was almost completely antagonized by the peripheral antagonist. From the above results, it was confirmed that the analgesic action of fentanyl was not caused by peripheral μ-opioid receptors but expressed via central μ-opioid receptors. Moreover, it was confirmed that the analgesic action of loperamide is expressed through peripheral μ-opioid receptors.

Claims (10)

The following general formula (I),

(In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 members, a C ¹ to C 6 alkyl group substituted with an alkoxy group having 1 to 6 carbon atoms, or 5 or Represents a 6-membered heterocyclic group,
R ² represents a substituent or a group or atom selected from a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. Represents a phenyl group or a 5- or 6-membered heterocyclic group which may have 1 to 3,
R ³ represents a hydrogen atom, a phenyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, or a methyl group substituted with an alkoxy group having 1 to 6 carbon atoms,
R ⁴ is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group substituted with a halogen atom, a nitro group, a cyano group, or amino as a substituent. Represents a phenyl group optionally having 1 to 3 groups or atoms selected from the group;
R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aralkyl group (the alkyl portion has 1 to 6 carbon atoms and the aryl portion has 6 to 10 carbon atoms);
R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a 5- or 6-membered heterocyclic group, and an aralkyl group (the alkyl portion has 1 to 6 carbon atoms and the aryl portion has 6 to 6 carbon atoms). 10), or a heterocyclic alkyl group (the alkyl moiety has 1 to 6 carbon atoms, the heterocyclic ring is a 5- or 6-membered ring, and may be condensed with a benzene ring).
Here, the alkyl group having 1 to 6 carbon atoms is a halogen atom, a 3- to 7-membered cycloalkyl group, an alkoxy group having 1 to 6 carbon atoms, an amino group, or an alkylamino group (the carbon number of the alkyl moiety is 1 to 6). 6), a dialkylamino group (wherein each alkyl moiety has 1 to 6 carbon atoms), an acylamino group having 2 to 6 carbon atoms, a carbamoyl group, an alkylcarbamoyl group (wherein the alkyl moiety has 1 to 6 carbon atoms), a dialkylcarbamoyl (each alkyl The portion may have 1 to 5 carbon atoms as a substituent, or a group or atom selected from 1 to 6), a hydroxyl group, a nitro group, or a cyano group.
In addition, a phenyl group, a heterocyclic group, an aryl part of an aralkyl group, and a heterocyclic part of a heterocyclic alkyl (including a benzene ring when the heterocyclic ring is condensed with a benzene ring) are a halogen atom, carbon number 1 Alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, amino group, alkylamino group (the alkyl moiety has 1 to 6 carbon atoms), dialkylamino Group (carbon number of each alkyl part is 1-6), acylamino group having 2-6 carbon atoms, carbamoyl group, alkylcarbamoyl group (carbon number of 1-6 of alkyl part), dialkylcarbamoyl (carbon number of each alkyl part is 1 to 6), 1 to 5 groups or atoms selected from hydroxyl group, hydroxymethyl group, nitro group, or cyano group may be substituted.
Further ^{R 6} are the heterocyclic (ring constituting atoms 5- to 7-membered ring together with the nitrogen atom ^{to which R 5} and ^{R 5} and ^{R 6} are attached, further in addition to the nitrogen atom ^{to which R 5} and ^{R 6} are attached This heterocycle may contain an alkyl group having 1 to 6 carbon atoms or an aralkyl group (the alkyl portion has 1 to 6 carbon atoms, and the carbon of the aryl portion). The number may be substituted with 6 to 10) or an acyl group having 2 to 6 carbon atoms).
R ⁷ represents a hydrogen atom or a methyl group,
And m represents 1 or 2. )
Or a salt thereof. The compound or a salt thereof according to claim 1, wherein R ³ is a methyl group substituted with an alkoxycarbonyl group having 2 to 8 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. The compound according to claim 1 or a salt thereof, wherein R ⁷ is a methyl group and R ³ is a hydrogen atom or an alkoxycarbonyl group having 2 to 8 carbon atoms. R ² represents a substituent or a group or atom selected from a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. The compound or salt thereof according to any one of claims 1 to 3, which is a phenyl group which may have 1 to 3 groups. R ² represents a substituent or a group or atom selected from a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. The compound or a salt thereof according to any one of claims 1 to 3, which is a 5- or 6-membered heterocyclic group optionally having 1 to 3 members. The heterocyclic group of R ² is a group selected from a pyridyl group, a pyrazinyl group, a pyrimidyl group, and a pyrazole group, and the substituent of the heterocyclic ring is a group or an atom selected from a halogen atom and an alkyl group having 1 to 6 carbon atoms. The compound according to any one of claims 1 to 3, or a salt thereof. R ⁶ is an aralkyl group (the alkyl part has 1 to 6 carbon atoms, and the aryl part has 6 to 10 carbon atoms) or a heterocyclic alkyl group (the alkyl part has 1 to 6 carbon atoms, the heterocyclic ring is 5 or 6 The compound or a salt thereof according to any one of claims 1 to 6, which is a membered ring and may be condensed with a benzene ring.
Here, the aryl part of the aralkyl group and the heterocyclic part of the heterocyclic alkyl (including the benzene ring when the heterocyclic ring is condensed with the benzene ring) are a halogen atom, an alkyl group having 1 to 6 carbon atoms. , An alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, an amino group, an alkylamino group (the alkyl moiety has 1 to 6 carbon atoms), a dialkylamino group (each alkyl moiety) 1-6), an acylamino group having 2-6 carbon atoms, a carbamoyl group, an alkylcarbamoyl group (1-6 carbon atoms in the alkyl moiety), a dialkylcarbamoyl (1-6 carbon atoms in each alkyl moiety), It may have 1 to 5 groups or atoms selected from a hydroxy group, a hydroxymethyl group, a nitro group, or a cyano group as a substituent. The compound or a salt thereof according to any one of claims 1 to 7, wherein m is 1. An analgesic comprising the compound according to any one of claims 1 to 8 or a salt thereof as an active ingredient. The analgesic according to claim 9, wherein the analgesic action is peripheral.