JPH11322786A - Depsipeptide containing non-natural amino acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new depsipeptide (salt) having an apolipoprotein E production-promoting action and useful for the treatments of dementia, hyperlipemia, etc. SOLUTION: The compound of formula I R<1> is a 5-20C alkyl or a 5-15C alkoxymethyl; R<2> is O-CO-CH(R<5> )-X-CH(R<6> )-NH (X is CH2 -CO, CH2 -CH2 or the like; R<5> and R<6> are each H or a 1-6C alkyl); R<3> is a group of formula II [Y is CH2 -CH2 , CH=CH or the like; R<9> and R<10> are each H or a 1-6C alkyl; R<11> is an amino-protecting group; (n) is 1-3]; R<4> is hydroxyl group, a 1-6C alkoxy, benzyloxy or the like], for example, a compound of formula III, is obtained, e.g., by reacting a compound of formula IV with a compound of formula V and subsequently reacting the obtained compound of formula VI with Fmoc-L-aspartic acid β-t-butyl ester.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】[0001]

【発明の属する技術分野】本発明は、新規なデプシペプ
チドおよびこれを有効成分とする医薬に関する。本発明
のデプシペプチドは、アポリポプロテインＥの産生促進
作用を有し、神経損傷治療薬、特に痴呆症治療薬として
有用であり、さらに高脂血症の治療薬としても有用であ
る。[0001] The present invention relates to a novel depsipeptide and a medicament containing the same as an active ingredient. The depsipeptide of the present invention has an apolipoprotein E production promoting effect, is useful as a therapeutic agent for nerve damage, particularly as a therapeutic agent for dementia, and is also useful as a therapeutic agent for hyperlipidemia.

【０００２】[0002]

【従来の技術】老人性痴呆症の治療薬として、脳循環代
謝改善薬が主として使用されているが、これらの薬物
は、老人性痴呆症の原因と考えられている中枢神経系の
崩壊には何ら改善作用を示さない。その結果痴呆の中核
的症状というべき記憶障害や計算能力障害に対しても何
ら改善作用を示さない。そこで新しいタイプの老人性痴
呆症の治療薬として、神経系の修復、成長を促進し、中
枢神経の崩壊を抑制する薬物が求められている。他方、
アポリポプロテインＥは、損傷し回復しつつある神経系
部位で高レベルで発現することが報告されており（例え
ば、M.J. Igunalius etal., Pro. Natl.Acad. Sci. U.
S.A., 83：1125(1986)参照）、神経系の修復に重要な役
割を担うであろうことが示唆されている。さらに最近、
アポリポプロテインＥをヒトの家族性高コレステロール
血症ホモ接合体のモデル動物であるWHHLウサギに静脈投
与すると、血漿コレステロール濃度の著明な減少が認め
られることが報告され（Yamada，et. al., Proceeding
ofNational Academy Science USA, Vol.86, pp665-66
9，1989）、また、マウス肝臓にラットアポリポプロテ
インＥの遺伝子を導入してアポリポプロテインＥを大量
に発現させると、血漿コレステロールとトリグリセリド
が顕著に低下することが報告された（Shimano, H. et.
al., Journal of Clinical Investigation, Vol.90,pp
2084-2091, 1992）。2. Description of the Related Art Drugs for improving cerebral circulation and metabolism are mainly used as therapeutic drugs for senile dementia, but these drugs are not suitable for the destruction of the central nervous system, which is considered to be the cause of senile dementia. No improvement effect is shown. As a result, it does not show any improvement effect on memory impairment or computational impairment, which is the core symptom of dementia. Therefore, a drug that promotes repair and growth of the nervous system and suppresses the breakdown of the central nervous system is required as a therapeutic agent for a new type of senile dementia. On the other hand,
Apolipoprotein E has been reported to be expressed at high levels in damaged and recovering nervous system sites (eg, MJ Igunalius et al., Pro. Natl. Acad. Sci. U.
SA, 83: 1125 (1986)), suggesting that it may play an important role in nervous system repair. More recently,
It has been reported that when apolipoprotein E is intravenously administered to WHHL rabbits, which are human model animals of familial hypercholesterolemia homozygous, a marked decrease in plasma cholesterol level is observed (Yamada, et. Al., Proceeding
ofNational Academy Science USA, Vol.86, pp665-66
9, 1989), and it has been reported that when apolipoprotein E gene is introduced into mouse liver in a large amount and apolipoprotein E is expressed in large amounts, plasma cholesterol and triglyceride are significantly reduced (Shimano, H. et al.). .
al., Journal of Clinical Investigation, Vol.90, pp
2084-2091, 1992).

【０００３】これらの報告で明らかになったように、血
漿アポリポプロテインＥ濃度を上昇させることは、高脂
血症、特に今までの薬剤では治療が困難だとされてきた
家族性高コレステロール血症ホモ接合体の治療法として
極めて有効とされている。本発明者らはさきに血漿アポ
リポプロテインＥ濃度を上昇させる有力な方法として、
アポリポプロテインＥの主要な産生臓器である肝臓での
アポリポプロテインＥ産生能の促進作用を有し、経口投
与可能な低分子の化合物として、種々のデプシペプチド
化合物が有用であることを見出して特願平８−１８３９
６０号、特願平８−２７１３２１号の発明を完成させ
た。[0003] As revealed by these reports, increasing plasma apolipoprotein E levels is associated with hyperlipidemia, especially familial hypercholesterolemia, which has been considered difficult to treat with conventional drugs. It is extremely effective as a treatment for homozygotes. The present inventors have previously proposed a possible method for increasing plasma apolipoprotein E concentration,
Various depsipeptide compounds have been found to be useful as orally administrable low-molecular-weight compounds, which have the effect of promoting the production of apolipoprotein E in the liver, which is a major organ for producing apolipoprotein E, and have been found to be useful in Japanese Patent Application Laid-Open No. H10-163,873. 8-1839
No. 60 and Japanese Patent Application No. 8-271321 were completed.

【０００４】[0004]

【発明が解決しようとする課題】かかる状況の許におい
て、本発明者らはアポリポプロテインＥの産生を促進す
る薬物を提供するべく鋭意研究の結果、特定構造のデプ
シペプチド誘導体がこれらの作用を有することを見いだ
して本発明を完成したのである。Under such circumstances, the present inventors have conducted intensive studies to provide a drug which promotes the production of apolipoprotein E. Thus, the present invention was completed.

【０００５】[0005]

【課題を解決するための手段】本発明は、一般式(１)According to the present invention, there is provided a compound represented by the general formula (1):

【化３】 ［式中、Ｒ¹は、直鎖状もしくは有枝鎖状のＣ₅〜Ｃ₂₀ア
ルキル基または直鎖状もしくは有枝鎖状のＣ₅〜Ｃ₁₅ア
ルコキシメチル基を示し、Ｒ²は、 −Ｏ−ＣＯ−ＣＨ(Ｒ⁵)−Ｘ−ＣＨ(Ｒ⁶)−ＮＨ− （式中、Ｘは、Ｎ(Ｒ⁷)−ＣＯ、Ｎ(Ｒ⁸)−ＣＨ₂、ＣＨ₂
−ＣＯ、ＣＨ₂−ＣＨ₂、ＣＨ＝ＣＨ、ＣＨ₂−ＣＨ(Ｏ
Ｈ)、ＣＨ(ＯＨ)−ＣＨ(ＯＨ)を示し、Ｒ⁵、Ｒ⁶、Ｒ⁷、
Ｒ⁸は、水素または直鎖状もしくは有枝鎖状のＣ₁〜Ｃ₆
アルキル基を示す）を示し、Ｒ³は、Embedded image [Wherein, R ¹ represents a linear or branched C ₅ -C ₂₀ alkyl group or a linear or branched C ₅ -C ₁₅ alkoxymethyl group, and R ² represents — ^{O-CO-CH (R 5} ) -X-CH (R 6) -NH- ( wherein, X ^{is, N (R 7) -CO,} N (R 8) -CH 2, CH 2
_{-CO, CH 2 -CH 2, CH} = CH, CH 2 -CH (O
H), CH (OH) -CH (OH), R ⁵ , R ⁶ , R ⁷ ,
R ⁸ is hydrogen or linear or branched C ₁ -C ₆
R ³ represents an alkyl group).

【化４】 （式中、Ｙは、Ｎ(Ｒ¹²)−ＣＯ、Ｎ(Ｒ¹³)−ＣＨ₂、Ｃ
Ｈ₂−ＣＯ、ＣＨ₂−ＣＨ₂、ＣＨ＝ＣＨ、ＣＨ₂−ＣＨ
(ＯＨ)、ＣＨ(ＯＨ)−ＣＨ(ＯＨ)を示し、ｎは１〜３の
整数を示し、Ｒ⁹、Ｒ¹⁰、Ｒ¹²、Ｒ¹³は、水素または直
鎖状もしくは有枝鎖状のＣ₁〜Ｃ₆アルキル基を示し、Ｒ
¹¹はアミンの保護基としてペプチド化学で通常用いられ
る保護基を示す）を示し、Ｒ⁴は、水酸基、直鎖状もし
くは有枝鎖状のＣ₁〜Ｃ₆アルコキシ基、ベンジルオキシ
基、Ａ、Ａ−Ｂ、または −ＮＨ−ＣＨ(Ｒ¹⁴)−Ｚ−ＣＨ(Ｒ¹⁵)−ＣＯＲ¹⁶ （式中、Ｚは、ＣＨ₂−Ｎ(Ｒ¹⁷)、ＣＯ−ＣＨ₂、ＣＯ−
Ｎ(Ｒ¹⁸)、ＣＨ₂−ＣＨ₂、ＣＨ＝ＣＨ、ＣＨ(ＯＨ)−Ｃ
Ｈ₂、ＣＨ(ＯＨ)−ＣＨ(ＯＨ)を示し、Ｒ¹⁴は水素、Ｃ₁
〜Ｃ₆アルキル基または−(ＣＨ₂)_m−ＣＯＲ¹⁹を示し、
Ｒ¹⁵、Ｒ¹⁷、Ｒ¹⁸は、水素または直鎖状もしくは有枝鎖
状のＣ₁〜Ｃ₆アルキル基を示し、Ｒ¹⁶は、水酸基、直鎖
状もしくは有枝鎖状のＣ₁〜Ｃ₆アルコキシ基またはベン
ジルオキシ基を示し、Ｒ¹⁹は水酸基、アミノ基またはＣ
₁〜Ｃ₆アルコキシ基を示し、ｍは１〜３の整数を示す）
を示し、Ａは、アラニン、バリン、ロイシン、イソロイ
シン、フェニルアラニン、チロシン、プロリン、アスパ
ラギン酸、アスパラギン、グルタミン酸、グルタミン、
セリン、リシンおよびβ−ｔ−ブチルアラニンからなる
アミノ酸残基またはこれらのアミノ酸残基のＮ−メチル
体を示し、Ｂは、アラニン、バリン、ロイシン、イソロ
イシン、セリン、トレオニン、リシン、ヒドロキシリシ
ン、アルギニン、システイン、メチオニン、フェニルア
ラニン、チロシン、トリプトファン、ヒスチジン、プロ
リン、４−ヒドロキシプロリン、アスパラギン酸、アス
パラギン、グルタミン酸、グルタミン、ピペリジン−４
−カルボン酸、ホモプロリン、オクタヒドロインドール
−２−カルボン酸、ノルバリン、ノルロイシン、α−ｔ
−ブチルグリシン、シクロヘキシルグリシン、アゼチジ
ン−２−カルボン酸、３−（３−ピリジル）アラニン、
（３−Ｎ−メチル）ピペリジルアラニン、３−（２−ナ
フチル）アラニン、β−シクロヘキシルアラニン、β−
ｔ−ブチルアラニン、９−アントラセニルアラニン、α
−メチルアラニンおよび２−アミノブタン酸から選ばれ
るアミノ酸残基またはこれらのアミノ酸残基のＮ−メチ
ル体を示し、ＡまたはＢにおける遊離のアミノ基、遊離
のカルボキシル基、遊離のω−カルバミド基、遊離の水
酸基、遊離のメルカプト基および／またはＮ−末端のア
ミノ基はそれらの保護基としてペプチド化学で通常用い
られる保護基でそれぞれ保護されていてもよく、そして
上記ＡまたはＢにおけるアミノ酸残基がリシン、ヒドロ
キシリシン、グルタミン酸またはアスパラギン酸である
場合は、隣接するアミノ酸とペプチド結合するアミノ基
またはカルボキシル基はα−位にあるものでもまたはω
−位にあるものでもよい。ただし、ＸがＮ(Ｒ⁷)−ＣＯ
であり、ＹがＮ(Ｒ¹²)−ＣＯであり、Ｒ⁴が水酸基、直
鎖状もしくは有枝鎖状のＣ₁〜Ｃ₆アルコキシ基、ベンジ
ルオキシ基、Ａ、Ａ−Ｂまたは−ＮＨ−ＣＨ(Ｒ¹⁴)−Ｚ
−ＣＨ(Ｒ¹⁵)−ＣＯＲ¹⁶｛ＺはＣＯ−Ｎ(Ｒ^{1 8})である｝
である場合を除く。］で示される非天然アミノ酸を含有
するデプシペプチドまたはその薬理学的に許容される塩
に関する。Embedded image(Where Y is N (R¹²) -CO, N (R¹³) -CH_Two, C
H_Two-CO, CH_Two-CH_Two, CH = CH, CH_Two-CH
(OH), CH (OH) -CH (OH), wherein n is 1 to 3
Represents an integer;⁹, R^Ten, R¹², R¹³Is hydrogen or direct
Chain or branched C₁~ C₆Represents an alkyl group;
¹¹Is commonly used in peptide chemistry as an amine protecting group.
R represents a protecting group).^FourIs a hydroxyl group, linear
Or branched C₁~ C₆Alkoxy group, benzyloxy
Group, A, AB, or -NH-CH (R¹⁴) -Z-CH (R^Fifteen) -COR¹⁶  (Where Z is CH_Two−N (R¹⁷), CO-CH_Two, CO-
N (R¹⁸), CH_Two-CH_Two, CH = CH, CH (OH) -C
H_Two, CH (OH) -CH (OH), R¹⁴Is hydrogen, C₁
~ C₆Alkyl group or-(CH_Two)_m-COR¹⁹Indicates that
R^Fifteen, R¹⁷, R¹⁸Is hydrogen or a linear or branched chain
C₁~ C₆Represents an alkyl group;¹⁶Is a hydroxyl group, straight chain
Or branched C₁~ C₆Alkoxy group or ben
Represents a zyloxy group;¹⁹Is a hydroxyl group, an amino group or C
₁~ C₆Represents an alkoxy group, and m represents an integer of 1 to 3)
A represents alanine, valine, leucine, isoleuc
Syn, phenylalanine, tyrosine, proline, Aspa
Laginic acid, asparagine, glutamic acid, glutamine,
Consists of serine, lysine and β-t-butylalanine
Amino acid residues or the N-methyl of these amino acid residues
Body, B is alanine, valine, leucine, isolo
Isine, serine, threonine, lysine, hydroxylysine
Arginine, cysteine, methionine, phenyla
Lanin, tyrosine, tryptophan, histidine, pro
Phosphorus, 4-hydroxyproline, aspartic acid, as
Paragine, glutamic acid, glutamine, piperidine-4
-Carboxylic acids, homoproline, octahydroindole
-2-carboxylic acid, norvaline, norleucine, α-t
-Butylglycine, cyclohexylglycine, azetidi
2-carboxylic acid, 3- (3-pyridyl) alanine,
(3-N-methyl) piperidylalanine, 3- (2-na)
Fthyl) alanine, β-cyclohexylalanine, β-
t-butylalanine, 9-anthracenylalanine, α
-Selected from methylalanine and 2-aminobutanoic acid
Amino acid residues or the N-methyl
A free amino group in A or B, free
Carboxyl group, free ω-carbamide group, free water
Acid groups, free mercapto groups and / or N-terminal
Mino groups are commonly used in peptide chemistry as their protecting groups
Each may be protected by a protecting group, and
The amino acid residue in the above A or B is lysine, hydro
Xylosine, glutamic acid or aspartic acid
In this case, an amino group that binds the peptide to the adjacent amino acid
Or the carboxyl group is in the α-position or ω
-Position. Where X is N (R⁷) -CO
And Y is N (R¹²) -CO and R^FourIs a hydroxyl group,
Chain or branched C₁~ C₆Alkoxy group, benzyl
Group, A, AB or -NH-CH (R¹⁴) -Z
-CH (R^Fifteen) -COR¹⁶｛Z is CO-N (R^{1 8})
Except when. ] Containing an unnatural amino acid
Depsipeptide or a pharmacologically acceptable salt thereof
About.

【０００６】本発明はまた、上記した非天然アミノ酸を
含有するデプシペプチドまたはその薬理学的に許容され
る塩を有効成分とする医薬にも関する。本発明は具体的
には、上記した非天然アミノ酸を含有するデプシペプチ
ドまたはその薬理学的に許容される塩を有効成分とする
アポリポプロテインＥ産生促進薬に関する。本発明はよ
り具体的には、上記した非天然アミノ酸を含有するデプ
シペプチドまたはその薬理学的に許容される塩を有効成
分とする神経損傷治療薬に関する。本発明はより具体的
には、上記した非天然アミノ酸を含有するデプシペプチ
ドまたはその薬理学的に許容される塩を有効成分とする
痴呆症治療薬にも関する。本発明はさらに、上記した非
天然アミノ酸を含有するデプシペプチドまたはその薬理
学的に許容される塩を有効成分とする高脂血症治療薬に
も関する。[0006] The present invention also relates to a medicament comprising, as an active ingredient, a depsipeptide containing the above-mentioned unnatural amino acid or a pharmaceutically acceptable salt thereof. The present invention specifically relates to an apolipoprotein E production enhancer comprising, as an active ingredient, a depsipeptide containing the above-mentioned unnatural amino acid or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a therapeutic agent for nerve damage, comprising, as an active ingredient, a depsipeptide containing the above-mentioned unnatural amino acid or a pharmaceutically acceptable salt thereof. More specifically, the present invention also relates to a therapeutic agent for dementia comprising, as an active ingredient, a depsipeptide containing the above-mentioned unnatural amino acid or a pharmaceutically acceptable salt thereof. The present invention further relates to a therapeutic agent for hyperlipidemia containing the above-mentioned unnatural amino acid-containing depsipeptide or a pharmaceutically acceptable salt thereof as an active ingredient.

【０００７】前記一般式(１)において好ましくは、Ｘは
ＣＨ＝ＣＨまたはＣＨ₂−ＣＨ₂であり、ＹはＮ(Ｒ¹²)−
ＣＯまたはＮ(Ｒ¹³)−ＣＨ₂であり、Ｒ⁴は水酸基、Ａ、
Ａ−Ｂまたは−ＮＨ−ＣＨ(Ｒ¹⁴)−Ｚ−ＣＨ(Ｒ¹⁵)−Ｃ
ＯＲ¹⁶（ＺはＣＨ＝ＣＨである）である。前記一般式
(１)の好ましい化合物は、ＸがＣＨ＝ＣＨであり、Ｙが
Ｎ(Ｒ¹²)−ＣＯまたはＮ(Ｒ¹³)−ＣＨ₂であり、Ｒ⁴が水
酸基、Ａ、Ａ−Ｂまたは−ＮＨ−ＣＨ(Ｒ¹⁴)−Ｚ−ＣＨ
(Ｒ¹⁵)−ＣＯＲ¹⁶（ＺはＣＨ＝ＣＨである）であるデプ
シペプチドまたはその薬理学的に許容される塩、および
ＸがＣＨ₂−ＣＨ₂であり、ＹがＮ(Ｒ¹²)−ＣＯであり、
Ｒ⁴がＡ−Ｂであるデプシペプチドまたはその薬理学的
に許容される塩である。前記一般式(１)において、Ｒ⁴
が水酸基であるか、またはＡがアスパラギン酸、アスパ
ラギン、グルタミン酸またはグルタミンであり、Ｂがア
ラニン、バリン、ロイシン、イソロイシン、フェニルア
ラニン、チロシン、プロリン、アスパラギン酸、アスパ
ラギン、グルタミン酸、グルタミンまたはβ−ｔ−ブチ
ルアラニンである非天然アミノ酸を含有するデプシペプ
チドまたはその薬理学的に許容される塩が好ましい。ま
た、前記一般式(１)において、Ｒ¹⁶は水酸基であること
が好ましい。In the general formula (1), preferably, X is CHＣＨCH or CH ₂ —CH ₂ and Y is N (R ¹² ) —
CO or N (R ¹³⁾ is -CH _2, R ⁴ is hydroxyl, A,
A-B or ^{-NH-CH (R 14) -Z} -CH (R 15) -C
OR ¹⁶ (Z is CH = CH). The general formula
Preferred compounds of (1) are those wherein X is CH = CH, Y is N (R ¹² ) -CO or N (R ¹³ ) -CH ₂ , and R ⁴ is hydroxyl, A, AB or -NH -CH (R ¹⁴⁾ -Z-CH
(R ¹⁵⁾ -COR ¹⁶ (Z is CH = is CH) and a depsipeptide or a pharmacologically acceptable salt thereof, and X is CH ₂ -CH _2, Y is N (R ¹²⁾ -CO And
A depsipeptide wherein R ⁴ is AB or a pharmacologically acceptable salt thereof. In the general formula (1), R ⁴
Is a hydroxyl group, or A is aspartic acid, asparagine, glutamic acid or glutamine, and B is alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, proline, aspartic acid, asparagine, glutamic acid, glutamine, β-t-butyl. A depsipeptide containing an unnatural amino acid that is alanine or a pharmaceutically acceptable salt thereof is preferred. In the general formula (1), R ¹⁶ is preferably a hydroxyl group.

【０００８】上記した本発明の一般式(１)を有する非天
然アミノ酸を含有するデプシペプチドを構成する上記ア
ミノ酸は、Ｌ−体またはＤ−体のいずれであってもよ
く、そして一般式(１)中のＡおよびＢにおける遊離のア
ミノ基、遊離のカルボキシル基、遊離のω−カルバミド
基、遊離の水酸基、遊離のメルカプト基および／または
Ｎ−末端のアミノ基はそれらの保護基としてペプチド化
学で通常用いられる保護基でそれぞれ保護されていても
よく、そして上記ＡおよびＢのアミノ酸残基がリシン、
ヒドロキシリシン、グルタミン酸またはアスパラギン酸
である場合は、隣接するアミノ酸とペプチド結合するア
ミノ基またはカルボキシル基はα−位にあるものでもま
たはω−位にあるものでもよい。[0008] The amino acid constituting the depsipeptide containing an unnatural amino acid having the general formula (1) of the present invention described above may be either an L-form or a D-form. In amino acids A and B, free amino groups, free carboxyl groups, free ω-carbamide groups, free hydroxyl groups, free mercapto groups and / or N-terminal amino groups are usually used as their protecting groups in peptide chemistry. Each of the amino acid residues of A and B may be protected with lysine,
In the case of hydroxylysine, glutamic acid or aspartic acid, the amino group or carboxyl group that binds to a peptide adjacent to an adjacent amino acid may be at the α-position or at the ω-position.

【０００９】そして上記した遊離のアミノ基の保護基と
してはｔ−ブトキシカルボニル（以下、「Ｂｏｃ」とい
う）基、ベンジルオキシカルボニル（以下、「Ｃｂｚ」
という）基、ｐ−メトキシベンジルオキシカルボニル基
または９−フルオレニルメトキシカルボニル（以下、
「Ｆｍｏｃ」という）基等が、また、遊離のカルボキシ
ル基の保護基としてはベンジルオキシ（以下、「ＯＢｚ
ｌ」という）基、ｔ−ブトキシ（以下、「ＯｔＢｕ」と
いう）基またはフェナシルオキシ（以下、「ＯＰａｃ」
という）基等が、ＧｌｎまたはＡｓｎのω−カルバミド
基の保護基としては４,４′−ジメトキシベンズヒドリ
ル（以下、「Ｍｂｈ」という）基またはトリチル（以下
「Ｔｒｔ」という）基等が、遊離の水酸基の保護基とし
てはＯＢｚｌ基、ＯｔＢｕ基等が、アミノ酸残基におけ
る遊離のメルカプト基の保護基としてはベンジル基、Ｔ
ｒｔ基、アセタミドメチル基等が挙げられる。上記デプ
シペプチドのＮ−末端アミノ基の保護基としては、Ｂｏ
ｃ基、Ｃｂｚ基、ｐ−メトキシベンジルオキシカルボニ
ル基およびＦｍｏｃ基などのペプチド化学で通常用いら
れる保護基が用いられる。上記デプシペプチドのＣ−末
端カルボキシル基の保護基としては、ＯＢｚｌ基、Ｏｔ
Ｂｕ基、ＯＰａｃ基等が用いられる。The protecting groups for the above free amino group include a t-butoxycarbonyl (hereinafter referred to as "Boc") group and a benzyloxycarbonyl (hereinafter referred to as "Cbz").
) Group, p-methoxybenzyloxycarbonyl group or 9-fluorenylmethoxycarbonyl (hereinafter, referred to as
And a protecting group for a free carboxyl group such as benzyloxy (hereinafter referred to as “OBz”).
l ") group, t-butoxy (hereinafter" OtBu ") group or phenacyloxy (hereinafter" OPac ") group
A protecting group for the ω-carbamide group of Gln or Asn, such as a 4,4′-dimethoxybenzhydryl (hereinafter, referred to as “Mbh”) group or a trityl (hereinafter, referred to as “Trt”) group; The protecting groups for free hydroxyl groups are OBzl group and OtBu group, and the protecting groups for free mercapto groups in amino acid residues are benzyl group and T
rt group, acetamide methyl group and the like. The protecting group for the N-terminal amino group of the depsipeptide may be Bo
Protecting groups usually used in peptide chemistry such as c group, Cbz group, p-methoxybenzyloxycarbonyl group and Fmoc group are used. Protecting groups for the C-terminal carboxyl group of the depsipeptide include OBzl group, Ot
A Bu group, an OPac group or the like is used.

【００１０】本発明の前記一般式(１)を有するデプシペ
プチドは、肝臓の諸機能を備えたＨｅｐ Ｇ２細胞のア
ポリポプロテインＥ産生を促進する作用を有する。アポ
リポプロテインＥは神経損傷の修復作用を有し、さらに
コレステロールとトリグリセリドの血中濃度を低下させ
る作用を有するので、アポリポプロテインＥの産生促進
作用を有する本発明のデプシペプチドは、神経損傷治療
薬、特に痴呆症治療薬および高脂血症治療薬として有用
である。The depsipeptide having the general formula (1) of the present invention has an action of promoting the production of apolipoprotein E by Hep G2 cells having various liver functions. Apolipoprotein E has a repair effect on nerve damage and also has an effect of lowering blood levels of cholesterol and triglyceride.Therefore, the depsipeptide of the present invention having an action of promoting production of apolipoprotein E is a therapeutic agent for nerve damage, particularly It is useful as a therapeutic drug for dementia and hyperlipidemia.

【００１１】本発明の前記一般式(１)で示される非天然
アミノ酸を含むデプシペプチドまたはその薬理学的に許
容される塩は、ペプチド合成において通常使用される方
法で製造することができる。例えば、泉屋信夫他著「ペ
プチド合成の基礎と実験」丸善(株)１９８５年などに記
載された縮合剤法、アジド法、クロリド法、酸無水物
法、混合酸無水物法、活性エステル法、酸化還元法、酵
素法などを用いることができる。The depsipeptide containing an unnatural amino acid represented by the general formula (1) or a pharmacologically acceptable salt thereof of the present invention can be produced by a method usually used in peptide synthesis. For example, the condensing agent method, azide method, chloride method, acid anhydride method, mixed acid anhydride method, mixed acid anhydride method, active ester method, described in Nobuo Izumiya et al. An oxidation-reduction method, an enzymatic method, or the like can be used.

【００１２】例えば、本発明の非天然アミノ酸を含有す
るデプシペプチドまたはその薬理学的に許容される塩
は、一般式（２）For example, the depsipeptide containing an unnatural amino acid of the present invention or a pharmaceutically acceptable salt thereof is represented by the general formula (2)

【化５】 （式中、Ｒ¹は前述したものと同一意義を有する）を有
する３−ヒドロキシカルボン酸のヒドロキシル基または
カルボキシル基を保護または活性化した後、この３−ヒ
ドロキシカルボン酸のヒドロキシル基には必要なＮ−末
端を保護したアミノカルボン酸すなわち Ｐ−ＨＮ−ＣＨ(Ｒ⁶)−Ｘ−ＣＨ(Ｒ⁵)−ＣＯＯＨ （式中、Ｐはアミノ基の保護基を示す）のカルボキシル
基を、またこの３−ヒドロキシカルボン酸のカルボキシ
ル基には必要なアミノカルボン酸誘導体、すなわち Ｈ₂Ｎ−ＣＨ(Ｒ¹⁴)−Ｚ−ＣＨ(Ｒ¹⁵)−ＣＯＲ¹⁶ のアミノ基をそれぞれ定法により縮合させ、Ｎ−末端ま
たはＣ−末端の保護基を脱保護した後に、そのアミノ基
およびカルボキシル基をペプチド合成の定法に従って順
次所望のアミノ酸と縮合させることにより製造すること
ができる。Embedded image(Where R¹Has the same meaning as described above)
The hydroxyl group of 3-hydroxycarboxylic acid or
After protecting or activating the carboxyl group,
N-terminal required for hydroxyl group of droxycarboxylic acid
End-protected aminocarboxylic acid, ie, P-HN-CH (R⁶) -X-CH (R^Five) -COOH (wherein P represents a protecting group for an amino group)
And the carboxy group of the 3-hydroxycarboxylic acid.
The required aminocarboxylic acid derivative, ie, H_TwoN-CH (R¹⁴) -Z-CH (R^Fifteen) -COR¹⁶  Are condensed according to a standard method, and the N-terminal and
Or after deprotection of the C-terminal protecting group, the amino group
And carboxyl groups in order according to the standard method of peptide synthesis.
Next, to produce by condensing with the desired amino acid
Can be.

【００１３】あるいは別法として、上記したアミノカル
ボン酸に先にあらかじめ必要なアミノ酸を縮合させ、次
いで上記した３−ヒドロキシカルボン酸のヒドロキシル
基またはカルボキシル基にエステル結合またはアミド結
合によって結合させることによって製造することができ
る。Alternatively, the above-mentioned aminocarboxylic acid can be prepared by condensing the above-mentioned aminocarboxylic acid with a necessary amino acid in advance, and then bonding it to the hydroxyl group or carboxyl group of the above-mentioned 3-hydroxycarboxylic acid by an ester bond or an amide bond. can do.

【００１４】上記した一般式(２)の化合物のカルボキシ
ル基の保護は、エーテル、メタノールなどの溶媒中、氷
冷下ないし室温でジアゾメタンと反応させるメチルエス
テル化反応や、ジメチルホルムアミド（以下、「ＤＭ
Ｆ」という）、ジメチルスルホキシド（以下、「ＤＭＳ
Ｏ」という）などの溶媒中、室温〜加熱下で、塩基性物
質例えばトリエチルアミンの存在下、ベンジルブロミド
を反応させるベンジルエステル化などによって行うこと
ができる。The carboxyl group of the compound represented by the general formula (2) is protected by a methyl esterification reaction by reacting with diazomethane in a solvent such as ether or methanol under ice-cooling or at room temperature, or dimethylformamide (hereinafter referred to as "DMDM").
F ”), dimethyl sulfoxide (hereinafter“ DMS ”).
O ") in the presence of a basic substance such as triethylamine in the presence of a basic substance such as triethylamine in a solvent such as benzyl esterification.

【００１５】カルボキシル基が保護された化合物のヒド
ロキシル基への、アミノカルボン酸の縮合は、エーテ
ル、アセトン、クロロホルム、ジクロロメタン、酢酸エ
チル、ＤＭＦ、テトラヒドロフラン（以下、「ＴＨＦ」
という）、アセトニトリル、ＤＭＳＯなどの溶媒中、氷
冷下ないし室温で、好ましくはジメチルアミノピリジン
（以下、「ＤＭＡＰ」という）のようなアシル化触媒の
存在下で縮合試薬としてのＮ,Ｎ′−ジシクロヘキシル
カルボジイミド（N,N′−Dicyclohexylcarbodiimide）
(以下、「ＤＣＣ」という）や、１−エチル−３−(３′
−ジメチルアミノプロピル）カルボジイミド（１−Ethy
l−３−(３′−dimethylaminopropyl)carbodiimide）塩
酸塩、すなわち水溶性カルボジイミド（以下、「ＷＳＣ
Ｉ」という）を用いて行われる。Condensation of an aminocarboxylic acid with a hydroxyl group of a compound having a protected carboxyl group can be carried out by ether, acetone, chloroform, dichloromethane, ethyl acetate, DMF, tetrahydrofuran (hereinafter referred to as “THF”).
N, N'- as a condensing reagent in a solvent such as acetonitrile, DMSO or the like under ice-cooling or room temperature, preferably in the presence of an acylation catalyst such as dimethylaminopyridine (hereinafter referred to as "DMAP"). Dicyclohexylcarbodiimide (N, N'-Dicyclohexylcarbodiimide)
(Hereinafter referred to as “DCC”), 1-ethyl-3- (3 ′
-Dimethylaminopropyl) carbodiimide (1-Ethy
l-3- (3′-dimethylaminopropyl) carbodiimide) hydrochloride, that is, water-soluble carbodiimide (hereinafter “WSC”)
I ").

【００１６】本発明のデプシペプチドの出発原料となる
一般式(２)の３−ヒドロキシカルボン酸の具体例として
は、３−ヒドロキシカプリル酸、３−ヒドロキシペラル
ゴン酸、３−ヒドロキ−カプリン酸、３−ヒドロキシラ
ウリン酸、３−ヒドロキシミリスチン酸、３−ヒドロキ
シパルミチン酸、３−ヒドロキシマルガリン酸、３−ヒ
ドロキシステアリン酸、４−オクチルオキシ−３−ヒド
ロキシ酪酸、４−ノニルオキシ−３−ヒドロキシ酪酸、
４−デシルオキシ−３−ヒドロキシ酪酸、４−ウンデシ
ルオキシ−３−ヒドロキシ酪酸、４−ドデシルオキシ−
３−ヒドロキシ酪酸または４−トリデシルオキシ−３−
ヒドロキシ酪酸等が挙げられる。これらの一般式(２)の
３−ヒドロキシカルボン酸はＲ−体またはＳ−体の光学
活性体並びにラセミ体を用いることができるが、Ｒ¹が
直鎖状または有枝鎖状のＣ₅〜Ｃ₂₀アルキル基の場合は
Ｒ−体を用いることが好ましく、Ｒ¹が直鎖状または有
枝鎖状のＣ₅〜Ｃ₁₅アルコキシメチル基である場合はＳ
−体を用いることが好ましい。Specific examples of the 3-hydroxycarboxylic acid of the general formula (2) which is a starting material of the depsipeptide of the present invention include 3-hydroxycaprylic acid, 3-hydroxypelargonic acid, 3-hydroxy-capric acid, Hydroxylauric acid, 3-hydroxymyristic acid, 3-hydroxypalmitic acid, 3-hydroxymargaric acid, 3-hydroxystearic acid, 4-octyloxy-3-hydroxybutyric acid, 4-nonyloxy-3-hydroxybutyric acid,
4-decyloxy-3-hydroxybutyric acid, 4-undecyloxy-3-hydroxybutyric acid, 4-dodecyloxy-
3-hydroxybutyric acid or 4-tridecyloxy-3-
Hydroxybutyric acid and the like. These 3-hydroxycarboxylic acids of the general formula (2) may be an optically active substance and racemic R- form or S- body, C ₅ ~ of R ¹ is a linear or branched chain it is preferable to use R- body case to C ₂₀ alkyl radical, if R ¹ is a linear or branched chain C ₅ -C ₁₅ alkoxymethyl group S
-It is preferred to use the body.

【００１７】前記一般式(１)を有するデプシペプチドを
製造するに際して、縮合剤法を用いる場合は、ＤＣＣ、
ＷＳＣＩ、Ｏ−（１Ｈ−ベンゾトリアゾール−１−イ
ル）−Ｎ,Ｎ,Ｎ′,Ｎ′−テトラメチルウロニウムテト
ラフルオロボレート（ＴＢＴＵ）、ベンゾトリアゾール
−１−イル−オキシ−トリス（ジメチルアミノ）ホスホ
ニウムヘキサフルオロホスフェート（ＢＯＰ）またはＯ
−（７−アザベンゾトリアゾール−１−イル）−１,２,
３−テトラメチルウロニウムヘキサフルオロホスフェー
ト（ＨＡＴＵ）等を用いることができる。また、同時
に、ラセミ化を抑制するために通常用いられる添加剤、
例えばＮ−ヒドロキシスクシンイミド、１−ヒドロキシ
ベンゾトリアゾール（1−Hydroxybenzotriazole)（以
下、「ＨＯＢｔ」という）、Ｎ−ヒドロキシ−５−ノル
ボネン−２,３−ジカルボジイミドまたは１−ヒドロキ
シ−７−アザベンゾトリアゾール（ＨＯＡｔ）等を加え
ることも好ましい。また、アジド法で用いられる主な縮
合剤としては、ジフェニルリン酸アジド（以下、「ＤＰ
ＰＡ」という）等が挙げられる。なお、縮合反応を行う
前に、通常公知の手段によって当該縮合反応に関与しな
いカルボキシル基、アミノ基、水酸基、メルカプト基な
らびにω−カルバミド基等へ保護手段を施すことが好ま
しい。この場合、保護手段に用いる保護基としては、前
述の各種保護基を用いることができる。In producing the depsipeptide having the general formula (1), when the condensing agent method is used, DCC,
WSCI, O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-yl-oxy-tris (dimethylamino) Phosphonium hexafluorophosphate (BOP) or O
-(7-azabenzotriazol-1-yl) -1,2,
3-Tetramethyluronium hexafluorophosphate (HATU) or the like can be used. Also, at the same time, additives usually used to suppress racemization,
For example, N-hydroxysuccinimide, 1-hydroxybenzotriazole (1-Hydroxybenzotriazole) (hereinafter, referred to as “HOBt”), N-hydroxy-5-norbonene-2,3-dicarbodiimide or 1-hydroxy-7-azabenzotriazole ( HOAt) is also preferable. The main condensing agent used in the azide method is diphenylphosphate azide (hereinafter referred to as “DP
PA "). Before performing the condensation reaction, it is preferable to protect the carboxyl group, amino group, hydroxyl group, mercapto group, ω-carbamide group and the like which are not involved in the condensation reaction by a generally known means. In this case, the above-mentioned various protecting groups can be used as the protecting group used for the protecting means.

【００１８】本発明のデプシペプチドの製造工程におけ
る保護基の脱離反応は、ペプチド結合に影響を与えずに
保護基を脱離できるものが必要であり、用いる保護基の
種類に応じて適宜選択すればよい。前記の各ペプチド合
成に用いる溶媒としては、例えばクロロホルム、ジクロ
ロメタン、酢酸エチル、ＤＭＦ、ＤＭＳＯ、ピリジン、
ジオキサン、ＴＨＦ、ジメトキシエタン、アセトニトリ
ルなどが挙げられ、必要に応じて２種以上の溶媒を合わ
せて用いてもよい。また、この縮合反応は通常の場合と
同様に、約−２０〜５０℃の範囲で行われる。また、ペ
プチド合成は、液相法および固相法のいずれによっても
製造でき、更にカラム法、バッチ法のいずれを用いても
よい。The elimination reaction of the protecting group in the production process of the depsipeptide of the present invention needs to be capable of eliminating the protecting group without affecting the peptide bond, and may be appropriately selected depending on the kind of the protecting group to be used. I just need. Examples of the solvent used for the above-mentioned peptide synthesis include chloroform, dichloromethane, ethyl acetate, DMF, DMSO, pyridine,
Examples thereof include dioxane, THF, dimethoxyethane, and acetonitrile. If necessary, two or more solvents may be used in combination. In addition, this condensation reaction is carried out in the range of about -20 to 50 ° C. as in the usual case. Further, peptide synthesis can be produced by any of a liquid phase method and a solid phase method, and further, any of a column method and a batch method may be used.

【００１９】本発明のデプシペプチドが塩の形態の化合
物である場合には、これを遊離の形態の化合物に変換
し、またこのようにして製造された本発明のデプシペプ
チドが遊離の形態の化合物である場合にはこれをその薬
理学的に許容される塩の形態の化合物に変換することが
できる。そして後者の場合においてこのデプシペプチド
がカルボキシル基の存在によって酸性化合物である時に
は、無機塩基との塩、例えばナトリウム塩、カリウム
塩、カルシウム塩、アンモニウム塩など、または有機塩
基との塩を、またこのペプチド誘導体がアミノ基の存在
によって塩基性化合物である時には、無機酸との塩、例
えば塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩など、ま
たは有機酸との塩、例えば酢酸塩、コハク酸塩、シュウ
酸塩、リンゴ酸塩、酒石酸塩などの薬理学的に許容され
る塩を形成させうる。When the depsipeptide of the present invention is a compound in the form of a salt, it is converted into a compound in a free form, and the thus prepared depsipeptide of the present invention is a compound in a free form. If desired, this can be converted into the compound in the form of its pharmacologically acceptable salts. And in the latter case, when the depsipeptide is an acidic compound due to the presence of a carboxyl group, a salt with an inorganic base, such as a sodium salt, a potassium salt, a calcium salt, an ammonium salt, or a salt with an organic base, and the peptide When the derivative is a basic compound due to the presence of an amino group, salts with inorganic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates, etc., or salts with organic acids, such as acetates, succinates Pharmaceutically acceptable salts such as acid, oxalate, malate and tartrate salts may be formed.

【００２０】本発明のデプシペプチドまたはその薬理学
的に許容しうる塩は種々の投与形態の製剤とすることが
できる。すなわち、この製剤は経口的に錠剤、糖衣錠、
硬カプセル剤、軟カプセル剤、顆粒剤、散剤等の固形製
剤および溶液、エマルジョンまたは懸濁液等の液体製剤
の形態で投与することができる。また、非経口投与の場
合には注射剤、坐剤等の形態で投与される。これらの製
剤の調製にあたっては製剤化のための慣用の添加剤、例
えば賦形剤、安定剤、防腐剤、溶解剤、湿潤剤、乳化
剤、滑沢剤、甘味剤、着色剤、香味剤、張度調製剤、緩
衝剤、酸化防止剤などを添加して製剤化することができ
る。The depsipeptide of the present invention or a pharmaceutically acceptable salt thereof can be formulated into various dosage forms. That is, this preparation is orally administered as tablets, dragees,
It can be administered in the form of solid preparations such as hard capsules, soft capsules, granules and powders and liquid preparations such as solutions, emulsions or suspensions. In the case of parenteral administration, it is administered in the form of injections, suppositories and the like. In preparing these preparations, conventional additives for preparation such as excipients, stabilizers, preservatives, solubilizers, wetting agents, emulsifiers, lubricants, sweeteners, coloring agents, flavoring agents, and tonics are used. The preparation can be prepared by adding a preparation, buffer, antioxidant and the like.

【００２１】添加剤としては、例えばデンプン、白糖、
果糖、乳糖、ブドウ糖、マンニトール、ソルビトール、
沈降性炭酸カルシウム、結晶セルロース、カルボキシメ
チルセルロース、デキストリン、ゼラチン、アラビアゴ
ム、ステアリン酸マグネシウム、タルク、ヒドロキシプ
ロピルメチルセルロース等が挙げられる。Examples of additives include starch, sucrose,
Fructose, lactose, glucose, mannitol, sorbitol,
Precipitated calcium carbonate, crystalline cellulose, carboxymethylcellulose, dextrin, gelatin, gum arabic, magnesium stearate, talc, hydroxypropylmethylcellulose and the like can be mentioned.

【００２２】本発明のデプシペプチドを液剤、注射剤と
して用いるときは本発明のデプシペプチドを慣用の希釈
剤中に溶解または懸濁して用いることができる。希釈剤
としては、生理食塩水、リンゲル液、ブドウ糖水溶液、
アルコール類、脂肪酸エステル類、グリコール類、グリ
セリン、動植物由来の油脂、パラフィン類などが含まれ
る。また、これらの製剤は、通常の方法で製造すること
ができる。When the depsipeptide of the present invention is used as a liquid preparation or an injection, the depsipeptide of the present invention can be dissolved or suspended in a conventional diluent. As a diluent, physiological saline, Ringer's solution, aqueous glucose solution,
Examples include alcohols, fatty acid esters, glycols, glycerin, fats and oils derived from animals and plants, paraffins, and the like. In addition, these preparations can be manufactured by a usual method.

【００２３】そして通常の臨床投与量として、成人一人
当たり経口の場合、０.５〜２０００mgの範囲、好まし
くは１〜１０００mgの範囲、さらに好ましくは５〜５０
０mgの範囲で用いられる。また、成人一人一日あたり非
経口の場合は、０.０５〜５０００mgの範囲で用いられ
る。The usual clinical dose is 0.5 to 2000 mg, preferably 1 to 1000 mg, and more preferably 5 to 50 mg per oral dose per adult.
Used in the range of 0 mg. In the case of parenteral administration per adult per day, the dose is 0.05 to 5000 mg.

【００２４】次に本発明のデプシペプチドの製造方法の
具体例を実施例として、また本発明のデプシペプチドの
アポリポプロテインＥ産生能についての試験を試験例と
して、また本発明のデプシペプチドを有効成分とする製
剤についての具体例を製剤例としてそれぞれ述べること
にする。Next, a specific example of the method for producing the depsipeptide of the present invention will be described as an example, a test on the apolipoprotein E-producing ability of the depsipeptide of the present invention will be described as a test example, and a preparation containing the depsipeptide of the present invention as an active ingredient will be described. Will be described as formulation examples.

【００２５】そして、実施例１における反応工程は反応
スキーム１に、実施例２における反応工程は反応スキー
ム２に、実施例３における反応工程は反応スキーム３
に、実施例４における反応工程は反応スキーム４に、実
施例５における反応工程は反応スキーム５にそして実施
例６における反応工程は反応スキーム６に示した。そし
て各実施例中の化合物番号は各反応スキーム中に示され
た化合物とその番号に対応するものである。The reaction steps in Example 1 are shown in Reaction Scheme 1, the reaction steps in Example 2 are shown in Reaction Scheme 2, and the reaction steps in Example 3 are shown in Reaction Scheme 3.
The reaction steps in Example 4 are shown in Reaction Scheme 4, the reaction steps in Example 5 are shown in Reaction Scheme 5, and the reaction steps in Example 6 are shown in Reaction Scheme 6. The compound numbers in each Example correspond to the compounds and their numbers shown in each reaction scheme.

【００２６】[0026]

【化６】 Embedded image

【００２７】[0027]

【化７】 Embedded image

【００２８】[0028]

【化８】 Embedded image

【００２９】[0029]

【化９】 Embedded image

【００３０】[0030]

【化１０】 Embedded image

【００３１】[0031]

【化１１】 Embedded image

【００３２】[0032]

【化１２】 Embedded image

【００３３】[0033]

【実施例】実施例１ １−i） ５−アミノ−３−ペンテン酸（１.００ｇ）の
ジオキサン（１７mL）、水（８.７mL）そして１Ｍ炭酸
ナトリウム水溶液（８.７mL）の混合溶液にジ−ｔ−ブ
チルジカーボネート（２.０９ｇ）を氷冷下加えた。こ
の溶液を室温で５時間撹拌した後、溶液を約１５mLまで
減圧下に濃縮した。この溶液を氷冷下１０％クエン酸水
溶液で約ｐＨ３にした。水層を酢酸エチルで抽出し、合
わせた有機層を水洗し無水硫酸ナトリウムで乾燥した。
溶媒を留去した後、酢酸エチル−ヘキサン系で再結晶を
行ない５−Ｂｏｃアミノ−３−ペンテン酸（中間体化合
物１）１.８１ｇを得た。¹ H-NMR (d ppm, CDCl₃) : 6.10 (1H, br s), 5.55-5.75
(2H, m), 4.66 (1H,br s), 3.65-3.80 (2H, m), 3.11
(2H, d, J=6.4 Hz), 1.45 (9H, s).EXAMPLES Example 1 1-i) To a mixed solution of 5-amino-3-pentenoic acid (1.00 g) in dioxane (17 mL), water (8.7 mL) and a 1M aqueous sodium carbonate solution (8.7 mL). Di-t-butyl dicarbonate (2.09 g) was added under ice cooling. After stirring the solution at room temperature for 5 hours, the solution was concentrated under reduced pressure to about 15 mL. This solution was adjusted to about pH 3 with a 10% aqueous citric acid solution under ice cooling. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and dried over anhydrous sodium sulfate.
After the solvent was distilled off, the residue was recrystallized from ethyl acetate-hexane to give 1.81 g of 5-Bocamino-3-pentenoic acid (intermediate compound 1). ¹ H-NMR (d ppm, CDCl ₃ ): 6.10 (1H, br s), 5.55-5.75
(2H, m), 4.66 (1H, br s), 3.65-3.80 (2H, m), 3.11
(2H, d, J = 6.4 Hz), 1.45 (9H, s).

【００３４】１−ii) ３−ヒドロキシミリスチン酸５.
００ｇをＤＭＦ５０mLに溶解し、トリエチルアミン２.
８５mLと臭化ベンジル２.４３mLを室温で加えた。この
反応混合物を室温で一夜撹拌した。溶媒を留去し、残留
物に酢酸エチルと水を加え、有機層を分離し、水で二度
洗浄し無水硫酸ナトリウムで乾燥した。溶媒を留去した
後、粗生成物をシリカゲルカラムクロマトグラフィーで
精製して、３−ヒドロキシミリスチン酸ベンジル（中間
体化合物２）３.６９ｇを得た。¹ H-NMR (δ ppm, CDCl₃) 7.33-7.40(m, 5H), 5.16(s, 2
H), 3.95-4.05(m, 1H), 2.85(d, J=4.4Hz, 1H), 2.56(d
d, J=2.9, 17Hz, 1H), 2.46(dd, J=9.0, 17Hz,1H), 1.2
0-1.60(m, 20H), 0.88(t, J=6.8Hz, 3H)1-ii) 3-hydroxymyristic acid 5.
Was dissolved in 50 mL of DMF, and triethylamine 2.
85 mL and 2.43 mL of benzyl bromide were added at room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was distilled off, and ethyl acetate and water were added to the residue. The organic layer was separated, washed twice with water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the crude product was purified by silica gel column chromatography to obtain 3.69 g of benzyl 3-hydroxymyristate (intermediate compound 2). ¹ H-NMR (δ ppm, CDCl ₃ ) 7.33-7.40 (m, 5H), 5.16 (s, 2
H), 3.95-4.05 (m, 1H), 2.85 (d, J = 4.4Hz, 1H), 2.56 (d
d, J = 2.9, 17Hz, 1H), 2.46 (dd, J = 9.0, 17Hz, 1H), 1.2
0-1.60 (m, 20H), 0.88 (t, J = 6.8Hz, 3H)

【００３５】１−iii) 中間体化合物１（１.００
ｇ）、中間体化合物２（１.５５ｇ）およびジメチルア
ミノピリジン（４０mg）のジクロロメタン（４０mL）溶
液に氷冷下、ＤＣＣ（１.４４ｇ）を加え、氷冷下で２
時間、続いて室温で一晩撹拌した。析出物を濾別した
後、ジクロロメタンを留去した。残留物に酢酸エチルと
１０％クエン酸水溶液を加えた。分液した酢酸エチル層
を水、５％炭酸水素ナトリウム水溶液そして水で順番に
洗浄後、無水硫酸ナトリウムで乾燥した。酢酸エチルを
留去した後、シリカゲルカラムクロマトグラフィーで精
製し中間体化合物３を２.２９ｇ得た。¹ H-NMR (δ ppm, CDCl₃) :7.30-7.40 (5H, m), 5.50-5.
68 (2H, m), 5.20-5.25 (1H, m), 5.11 (2H, s), 4.59
(1H, br s), 3.71 (2H, br s), 2.96 (2H, d,J=4.9 H
z), 2.57-2.66 (2H, m), 1.50-1.65 (2H, m), 1.44 (9
H, s), 1.20-1.35(18H, m), 0.88 (3H, t, J=6.8 Hz).1-iii) Intermediate compound 1 (1.00
g), intermediate compound 2 (1.55 g) and dimethylaminopyridine (40 mg) in dichloromethane (40 mL) were added with DCC (1.44 g) under ice-cooling.
Stirred for hours, then overnight at room temperature. After the precipitate was separated by filtration, dichloromethane was distilled off. Ethyl acetate and 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 2.29 g of intermediate compound 3. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.30-7.40 (5H, m), 5.50-5.
68 (2H, m), 5.20-5.25 (1H, m), 5.11 (2H, s), 4.59
(1H, br s), 3.71 (2H, br s), 2.96 (2H, d, J = 4.9 H
z), 2.57-2.66 (2H, m), 1.50-1.65 (2H, m), 1.44 (9
H, s), 1.20-1.35 (18H, m), 0.88 (3H, t, J = 6.8 Hz).

【００３６】１−iv) 中間体化合物３（１.２９ｇ）を
トリフルオロ酢酸（以下、「ＴＦＡ」という）（１３m
L）に溶解し、溶液を室温で３０分撹拌した。ＴＦＡを
留去した後、残留物を酢酸エチルに溶解し、飽和炭酸水
素ナトリウム水溶液で洗浄した。これを無水硫酸ナトリ
ウムで乾燥後、酢酸エチルを留去してアミン体を得た。
得られたアミン体とＦｍｏｃ−Ｌ−アスパラギン酸β−
ｔ−ブチルエステル（Fmoc−Asp（OtBu)）(１.００ｇ）
とＨＯＢｔ・１水和物（０.４１ｇ）とのジクロロメタ
ン（３０mL）溶液に氷冷下、ＷＳＣＩ（０.５１ｇ）を
加えた。この溶液を氷冷下で２時間撹拌した後、室温で
一晩撹拌した。ジクロロメタンを留去した後、残留物を
酢酸エチルに溶解し、１０％クエン酸水溶液、水、５％
炭酸水素ナトリウム水溶液そして水で順番に洗浄した
後、無水硫酸ナトリウムで乾燥した。酢酸エチルを留去
した後、シリカゲルカラムクロマトグラフィーで精製し
て化合物１を１.５９ｇ得た。¹ H-NMR (δ ppm, CDCl₃) :7.76 (2H, d, J=7.3 Hz), 7.
58 (2H, d, 7.3 Hz),7.40 (2H, t, 7.3 Hz), 7.27-7.35
(7H, m), 6.53 (1H, br s), 5.94 (1H, d, J=7.8 Hz),
5.62-5.67 (1H, m), 5.45-5.55 (1H, m), 5.19-5.26
(1H, m), 5.10(2H, s), 4.50 (1H, br s), 4.43 (2H,
d, J=6.8 Hz), 4.22 (1H, t, J=6.8 Hz), 3.80-3.85 (2
H, m), 2.94 (2H, d, J=6.8 Hz), 2.89 (1H, br s), 2.
50-2.65(3H, m), 1.50-1.65 (2H, m), 1.44 (9H, s),
1.20-1.35 (18H, m), 0.88 (3H,t, J=6.8 Hz).1-iv) Intermediate compound 3 (1.29 g) was treated with trifluoroacetic acid (hereinafter referred to as "TFA") (13 m
L) and the solution was stirred at room temperature for 30 minutes. After the TFA was distilled off, the residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous sodium sulfate, ethyl acetate was distilled off to obtain an amine compound.
The obtained amine compound and Fmoc-L-aspartic acid β-
t-butyl ester (Fmoc-Asp (OtBu)) (1.00 g)
To a solution of HOBt.monohydrate (0.41 g) in dichloromethane (30 mL) was added WSCI (0.51 g) under ice-cooling. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, the residue was dissolved in ethyl acetate, and a 10% aqueous citric acid solution, water and 5%
After washing with an aqueous sodium hydrogen carbonate solution and water in that order, it was dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 1.59 g of Compound 1. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.3 Hz), 7.
58 (2H, d, 7.3 Hz), 7.40 (2H, t, 7.3 Hz), 7.27-7.35
(7H, m), 6.53 (1H, br s), 5.94 (1H, d, J = 7.8 Hz),
5.62-5.67 (1H, m), 5.45-5.55 (1H, m), 5.19-5.26
(1H, m), 5.10 (2H, s), 4.50 (1H, br s), 4.43 (2H,
d, J = 6.8 Hz), 4.22 (1H, t, J = 6.8 Hz), 3.80-3.85 (2
H, m), 2.94 (2H, d, J = 6.8 Hz), 2.89 (1H, br s), 2.
50-2.65 (3H, m), 1.50-1.65 (2H, m), 1.44 (9H, s),
1.20-1.35 (18H, m), 0.88 (3H, t, J = 6.8 Hz).

【００３７】１−v) 化合物１（１.５９ｇ）のＤＭＦ
（２１mL）溶液にジエチルアミン（２.１mL）を加え室
温で４時間撹拌した。溶媒を留去した後、得られた粗生
成物をシリカゲルカラムクロマトグラフィーで精製しア
ミン体を０.９２ｇ得た。得られたアミン体（０.５０
ｇ）とＣｂｚ−Ｌ−バリン（０.２１ｇ）およびＨＯＢ
ｔ・１水和物（０.１４ｇ）のジクロロメタン（３０m
L）溶液に氷冷下、ＷＳＣＩ（０.１７ｇ）を加えた。こ
の溶液を氷冷下で２時間撹拌した後、室温で一晩撹拌し
た。ジクロロメタンを留去した後、残留物に酢酸エチル
と１０％クエン酸水溶液を加えた。分液した酢酸エチル
層を水、５％炭酸水素ナトリウム水溶液そして水で順番
に洗浄後、無水硫酸ナトリウムで乾燥した。酢酸エチル
を留去した後、シリカゲルカラムクロマトグラフィーで
精製し化合物２を０.６３ｇ得た。¹ H-NMR (δ ppm, CD₃OD) :7.25-7.35 (10H, m), 5.45-
5.70 (2H, m), 5.15-5.25 (1H, m), 5.05-5.15 (4H,
m), 4.60-4.70 (1H, m), 3.85-3.90 (2H, m), 3.65-3.7
5 (1H, m), 2.55-2.90 (6H, m), 2.00-2.10 (1H, m),
1.50-1.65 (2H, m),1.43 (9H, s), 1.20-1.45 (18H,
m), 0.80-1.00 (9H, m).1-v) DMF of compound 1 (1.59 g)
(21 mL), diethylamine (2.1 mL) was added to the solution, and the mixture was stirred at room temperature for 4 hours. After evaporating the solvent, the obtained crude product was purified by silica gel column chromatography to obtain 0.92 g of an amine compound. The obtained amine compound (0.50)
g) and Cbz-L-valine (0.21 g) and HOB
t.monohydrate (0.14 g) in dichloromethane (30 m
L) WSCI (0.17 g) was added to the solution under ice cooling. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 0.63 g of Compound 2. ¹ H-NMR (δ ppm, CD ₃ OD): 7.25-7.35 (10H, m), 5.45-
5.70 (2H, m), 5.15-5.25 (1H, m), 5.05-5.15 (4H,
m), 4.60-4.70 (1H, m), 3.85-3.90 (2H, m), 3.65-3.7
5 (1H, m), 2.55-2.90 (6H, m), 2.00-2.10 (1H, m),
1.50-1.65 (2H, m), 1.43 (9H, s), 1.20-1.45 (18H,
m), 0.80-1.00 (9H, m).

【００３８】１−vi) 化合物２（０.５３ｇ）のメタノ
ール（１５mL）溶液に蟻酸アンモニウム（０.２４ｇ）
と５％パラジウム炭素（２５mg）を加え、約７０℃で４
時間撹拌した。パラジウム炭素を濾別し、メタノールを
留去した後、得られた粗生成物をシリカゲルカラムクロ
マトグラフィーで精製し化合物３を０.２８ｇ得た。¹ H-NMR (δ ppm, CD₃OD) :7.25-7.40 (5H, m), 5.50-5.
75 (2H, m), 5.15-5.30 (1H, m), 5.11, 5.10 (2H, 2
s), 4.60-4.70 (1H, m), 3.85-3.90 (1H, m), 3.70-3.8
0 (2H, m), 2.35-3.05 (6H, m), 2.00-2.15 (1H, m),
1.50-1.65 (2H, m), 1.43, 1.44 (9H, 2s), 1.20-1.40
(18H, m), 0.85-1.05 (9H, m).1-vi) Ammonium formate (0.24 g) was added to a solution of compound 2 (0.53 g) in methanol (15 mL).
And 5% palladium on carbon (25 mg).
Stirred for hours. After filtering off palladium carbon and distilling off methanol, the obtained crude product was purified by silica gel column chromatography to obtain 0.28 g of compound 3. ¹ H-NMR (δ ppm, CD ₃ OD): 7.25-7.40 (5H, m), 5.50-5.
75 (2H, m), 5.15-5.30 (1H, m), 5.11, 5.10 (2H, 2
s), 4.60-4.70 (1H, m), 3.85-3.90 (1H, m), 3.70-3.8
0 (2H, m), 2.35-3.05 (6H, m), 2.00-2.15 (1H, m),
1.50-1.65 (2H, m), 1.43, 1.44 (9H, 2s), 1.20-1.40
(18H, m), 0.85-1.05 (9H, m).

【００３９】１−vii) 化合物３（０.１４ｇ）とＮ−
γ−Ｍｂｈ−Ｌ−グルタミンエチルエステル（Gln（Mb
h)−OEt）(７５mg）およびＨＯＢｔ・１水和物（３２m
g）のジクロロメタン（１０mL）溶液に氷冷下、ＷＳＣ
Ｉ（４０mg）を加えた。この溶液を氷冷下で２時間撹拌
した後、室温で一晩撹拌した。ジクロロメタンを留去し
た後、残留物に酢酸エチルと１０％クエン酸水溶液を加
えた。分液した酢酸エチル層を水、５％炭酸水素ナトリ
ウム水溶液そして水で順番に洗浄後、無水硫酸ナトリウ
ムで乾燥した。酢酸エチルを留去した後、シリカゲルカ
ラムクロマトグラフィーで精製し化合物４を０.０８ｇ
得た。¹ H-NMR (δ ppm, CD₃OD) :7.25-7.40 (5H, m), 7.10-7.
15 (4H, m), 6.85 (4H, d, J=8.8 Hz), 6.08 (1H, s),
5.45-5.70 (2H, m), 5.15-5.25 (1H, m), 5.09(2H, s),
4.60-4.75 (1H, m), 4.30-4.40 (1H, m), 4.10-4.20
(2H, m), 3.88(1H, d, J=6.4 Hz), 3.76 (6H, s), 3.60
-3.80 (2H, m), 2.95-3.05 (2H, m), 2.25-2.85 (6H,
m), 1.90-2.20 (3H, m), 1.50-1.70 (2H, m), 1.42, 1.
43 (9H,2s), 1.20-1.45 (21H, m), 0.85-1.00 (9H, m).1-vii) Compound 3 (0.14 g) and N-
γ-Mbh-L-glutamine ethyl ester (Gln (Mb
h) -OEt) (75 mg) and HOBt monohydrate (32 m
g) in dichloromethane (10 mL) solution under ice-cooling
I (40 mg) was added. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 0.08 g of compound 4.
Obtained. ¹ H-NMR (δ ppm, CD ₃ OD): 7.25-7.40 (5H, m), 7.10-7.
15 (4H, m), 6.85 (4H, d, J = 8.8 Hz), 6.08 (1H, s),
5.45-5.70 (2H, m), 5.15-5.25 (1H, m), 5.09 (2H, s),
4.60-4.75 (1H, m), 4.30-4.40 (1H, m), 4.10-4.20
(2H, m), 3.88 (1H, d, J = 6.4 Hz), 3.76 (6H, s), 3.60
-3.80 (2H, m), 2.95-3.05 (2H, m), 2.25-2.85 (6H,
m), 1.90-2.20 (3H, m), 1.50-1.70 (2H, m), 1.42, 1.
43 (9H, 2s), 1.20-1.45 (21H, m), 0.85-1.00 (9H, m).

【００４０】１−viii) 化合物４（０.０８ｇ）のＴＦ
Ａ（２mL）溶液を室温で３.５時間撹拌した。ＴＦＡを
留去した後、残留物に酢酸エチルと５％炭酸水素ナトリ
ウム水溶液を加えた。分液した水層を酢酸エチルで洗浄
後、濃塩酸で約ｐＨ４にした。生成した固体を濾取・乾
燥して化合物５を０.０２ｇ得た。¹ H-NMR (δ ppm, CD₃OD) :7.25-7.40 (5H, m), 5.65-5.
75 (1H, m), 5.50-5.60 (1H, m), 5.15-5.30 (1H, m),
5.11 (2H, 2s), 4.65-4.75 (1H, m), 4.35-4.45 (1H,
m), 4.10-4.20 (2H, m), 3.90 (1H, d, J=6.4 Hz), 3.6
0-3.80 (2H, m),3.00-3.10 (2H, m), 2.00-3.00 (8H,
m), 1.85-2.00 (1H, m), 1.55-1.70 (2H,m), 1.20-1.40
(21H, m), 0.85-1.05 (9H, m).1-viii) TF of compound 4 (0.08 g)
The A (2 mL) solution was stirred at room temperature for 3.5 hours. After the TFA was distilled off, ethyl acetate and a 5% aqueous sodium hydrogen carbonate solution were added to the residue. The separated aqueous layer was washed with ethyl acetate and adjusted to about pH 4 with concentrated hydrochloric acid. The resulting solid was collected by filtration and dried to obtain 0.02 g of Compound 5. ¹ H-NMR (δ ppm, CD ₃ OD): 7.25-7.40 (5H, m), 5.65-5.
75 (1H, m), 5.50-5.60 (1H, m), 5.15-5.30 (1H, m),
5.11 (2H, 2s), 4.65-4.75 (1H, m), 4.35-4.45 (1H,
m), 4.10-4.20 (2H, m), 3.90 (1H, d, J = 6.4 Hz), 3.6
0-3.80 (2H, m), 3.00-3.10 (2H, m), 2.00-3.00 (8H,
m), 1.85-2.00 (1H, m), 1.55-1.70 (2H, m), 1.20-1.40
(21H, m), 0.85-1.05 (9H, m).

【００４１】１−ix) 上記した化合物４の合成過程で
用いたＧｌｎ(Ｍｂｈ)−ＯＥｔは次のようにして合成し
た。Ｎ−α−Ｃｂｚ−Ｎ−γ−Ｍｂｈ−Ｌ−グルタミン
（Cbz−Gln（Mbh)）(５.００ｇ）および炭酸水素ナトリ
ウム（１.６６ｇ）のＤＭＦ（５０mL）懸濁液に臭化エ
チル（７.５２mL）のＤＭＦ（５０mL）溶液を室温で滴
下して加えた。この反応溶液を室温で一晩撹拌した後、
水を加えた。水層を酢酸エチルで抽出し、合わせた有機
層を水洗し無水硫酸ナトリウムで乾燥した。溶媒を留去
した後、得られた粗生成物を酢酸エチル−ヘキサン系で
再結晶を行ない、Ｃｂｚ−Ｇｌｎ(Ｍｂｈ)−ＯＥｔを
４.６２ｇ得た。¹ H-NMR (δ ppm, CDCl₃) : 7.27-7.40 (5H, m), 7.14
(4H, dd, J=6.1, 7.8 Hz), 6.84 (4H, dd, J=0.92, 8.8
Hz), 6.45 (1H, d, J=7.8 Hz), 6.14 (1H, d,J=7.8 H
z), 5.60 (1H, d, J=7.8 Hz), 5.09 (2H, s), 4.29-4.3
8 (1H, m), 4.11-4.22 (2H, m), 3.78 (6H, s), 2.19-
2.40 (3H, m), 1.90-2.02 (1H, m), 1.25(3H, t, J=7.1
Hz).1-ix) Gln (Mbh) -OEt used in the process of synthesizing compound 4 was synthesized as follows. Ethyl bromide was added to a suspension of N-α-Cbz-N-γ-Mbh-L-glutamine (Cbz-Gln (Mbh)) (5.00 g) and sodium bicarbonate (1.66 g) in DMF (50 mL). (7.52 mL) in DMF (50 mL) was added dropwise at room temperature. After stirring the reaction solution at room temperature overnight,
Water was added. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent, the obtained crude product was recrystallized from ethyl acetate-hexane to give 4.62 g of Cbz-Gln (Mbh) -OEt. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.27-7.40 (5H, m), 7.14
(4H, dd, J = 6.1, 7.8 Hz), 6.84 (4H, dd, J = 0.92, 8.8
Hz), 6.45 (1H, d, J = 7.8 Hz), 6.14 (1H, d, J = 7.8 H
z), 5.60 (1H, d, J = 7.8 Hz), 5.09 (2H, s), 4.29-4.3
8 (1H, m), 4.11-4.22 (2H, m), 3.78 (6H, s), 2.19-
2.40 (3H, m), 1.90-2.02 (1H, m), 1.25 (3H, t, J = 7.1
Hz).

【００４２】このＣｂｚ−Ｇｌｎ(Ｍｂｈ)−ＯＥｔ
（２.６２ｇ）をメタノール（５０mL）に溶解し５％パ
ラジウム炭素（０.２６ｇ）を加え、水素雰囲気下室温
で４時間撹拌した。パラジウム炭素を濾別し、メタノー
ルを留去した後、得られた粗生成物を酢酸エチル−ヘキ
サン系で再結晶を行ない、Ｇｌｎ(Ｍｂｈ)−ＯＥｔを
１.９５ｇ得た。¹ H-NMR (δ ppm, CDCl₃) : 7.13 (4H, d, J=8.8 Hz),
6.85 (4H, td, J=2.6,8.8 Hz), 6.52 (1H, d, J=7.8 H
z), 6.14 (1H, d, J=7.8 Hz), 4.16 (2H, q, J=7.2 H
z), 3.79 (6H, s), 3.40-3.47 (1H, m), 2.33-2.48 (2
H, m), 2.08-2.20 (1H, m), 1.78-1.89 (1H, m), 1.56
(2H, s), 1.26 (3H, t, J=7.3 Hz).This Cbz-Gln (Mbh) -OEt
(2.62 g) was dissolved in methanol (50 mL), 5% palladium carbon (0.26 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After filtering off the palladium carbon and distilling off methanol, the obtained crude product was recrystallized with ethyl acetate-hexane to obtain 1.95 g of Gln (Mbh) -OEt. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.13 (4H, d, J = 8.8 Hz),
6.85 (4H, td, J = 2.6,8.8 Hz), 6.52 (1H, d, J = 7.8 H
z), 6.14 (1H, d, J = 7.8 Hz), 4.16 (2H, q, J = 7.2 H
z), 3.79 (6H, s), 3.40-3.47 (1H, m), 2.33-2.48 (2
H, m), 2.08-2.20 (1H, m), 1.78-1.89 (1H, m), 1.56
(2H, s), 1.26 (3H, t, J = 7.3 Hz).

【００４３】実施例２ ２−i) 化合物３（１２０mg）とＧｌｎ(Ｍｂｈ)−Ｏｔ
Ｂｕ（８６mg）およびＨＯＢｔ・１水和物（２５mg）の
ジクロロメタン（１０mL）溶液に氷冷下、ＷＳＣＩ（３
１mg）を加えた。この溶液を氷冷下で２時間撹拌した
後、室温で一晩撹拌した。ジクロロメタンを留去した
後、残留物に酢酸エチルと１０％クエン酸水溶液を加え
た。分液した酢酸エチル層を水、５％炭酸水素ナトリウ
ム水溶液そして水で順番に洗浄後、無水硫酸ナトリウム
で乾燥した。酢酸エチルを留去した後、シリカゲルカラ
ムクロマトグラフィーで精製し化合物６を０.０８ｇ得
た。¹ H-NMR (δ ppm, CD₃OD) :7.28-7.41 (8H, m), 7.11-7.
18 (4H, m), 6.62-6.96 (6H, m), 6.16 (1H, d, J=8.3
Hz), 5.53-5.78 (1H, m), 5.12-5.53 (2H,m),5.05-5.12
(2H, m), 4.65-4.76 (1H, m), 4.39-4.49 (1H, m), 3.
96-4.05 (1H,m), 3.63-3.85 (8H, m), 2.78-3.04 (2H,
m), 2.52-2.67 (1H,m), 2.08-2.51 (7H, m), 1.73-1.96
(1H, m), 1.51-1.67 (2H, m), 1.33-1.50 (18H, m),
1.21-1.33 (18H, m), 0.85-1.00 (9H, m).Example 2 2-i) Compound 3 (120 mg) and Gln (Mbh) -Ot
To a solution of Bu (86 mg) and HOBt monohydrate (25 mg) in dichloromethane (10 mL) was added WSCI (3
1 mg) was added. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography to obtain 0.08 g of compound 6. ¹ H-NMR (δ ppm, CD ₃ OD): 7.28-7.41 (8H, m), 7.11-7.
18 (4H, m), 6.62-6.96 (6H, m), 6.16 (1H, d, J = 8.3
Hz), 5.53-5.78 (1H, m), 5.12-5.53 (2H, m), 5.05-5.12
(2H, m), 4.65-4.76 (1H, m), 4.39-4.49 (1H, m), 3.
96-4.05 (1H, m), 3.63-3.85 (8H, m), 2.78-3.04 (2H,
m), 2.52-2.67 (1H, m), 2.08-2.51 (7H, m), 1.73-1.96
(1H, m), 1.51-1.67 (2H, m), 1.33-1.50 (18H, m),
1.21-1.33 (18H, m), 0.85-1.00 (9H, m).

【００４４】２−ii) 化合物６（０.０８ｇ）のＴＦＡ
（２mL）溶液を室温で１時間撹拌した。ＴＦＡを留去し
た後、残留物に酢酸エチルと５％炭酸水素ナトリウム水
溶液を加えた。分液した水層を濃塩酸で約ｐＨ４にし
た。生成した固体を濾取・乾燥して化合物７を０.０１
ｇ得た。¹ H-NMR (δ ppm, CD₃OD) :7.23-7.39 (5H, m), 5.65-5.
74 (1H, m), 5.50-5.59 (1H, m), 5.17-5.29 (1H, m),
5.11 (1H, s), 5.10 (1H, s), 4.64-4.74 (1H,m), 4.32
-4.40 (1H, m), 3.87-3.92 (1H, m), 3.68-3.79 (2H,
m), 3.01-3.07(1H, m), 2.72-2.91 (2H, m), 2.45-2.56
(2H, m), 2.22-2.40 (3H, m), 2.04-2.19 (2H, m), 1.
89-1.99 (1H, m), 1.55-1.67 (2H, m), 1.21-1.37 (18
H, m), 0.86-1.07 (9H, m).2-ii) TFA of compound 6 (0.08 g)
(2 mL) The solution was stirred at room temperature for 1 hour. After the TFA was distilled off, ethyl acetate and a 5% aqueous sodium hydrogen carbonate solution were added to the residue. The separated aqueous layer was adjusted to about pH 4 with concentrated hydrochloric acid. The resulting solid was collected by filtration and dried to give Compound 7 in 0.01.
g was obtained. ¹ H-NMR (δ ppm, CD ₃ OD): 7.23-7.39 (5H, m), 5.65-5.
74 (1H, m), 5.50-5.59 (1H, m), 5.17-5.29 (1H, m),
5.11 (1H, s), 5.10 (1H, s), 4.64-4.74 (1H, m), 4.32
-4.40 (1H, m), 3.87-3.92 (1H, m), 3.68-3.79 (2H,
m), 3.01-3.07 (1H, m), 2.72-2.91 (2H, m), 2.45-2.56
(2H, m), 2.22-2.40 (3H, m), 2.04-2.19 (2H, m), 1.
89-1.99 (1H, m), 1.55-1.67 (2H, m), 1.21-1.37 (18
H, m), 0.86-1.07 (9H, m).

【００４５】２−iii) 上記した化合物６の合成過程で
用いたＧｌｎ(Ｍｂｈ)−ＯｔＢｕは次のようにして合成
した。すなわちＮ−α−Ｃｂｚ−Ｎ−γ−Ｍｂｈ−Ｌ−
グルタミン（Cbz−Gln（Mbh)）(３.００ｇ）と第三ブチ
ルアルコール（０.６２mL）とジメチルアミノピリジン
（０.３６ｇ）のＤＭＦ（２０mL）溶液に氷冷下、ＷＳ
ＣＩ（１.２５ｇ）を加えた。この溶液を氷冷下で２時
間撹拌した後、室温で一晩撹拌した。ＤＭＦを留去した
後、残留物に酢酸エチルと１０％クエン酸水溶液を加え
た。分液した酢酸エチル層を水、５％炭酸水素ナトリウ
ム水溶液そして水で順番に洗浄後、無水硫酸ナトリウム
で乾燥した。酢酸エチルを留去した後、シリカゲルカラ
ムクロマトグラフィーおよび酢酸エチル−ヘキサン系で
の再結晶化で精製しＮ−α−Ｃｂｚ−Ｎ−γ−Ｍｂｈ−
Ｌ−グルタミン−ｔ−ブチルエステル（Cbz−Gln（Mbh)
−OBu）１.２８ｇを得た。¹ H-NMR (δ ppm, CDCl₃) : 7.24-7.39 (5H, m), 7.04-
7.20 (4H, m), 6.76-6.88 (4H, m), 6.57 (1H, d, J=7.
3 Hz), 6.13 (1H, d, J=8.3 Hz), 5.52 (1H, d,J=8.3 H
z), 5.08 (2H, s), 4.16-4.26 (1H, m), 3.78 (6H, s),
2.12-2.41 (3H, m), 1.84-2.06 (1H, m), 1.44 (9H,
s).2-iii) Gln (Mbh) -OtBu used in the process of synthesizing compound 6 was synthesized as follows. That is, N-α-Cbz-N-γ-Mbh-L-
Glutamine (Cbz-Gln (Mbh)) (3.00 g), tert-butyl alcohol (0.62 mL) and dimethylaminopyridine (0.36 g) in DMF (20 mL) were added under ice-cooling to WS.
CI (1.25 g) was added. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After distilling off DMF, ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The separated ethyl acetate layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After the ethyl acetate was distilled off, the residue was purified by silica gel column chromatography and recrystallization from ethyl acetate-hexane to give N-α-Cbz-N-γ-Mbh-.
L-glutamine-t-butyl ester (Cbz-Gln (Mbh)
-OBu) 1.28 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.24-7.39 (5H, m), 7.04-
7.20 (4H, m), 6.76-6.88 (4H, m), 6.57 (1H, d, J = 7.
3 Hz), 6.13 (1H, d, J = 8.3 Hz), 5.52 (1H, d, J = 8.3 H
z), 5.08 (2H, s), 4.16-4.26 (1H, m), 3.78 (6H, s),
2.12-2.41 (3H, m), 1.84-2.06 (1H, m), 1.44 (9H,
s).

【００４６】このＣｂｚ−Ｇｌｎ(Ｍｂｈ)−ＯＢｕ
（０.１１ｇ）をメタノール（５mL）に溶解し５％パラ
ジウム炭素（１０mg）を加え、水素雰囲気下で４時間撹
拌した。パラジウム炭素を濾別し、メタノールを留去し
てＧｌｎ(Ｍｂｈ)−ＯＢｕを得た。This Cbz-Gln (Mbh) -OBu
(0.11 g) was dissolved in methanol (5 mL), 5% palladium on carbon (10 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. Palladium carbon was removed by filtration, and methanol was distilled off to obtain Gln (Mbh) -OBu.

【００４７】実施例３ ３−i) Ｎ−ｔ−ブチルカルボニル−Ｄ−ロイシン・１
水和物（Boc−D−Leu−OH・H₂O）(２.５ｇ）のＴＨＦ
（１２mL）溶液にトリエチルアミン（１.２５ｇ）を加
えた後、氷冷下クロルギ酸エチル（１.０９ｇ）を加え
た。この溶液を氷冷下３０分間撹拌し濾過した。濾液に
ＮａＢＨ₄（９４６mg）の水（１２mL）懸濁液を氷冷下
に徐々に加えた。この溶液を氷冷下４時間撹拌しエーテ
ル（１００mL）を加えた。水層をクロロホルム（２００
mL）で３回抽出し合わせた有機層を無水硫酸ナトリウム
で乾燥した。溶媒を留去した後、シリカゲルカラムクロ
マトグラフィーで精製し中間体化合物４を１.３５ｇ得
た。¹ H-NMR (δ ppm, CDCl₃) :4.55 (1H, br s), 3.64-3.72
(2H, m), 3.47-3.52(1H, m), 2.43 (1H, br s), 1.61-
1.72 (1H, m), 1.24-1.36 (2H, m), 1.45 (9H, s), 0.9
2-0.95 (6H, m).Example 3 3-i) Nt-butylcarbonyl-D-leucine-1
THF of hydrate (Boc-D-Leu-OH.H ₂ O) (2.5 g)
(12 mL), triethylamine (1.25 g) was added to the solution, and then ethyl chloroformate (1.09 g) was added under ice cooling. This solution was stirred for 30 minutes under ice cooling and filtered. A suspension of NaBH ₄ (946 mg) in water (12 mL) was gradually added to the filtrate under ice-cooling. The solution was stirred for 4 hours under ice cooling, and ether (100 mL) was added. The aqueous layer was chloroform (200
The mixture was extracted three times with an organic layer and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 1.35 g of intermediate compound 4. ¹ H-NMR (δ ppm, CDCl ₃ ): 4.55 (1H, br s), 3.64-3.72
(2H, m), 3.47-3.52 (1H, m), 2.43 (1H, br s), 1.61-
1.72 (1H, m), 1.24-1.36 (2H, m), 1.45 (9H, s), 0.9
2-0.95 (6H, m).

【００４８】３−ii) 中間体化合物４（１.３５ｇ）と
トリエチルアミン（１.９ｇ）とのジクロロメタン（４
０mL）溶液に氷冷下メシルクロライド（１.７８ｇ）を
加えた。この溶液を氷冷下１時間撹拌後、クロロホルム
（１００mL）を加え、水（５０mL）で２回洗浄した。有
機層を無水硫酸ナトリウムで乾燥した。溶媒を留去した
後、シリカゲルカラムクロマトグラフィーで精製し中間
体化合物５を１.７６ｇ得た。¹ H-NMR (δ ppm, CDCl₃) :4.50-4.56 (1H, m), 4.16 (1
H, br d, J=4.0 Hz),4.15 (1H, dd, J=4.0, 10 Hz), 3.
92 (1H, br s), 3.03 (3H, s), 1.65-1.73 (1H, m), 1.
44 (9H, s), 1.28-1.45 (2H, m), 0.94 (3H, d, J=3.2
Hz), 0.93 (3H, d, J=3.2 Hz).3-ii) Intermediate compound 4 (1.35 g) and triethylamine (1.9 g) in dichloromethane (4
Mesyl chloride (1.78 g) was added to the solution under ice-cooling. After stirring this solution for 1 hour under ice cooling, chloroform (100 mL) was added, and the mixture was washed twice with water (50 mL). The organic layer was dried with anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 1.76 g of intermediate compound 5. ¹ H-NMR (δ ppm, CDCl ₃ ): 4.50-4.56 (1H, m), 4.16 (1
H, br d, J = 4.0 Hz), 4.15 (1H, dd, J = 4.0, 10 Hz), 3.
92 (1H, br s), 3.03 (3H, s), 1.65-1.73 (1H, m), 1.
44 (9H, s), 1.28-1.45 (2H, m), 0.94 (3H, d, J = 3.2
Hz), 0.93 (3H, d, J = 3.2 Hz).

【００４９】３−iii) ナトリウムメトキサイド（１.
０３ｇ）とチオフェノール（２.１７ｇ）のＴＨＦ（８m
L）とメタノール（３mL）溶液に中間体化合物４（１.７
６ｇ）のＴＨＦ（７mL）溶液を加えた。この溶液を５０
℃で４時間撹拌した後、クロロホルム（５０mL）と１０
％水酸化ナトリウム水溶液（１５mL）を加えた。有機層
を５％水酸化ナトリウム水溶液と飽和重曹水で洗浄後、
無水硫酸ナトリウムで乾燥した。溶媒を留去した後、シ
リカゲルカラムクロマトグラフィーで精製し中間体化合
物６を１.７７ｇ得た。¹ H-NMR (δ ppm, CDCl₃) :7.37-7.40 (2H, m), 7.26-7.
29 (2H, m), 7.15-7.19 (1H, m), 4.50-4.57 (1H, m),
3.75-3.91 (1H, m), 2.93-3.10 (2H, m), 1.57-1.65 (1
H, m), 1.41 (9H, s), 1.38-1.48 (2H, m), 0.90 (3H,
d, J=6.4 Hz),0.87 (3H, d, J=6.4 Hz).3-iii) Sodium methoxide (1.
03g) and thiophenol (2.17g) in THF (8m
L) and methanol (3 mL) in solution.
A solution of 6 g) in THF (7 mL) was added. Add this solution to 50
After stirring at 4 ° C for 4 hours, chloroform (50 mL) and 10 mL
A 15% aqueous solution of sodium hydroxide (15 mL) was added. After washing the organic layer with a 5% aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogen carbonate solution,
Dry over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 1.77 g of intermediate compound 6. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.37-7.40 (2H, m), 7.26-7.
29 (2H, m), 7.15-7.19 (1H, m), 4.50-4.57 (1H, m),
3.75-3.91 (1H, m), 2.93-3.10 (2H, m), 1.57-1.65 (1
H, m), 1.41 (9H, s), 1.38-1.48 (2H, m), 0.90 (3H,
d, J = 6.4 Hz), 0.87 (3H, d, J = 6.4 Hz).

【００５０】３−iv) 別法として、３−ｉ)で得られた
中間体化合物４（１.２０ｇ）のＴＨＦ（１５mL）溶液
に氷冷下、ジフェニルジスルフィド（１.８８ｇ）とト
リｎ−ブチルフォスフィン（１.６８ｇ）を加えた。こ
の溶液を室温で１６時間撹拌した。溶媒を留去した後、
シリカゲルカラムクロマトグラフィーで精製し中間体化
合物６を１.７０ｇ得た。3-iv) Alternatively, a solution of the intermediate compound 4 (1.20 g) obtained in 3-i) in THF (15 mL) was added with diphenyl disulfide (1.88 g) and tri-n- Butylphosphine (1.68 g) was added. The solution was stirred at room temperature for 16 hours. After distilling off the solvent,
Purification by silica gel column chromatography gave 1.70 g of intermediate compound 6.

【００５１】３−v) 得られた中間体化合物６（１.７
０ｇ）のジクロロメタン（４５mL）溶液に氷冷下ｍＣＰ
ＢＡ（３.０３ｇ）を加えた。この溶液を氷冷下で１時
間撹拌した後、クロロホルム（５０mL）と１５％水酸化
ナトリウム水溶液（１５mL）そして亜硫酸水素ナトリウ
ム（１５mL）を加えた。水層をクロロホルム（２０mL）
で２回抽出後、合わせた有機層を無水硫酸ナトリウムで
乾燥した。溶媒を留去した後、ヘキサン−酢酸エチルよ
り結晶化し中間体化合物７を１.７４ｇ得た。¹ H-NMR (δ ppm, CDCl₃) :7.91-7.94 (2H, m), 7.64 (1
H, m), 7.55-7.59 (2H, m), 4.82 (1H, br s), 3.94-4.
01 (1H, m), 3.41-3.44 (1H, m), 3.23-3.28 (1H, m),
1.50-1.72 (3H, m), 1.40 (9H, s), 0.87-0.90 (6H,
m).3-v) Intermediate compound 6 obtained (1.7)
0g) in dichloromethane (45 mL) solution under ice cooling
BA (3.03 g) was added. After the solution was stirred for 1 hour under ice cooling, chloroform (50 mL), a 15% aqueous sodium hydroxide solution (15 mL) and sodium bisulfite (15 mL) were added. The aqueous layer is chloroform (20 mL)
, And the combined organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was crystallized from hexane-ethyl acetate to obtain 1.74 g of intermediate compound 7. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.91-7.94 (2H, m), 7.64 (1
H, m), 7.55-7.59 (2H, m), 4.82 (1H, br s), 3.94-4.
01 (1H, m), 3.41-3.44 (1H, m), 3.23-3.28 (1H, m),
1.50-1.72 (3H, m), 1.40 (9H, s), 0.87-0.90 (6H,
m).

【００５２】３−vi) １−メチル−(Ｓ)−２−ヒドロ
キシプロピオン酸メチル（１.１８ｇ）とジヒドロピラ
ン（１.１０ｇ）のジクロロメタン（２０mL）溶液に室
温下、ｐ−トルエンスルホン酸（５０mg）を加えた。こ
の溶液を室温で４時間撹拌した後、クロロホルム（１０
０mL）と水（８０mL）を加えた。水層をクロロホルム
（２０mL）で抽出し合わせた有機層を無水硫酸ナトリウ
ムで乾燥した。溶媒を留去した後、シリカゲルカラムク
ロマトグラフィーで精製し中間体化合物８を２.０３ｇ
得た。¹ H-NMR (δ ppm, CDCl₃) :4.60 and 4.62 (1H, t, J=3.
2 Hz), 3.74-3.94 (2H, m), 3.70 (s, 3H), 3.42-3.62
(2H, m), 2.74 (1H, m), 1.52-1.80 (6H, m),1.18 and
1.20 (3H, d, J=6.8 Hz).3-vi) To a solution of methyl 1-methyl- (S) -2-hydroxypropionate (1.18 g) and dihydropyran (1.10 g) in dichloromethane (20 mL) at room temperature was added p-toluenesulfonic acid ( 50 mg) was added. After the solution was stirred at room temperature for 4 hours, chloroform (10
(0 mL) and water (80 mL). The aqueous layer was extracted with chloroform (20 mL), and the combined organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 2.03 g of intermediate compound 8.
Obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 4.60 and 4.62 (1H, t, J = 3.
2 Hz), 3.74-3.94 (2H, m), 3.70 (s, 3H), 3.42-3.62
(2H, m), 2.74 (1H, m), 1.52-1.80 (6H, m), 1.18 and
1.20 (3H, d, J = 6.8 Hz).

【００５３】３−vii) 中間体化合物７（６８３mg）の
ＴＨＦ（２４mL）溶液に、−７８℃でメチルリチウム
（ジエチルエーテル中 １.０３Ｍ）(４.２７mL）を加え
た。この溶液を−７８℃で３０分間撹拌した（溶液
Ａ）。中間体化合物８（９７１mg）のジエチルエーテル
（１４mL）溶液に、−７８℃でＤＩＢＡＨ（ヘキサン溶
液中０.９５Ｍ）(５.５mL）を滴下した。この溶液を−
７８℃で３０分間撹拌した（溶液Ｂ）。溶液Ｂを溶液Ａ
にカニューレを用いて加え−７８℃で３０分間撹拌し
た。この溶液にジエチルエーテル（１００mL）、水（８
０mL）、飽和塩化アンモニウム水溶液（１００mL）を加
え、室温まで昇温後飽和ロッシェル塩水溶液（１００m
L）を加えた。水層をジエチルエーテル（１００mL）で
２回抽出後、合わせた有機層を飽和ロッシェル塩水溶
液、飽和塩化アンモニウム水溶液、水、飽和食塩水で順
次洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を
留去した後、得られた中間体化合物９をそのまま次の反
応に用いた。3-vii) To a solution of intermediate compound 7 (683 mg) in THF (24 mL) at -78 ° C was added methyllithium (1.03 M in diethyl ether) (4.27 mL). The solution was stirred at -78 C for 30 minutes (Solution A). To a solution of intermediate compound 8 (971 mg) in diethyl ether (14 mL) at −78 ° C. was added dropwise DIBAH (0.95 M in hexane) (5.5 mL). This solution is
Stirred at 78 ° C. for 30 minutes (solution B). Solution B to solution A
Was added using a cannula and stirred at -78 ° C for 30 minutes. To this solution, diethyl ether (100 mL) and water (8
0 mL) and a saturated aqueous solution of ammonium chloride (100 mL).
L) was added. After the aqueous layer was extracted twice with diethyl ether (100 mL), the combined organic layers were sequentially washed with a saturated aqueous solution of Rochelle salt, a saturated aqueous solution of ammonium chloride, water, and saturated saline, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained intermediate compound 9 was directly used in the next reaction.

【００５４】３−viii) 得られた中間体化合物９のメ
タノール（４０mL）溶液にリン酸ナトリウム（３.２５
ｇ）と５％ナトリウムアマルガム（１２.５ｇ）を氷冷
下加えた。この溶液を氷冷下４時間撹拌した後、濾過し
た。濾液を減圧濃縮後、ジエチルエーテル（１００mL）
を加え、水（５０mL）で２回洗浄した。有機層を無水硫
酸ナトリウムで乾燥した。溶媒を留去した後、シリカゲ
ルカラムクロマトグラフィーで精製し中間体化合物１０
を３３０mg得た。¹ H-NMR (δ ppm, CDCl₃) :5.51-5.59 (1H, m), 5.31-5.
41 (1H, m), 4.55-4.60 (1H, m), 4.25-4.41 (1H, m),
4.00-4.16 (1H, m), 3.81-3.88 (1H, m), 3.45-3.63 (2
H, m), 3.17-3.30 (1H, m), 2.41-2.49 (1H, m), 1.39
(9H, s), 1.23-1.87 (9H, m), 1.02 and 1.03 (3H, d,
J=4.4 Hz), 0.92 (3H, d, 4.4 Hz), 0.90 (3H, d, J=4.
4 Hz).3-viii) To a solution of the obtained intermediate compound 9 in methanol (40 mL) was added sodium phosphate (3.25).
g) and 5% sodium amalgam (12.5 g) were added under ice cooling. This solution was stirred for 4 hours under ice cooling, and then filtered. After the filtrate was concentrated under reduced pressure, diethyl ether (100 mL)
Was added and washed twice with water (50 mL). The organic layer was dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give intermediate compound 10
330 mg were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 5.51-5.59 (1H, m), 5.31-5.
41 (1H, m), 4.55-4.60 (1H, m), 4.25-4.41 (1H, m),
4.00-4.16 (1H, m), 3.81-3.88 (1H, m), 3.45-3.63 (2
H, m), 3.17-3.30 (1H, m), 2.41-2.49 (1H, m), 1.39
(9H, s), 1.23-1.87 (9H, m), 1.02 and 1.03 (3H, d,
J = 4.4 Hz), 0.92 (3H, d, 4.4 Hz), 0.90 (3H, d, J = 4.
4 Hz).

【００５５】３−ix) 中間体化合物１０（３３０mg）
のアセトン（５０mL）溶液に、ジョーンズ試薬（１.９
２Ｍ）(１.６mL）を氷冷下加えた。この溶液を氷冷下で
２時間撹拌後、水（１００mL）、ジエチルエーテル（５
０mL）を加えた。水層をジエチルエーテル（５０mL）で
２回抽出後、合わせた有機層を５％水酸化ナトリウム水
溶液（５０mL）で３回洗浄した。水層に３Ｎ塩酸水を加
え、ｐＨ３〜４とした後、ジエチルエーテル（５０mL）
で３回抽出し合わせた有機層を無水硫酸ナトリウムで乾
燥した。溶媒を留去した後、得られた中間体化合物１１
をそのまま次の反応に用いた。3-ix) Intermediate compound 10 (330 mg)
In acetone (50 mL) was added to Jones reagent (1.9).
2M) (1.6 mL) was added under ice cooling. The solution was stirred under ice cooling for 2 hours, and then water (100 mL) and diethyl ether (5 mL) were added.
0 mL) was added. After the aqueous layer was extracted twice with diethyl ether (50 mL), the combined organic layers were washed three times with a 5% aqueous sodium hydroxide solution (50 mL). 3N hydrochloric acid was added to the aqueous layer to adjust the pH to 3-4, and then diethyl ether (50 mL) was added.
The organic layer was extracted three times and dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting intermediate compound 11
Was used for the next reaction as it was.

【００５６】３−ｘ) 得られた中間体化合物１１にＴ
ＦＡ（３mL）を加え室温で２時間撹拌した。溶媒を留去
した後、得られた中間体化合物１２をそのまま次の反応
に用いた。3-x) T was added to the obtained intermediate compound 11.
FA (3 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the obtained intermediate compound 12 was directly used in the next reaction.

【００５７】３−xi) 得られた中間体化合物１２の１
０％炭酸ナトリウム水溶液（６mL）にＦｍｏｃ−Ｃｌ
（３６５mg）のジオキサン（６mL）溶液を加えた。この
溶液を室温で４時間撹拌した後、イソプロピルエーテル
（２０mL）と水（１０mL）を加えた。水層をイソプロピ
ルエーテルで洗浄後、ｐＨ３まで３Ｎ塩酸水を加え酢酸
エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥
した。溶媒を留去した後、シリカゲルカラムクロマトグ
ラフィーで精製し中間体化合物１３を５０mg得た。¹ H-NMR (δ ppm, CDCl₃) :7.73-7.75 (2H, m), 7.56-7.
58 (2H, m), 7.36-7.37 (2H, m), 7.27-7.31 (2H, m),
5.28-5.76 (2H, m), 4.63-4.75 (1H, m), 4.34-4.54 (2
H, m), 4.13-4.28 (2H, m), 2.96-3.22 (1H, m), 1.50-
1.67 (1H, m),1.14-1.43 (5H, m), 0.69-0.99 (6H, m).3-xi) 1 of the obtained intermediate compound 12
Fmoc-Cl in 0% aqueous sodium carbonate (6 mL)
(365 mg) in dioxane (6 mL) was added. After the solution was stirred at room temperature for 4 hours, isopropyl ether (20 mL) and water (10 mL) were added. After washing the aqueous layer with isopropyl ether, 3N aqueous hydrochloric acid was added to pH 3 and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain 50 mg of an intermediate compound 13. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.73-7.75 (2H, m), 7.56-7.
58 (2H, m), 7.36-7.37 (2H, m), 7.27-7.31 (2H, m),
5.28-5.76 (2H, m), 4.63-4.75 (1H, m), 4.34-4.54 (2
H, m), 4.13-4.28 (2H, m), 2.96-3.22 (1H, m), 1.50-
1.67 (1H, m), 1.14-1.43 (5H, m), 0.69-0.99 (6H, m).

【００５８】３−xii) 中間体化合物１３（１６０mg）
と中間体化合物１４（３６９mg）のジクロロメタン（５
mL）溶液にジメチルアミノピリジン（１０mg）とＤＣＣ
（９９mg）を氷冷下加えた。この溶液を室温で６時間撹
拌した後、セライト濾過した。濾液から溶媒を留去した
後、クロロホルムを加え水、５％炭酸水素ナトリウム水
溶液、１０％クエン酸水溶液、飽和食塩水で順次洗浄し
た。無水硫酸ナトリウムで乾燥後、溶媒を留去し、残査
をシリカゲルカラムクロマトグラフィーで精製し中間体
化合物１５を３１０mg得た。¹ H-NMR (δ ppm, CDCl₃) : 7.71-7.81 (2H, m), 7.52-
7.69 (2H, m), 7.09-7.43 (8H, m), 6.48-6.89 (5H,
m), 6.07-6.28 (1H, m), 5.35-5.78 (1H, m), 5.05-5.2
8 (1H, m), 3.98-4.48 (7H, m), 3.76 and 3.78 (3H,
s), 3.75 and 3.76(3H, s), 3.41-3.54 (1H, m), 1.41
and 1.42 (9H, s), 1.02-2.46 (3H, m), 0.67-0.96 (15
H, m).3-xii) Intermediate compound 13 (160 mg)
And intermediate compound 14 (369 mg) in dichloromethane (5
dimethylaminopyridine (10 mg) and DCC
(99 mg) was added under ice cooling. The solution was stirred at room temperature for 6 hours and then filtered through celite. After the solvent was distilled off from the filtrate, chloroform was added, and the mixture was washed successively with water, a 5% aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution, and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 310 mg of intermediate compound 15. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.71-7.81 (2H, m), 7.52-
7.69 (2H, m), 7.09-7.43 (8H, m), 6.48-6.89 (5H,
m), 6.07-6.28 (1H, m), 5.35-5.78 (1H, m), 5.05-5.2
8 (1H, m), 3.98-4.48 (7H, m), 3.76 and 3.78 (3H,
s), 3.75 and 3.76 (3H, s), 3.41-3.54 (1H, m), 1.41
and 1.42 (9H, s), 1.02-2.46 (3H, m), 0.67-0.96 (15
H, m).

【００５９】３−xiii) 中間体化合物１５(３１０mg）
のＤＭＦ（３mL）溶液にジエチルアミン（０.３mL）を
室温で加えた。この溶液を室温で２.５時間撹拌した
後、溶媒を留去した。残査をシリカゲルカラムクロマト
グラフィーで精製し中間体化合物１６を２００mg得た。¹ H-NMR (δ ppm, CDCl₃) : 7.60-7.69 (1H, m), 7.12-
7.25 (4H, m), 6.63-6.88 (5H, m), 6.15-6.23 (1H,
m), 5.59-5.76 (1H, m), 5.38-5.53 (1H, m), 5.13-5.2
2 (1H, m), 4.25-4.46 (2H, m), 3.78 and 3.79 (3H,
s), 3.76 and 3.78(3H, s),, 3.29-3.41 (1H, m), 3.00
-3.16 (1H, m), 2.32-2.77 (4H, m), 1.40and 1.42 (9
H, s), 1.17-1.67 (31H, m), 0.82-0.94 (15H, m).3-xiii) Intermediate compound 15 (310 mg)
To a DMF (3 mL) solution of was added diethylamine (0.3 mL) at room temperature. After the solution was stirred at room temperature for 2.5 hours, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 200 mg of intermediate compound 16. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.60-7.69 (1H, m), 7.12-
7.25 (4H, m), 6.63-6.88 (5H, m), 6.15-6.23 (1H,
m), 5.59-5.76 (1H, m), 5.38-5.53 (1H, m), 5.13-5.2
2 (1H, m), 4.25-4.46 (2H, m), 3.78 and 3.79 (3H,
s), 3.76 and 3.78 (3H, s) ,, 3.29-3.41 (1H, m), 3.00
-3.16 (1H, m), 2.32-2.77 (4H, m), 1.40and 1.42 (9
H, s), 1.17-1.67 (31H, m), 0.82-0.94 (15H, m).

【００６０】３−xiv) 中間体化合物１６（２００mg）
とＦｍｏｃ−Ｌ−アスパラギン酸β−ｔ−ブチルエステ
ル（ＦｍｏｃＡｓｐ(ＯｔＢｕ)）(１０６mg）のジクロ
ロメタン（５mL）溶液にＨＯＢｔ・１水和物（３５mg）
とＷＳＣＩ（５０mg）を氷冷下に加えた。この溶液を室
温で６６時間撹拌後、溶媒を留去し、残査をクロロホル
ムに溶解した。この溶液を水、５％炭酸水素ナトリウム
水溶液、１０％クエン酸水溶液、飽和食塩水で順次洗浄
した。無水硫酸ナトリウムで乾燥後、溶媒を留去し、残
査をシリカゲルカラムクロマトグラフィーで精製し化合
物８を２２０mg得た。¹ H-NMR (δ ppm, CDCl₃) : 7.72-7.79 (2H, m), 7.51-
7.62 (m, 2H), 7.27-7.43 (4H, m), 7.03-7.24 (5H,
m), 6.56-6.87 (6H, m), 6.07-6.48 (2H, m), 5.54-5.7
5 (1H, m), 5.35-5.49 (1H, m), 5.09-5.22 (1H, m),
4.17-4.73 (7H, m),3.76 and 3.77 (3H, s), 3.76 (3H,
s), 1.88-3.08 (7H, m), 1.42 and 1.43 (9H, s), 1.4
1 and 1.42 (9H, s), 1.09-1.70 (31H, m), 0.71-0.92
(15H, m).3-xiv) Intermediate compound 16 (200 mg)
And Hmoc-L-aspartic acid β-t-butyl ester (FmocAsp (OtBu)) (106 mg) in dichloromethane (5 mL) solution of HOBt monohydrate (35 mg)
And WSCI (50 mg) were added under ice cooling. After stirring this solution at room temperature for 66 hours, the solvent was distilled off, and the residue was dissolved in chloroform. This solution was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution, and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 220 mg of compound 8. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.72-7.79 (2H, m), 7.51-
7.62 (m, 2H), 7.27-7.43 (4H, m), 7.03-7.24 (5H,
m), 6.56-6.87 (6H, m), 6.07-6.48 (2H, m), 5.54-5.7
5 (1H, m), 5.35-5.49 (1H, m), 5.09-5.22 (1H, m),
4.17-4.73 (7H, m), 3.76 and 3.77 (3H, s), 3.76 (3H,
s), 1.88-3.08 (7H, m), 1.42 and 1.43 (9H, s), 1.4
1 and 1.42 (9H, s), 1.09-1.70 (31H, m), 0.71-0.92
(15H, m).

【００６１】３−xv) 化合物８（２２０mg）のＤＭＦ
（２mL）溶液にジエチルアミン（０.２mL）を室温下に
加えた。この溶液を室温で２.５時間撹拌した後、溶媒
を留去した。残査をシリカゲルカラムクロマトグラフィ
ーで精製し化合物９を１６０mg得た。¹ H-NMR (δ ppm, CDCl₃) : 7.27-7.58 (2H, m), 7.12-
7.25 (4H, m), 6.62-7.01 (6H, m), 6.19-6.25 (1H,
m), 5.55-5.77 (1H, m), 5.39-5.51 (1H, m), 5.12-5.2
5 (1H, m), 4.25-4.47 (3H, m), 3.79 and 3.79 (6H,
s), 3.58-3.70 (1H,m), 2.99-3.10 (1H, m), 2.78-2.87
(1H, m), 2.28-2.51 (5H, m), 1.45 (9H,2s), 1.43 (9
H, s), 1.15-2.15 (31H, m), 0.82-0.93 (15H, m).3-xv) Compound 8 (220 mg) in DMF
(2 mL) To the solution was added diethylamine (0.2 mL) at room temperature. After the solution was stirred at room temperature for 2.5 hours, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain Compound 9 (160 mg). ¹ H-NMR (δ ppm, CDCl ₃ ): 7.27-7.58 (2H, m), 7.12-
7.25 (4H, m), 6.62-7.01 (6H, m), 6.19-6.25 (1H,
m), 5.55-5.77 (1H, m), 5.39-5.51 (1H, m), 5.12-5.2
5 (1H, m), 4.25-4.47 (3H, m), 3.79 and 3.79 (6H,
s), 3.58-3.70 (1H, m), 2.99-3.10 (1H, m), 2.78-2.87
(1H, m), 2.28-2.51 (5H, m), 1.45 (9H, 2s), 1.43 (9
H, s), 1.15-2.15 (31H, m), 0.82-0.93 (15H, m).

【００６２】３−xvi) 化合物９（１６０mg）とＦｍｏ
ｃ−Ｌ−バリン（５９mg）のジクロロメタン（３mL）溶
液にＨＯＢｔ・１水和物（２４mg）とＷＳＣＩ（３３m
g）を氷冷下加えた。この溶液を室温で１６時間撹拌
後、溶媒を留去し、残査をクロロホルムに溶解した。こ
の溶液を水、５％炭酸水素ナトリウム水溶液、１０％ク
エン酸水溶液、飽和食塩水で順次洗浄した。無水硫酸ナ
トリウムで乾燥後、溶媒を留去し、残査をシリカゲルカ
ラムクロマトグラフィーで精製し粗目的物を得た。これ
をクロロホルム−酢酸エチル−ヘキサン系により固化さ
せて、化合物１０を２００mg得た。¹ H-NMR (δ ppm, CDCl₃) : 7.73-7.80 (2H, m), 7.27-
7.61 (8H, m), 7.09-7.23 (5H, m), 6.60-6.97 (6H,
m), 6.18-6.26 (1H, m), 5.31-5.73 (3H, m), 5.09-5.2
3 (1H, m), 4.75-4.96 (1H, m), 4.15-4.52 (6H, m),
3.96-4.11 (1H, m),3.76 (3H, 2s), 3.74 and 3.76 (3
H, s), 2.17-3.04 (7H, m), 1.08-2.15 (32H, m), 0.75
-1.00 (21H, m).3-xvi) Compound 9 (160 mg) and Fmo
To a solution of c-L-valine (59 mg) in dichloromethane (3 mL) was added HOBt monohydrate (24 mg) and WSCI (33 mM).
g) was added under ice cooling. After stirring this solution at room temperature for 16 hours, the solvent was distilled off, and the residue was dissolved in chloroform. This solution was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution, and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain a crude target product. This was solidified with a chloroform-ethyl acetate-hexane system to obtain 200 mg of a compound 10. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.73-7.80 (2H, m), 7.27-
7.61 (8H, m), 7.09-7.23 (5H, m), 6.60-6.97 (6H,
m), 6.18-6.26 (1H, m), 5.31-5.73 (3H, m), 5.09-5.2
3 (1H, m), 4.75-4.96 (1H, m), 4.15-4.52 (6H, m),
3.96-4.11 (1H, m), 3.76 (3H, 2s), 3.74 and 3.76 (3
H, s), 2.17-3.04 (7H, m), 1.08-2.15 (32H, m), 0.75
-1.00 (21H, m).

【００６３】３−xvii) 化合物１０（２００mg）をＴ
ＦＡ（３mL）に溶解した。この溶液を室温で３時間撹拌
した後、溶媒を留去した。残査をクロロホルム−メタノ
ール−ジエチルエーテル系により固化させて化合物１１
を７０mg得た。¹ H-NMR (δ ppm, CDCl₃) : 7.79 (2H, d, J=7.6 Hz),
7.41-7.75 (2H, m), 7.39 (2H, t, J=7.6 Hz), 7.32 (2
H, t, J=7.6 Hz), 5.54-5.70 (1H, m), 5.38-5.49 (1H,
m), 5.10-5.25 (1H, m), 4.65-4.80 (1H, m), 4.20-4.
50 (6H, m), 3.83-3.90 (1H, m), 2.71-3.04 (3H, m),
2.22-2.58 (4H, m), 1.85-2.14 (3H, m),1.06-1.78 (29
H, m), 0.81-1.00 (21H, m).3-xvii) Compound 10 (200 mg) was converted to T
Dissolved in FA (3 mL). After the solution was stirred at room temperature for 3 hours, the solvent was distilled off. The residue was solidified with a chloroform-methanol-diethyl ether system to give compound 11.
70 mg was obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.79 (2H, d, J = 7.6 Hz),
7.41-7.75 (2H, m), 7.39 (2H, t, J = 7.6 Hz), 7.32 (2
H, t, J = 7.6 Hz), 5.54-5.70 (1H, m), 5.38-5.49 (1H,
m), 5.10-5.25 (1H, m), 4.65-4.80 (1H, m), 4.20-4.
50 (6H, m), 3.83-3.90 (1H, m), 2.71-3.04 (3H, m),
2.22-2.58 (4H, m), 1.85-2.14 (3H, m), 1.06-1.78 (29
H, m), 0.81-1.00 (21H, m).

【００６４】実施例４ ４−ｉ） ジオキサン（１６２mL)、水（８３mL)、１Ｍ
炭酸ナトリウム水（８３mL）の混合溶液に５―アミノ吉
草酸（１０ｇ）を加えた。この溶液にジ―ｔ―ブチル―
ジカルボナート（１９.９ｇ）を氷冷下加えた。室温で
一晩攪拌後、溶液を約１００mLまで減圧下濃縮した。氷
冷下、１０％クエン酸水でｐＨ３に調整した後、酢酸エ
チルで抽出した。有機層を水で洗浄後、硫酸ナトリウム
で乾燥した。溶媒を除いた後、ヘキサン−酢酸エチル系
で再結晶を行いＮ−Ｂｏｃ−５−アミノ吉草酸を１７ｇ
得た。¹ H-NMR(δ ppm, CDCl₃) : 5.78 (1H,br s), 4.61 (1H,
br s), 3.05-3.20 (2H, m), 2.38 (2H, t, J=7.3 Hz),
1.60-1.70 (2H, m), 1.44 (9H, s), 1.35-1.60(2H, m).Example 4 4-i) Dioxane (162 mL), water (83 mL), 1M
To a mixed solution of aqueous sodium carbonate (83 mL) was added 5-aminovaleric acid (10 g). Di-t-butyl-
Dicarbonate (19.9 g) was added under ice cooling. After stirring at room temperature overnight, the solution was concentrated under reduced pressure to about 100 mL. After adjusting the pH to 3 with 10% aqueous citric acid under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. After removing the solvent, recrystallization was performed with hexane-ethyl acetate to obtain 17 g of N-Boc-5-aminovaleric acid.
Obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 5.78 (1H, brs), 4.61 (1H,
br s), 3.05-3.20 (2H, m), 2.38 (2H, t, J = 7.3 Hz),
1.60-1.70 (2H, m), 1.44 (9H, s), 1.35-1.60 (2H, m).

【００６５】４−ii） 得られたＮ−Ｂｏｃ−５−アミ
ノ吉草酸（３ｇ)、ジメチルアミノピリジン（０.１５
ｇ）とベンジルアルコール（１.３６mL）のジクロロメ
タン（５０mL）溶液に氷冷下ＷＳＣＩ（２.８９ｇ）を
加えた。この溶液を氷冷下で２時間攪拌した後、室温で
一晩攪拌した。溶媒を留去した後、残留物に酢酸エチル
と水を加えた。分液した酢酸エチルを５％炭酸水素ナト
リウム水溶液で２回、水で２回洗浄後、無水硫酸ナトリ
ウムで乾燥した。溶媒を留去した後、シリカゲルカラム
クロマトグラフィーで精製してＮ−Ｂｏｃ−５−アミノ
吉草酸ベンジルを４ｇ得た。¹ H-NMR(δ ppm, CDCl₃) : 7.27-7.37 (5H, m), 5.11 (2
H, s), 4.53 (1H, brs), 3.05-3.15 (2H, m), 2.38 (2
H, t, J=7.3 Hz), 1.55-1.70 (2H, m), 1.44 (9H, s),
1.35-1.60 (2H, m).4-ii) The obtained N-Boc-5-aminovaleric acid (3 g) and dimethylaminopyridine (0.15)
g) and WSCI (2.89 g) were added to a solution of benzyl alcohol (1.36 mL) in dichloromethane (50 mL) under ice-cooling. The solution was stirred for 2 hours under ice cooling, and then stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate and water were added to the residue. The separated ethyl acetate was washed twice with a 5% aqueous sodium hydrogen carbonate solution and twice with water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 4 g of benzyl N-Boc-5-aminovalerate. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.27-7.37 (5H, m), 5.11 (2
H, s), 4.53 (1H, brs), 3.05-3.15 (2H, m), 2.38 (2
H, t, J = 7.3 Hz), 1.55-1.70 (2H, m), 1.44 (9H, s),
1.35-1.60 (2H, m).

【００６６】４−iii） 得られたＮ−Ｂｏｃ−５−ア
ミノ吉草酸ベンジル（４ｇ）にＴＦＡ（５０mL）を加え
て２０分室温で攪拌した。ＴＦＡを留去した後、酢酸エ
チルと飽和炭酸水素ナトリウム水溶液を加えた。分液し
た酢酸エチルを無水硫酸ナトリウムで乾燥した。溶媒を
留去して５−アミノ吉草酸ベンジルを２.７ｇ得た。¹ H-NMR(δ ppm, CDCl₃) : 7.80 (2H, br s), 7.25-7.38
(5H, m), 5.07 (2H,s), 2.85-2.95 (2H, m), 2.35-2.4
5 (2H, m), 1.60-1.70 (4H, m).4-iii) TFA (50 mL) was added to the obtained benzyl N-Boc-5-aminovalerate (4 g), and the mixture was stirred at room temperature for 20 minutes. After the TFA was distilled off, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added. The separated ethyl acetate was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2.7 g of benzyl 5-aminovalerate. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.80 (2H, br s), 7.25-7.38
(5H, m), 5.07 (2H, s), 2.85-2.95 (2H, m), 2.35-2.4
5 (2H, m), 1.60-1.70 (4H, m).

【００６７】４−iv） 得られた５−アミノ吉草酸ベン
ジル（２.０４ｇ)、Ｆｍｏｃ−アスパラギン酸β−ｔ−
ブチルエステル（２.０３ｇ）とＨＯＢｔ・１水和物
（０.８３ｇ）のジクロロメタン（３０mL）溶液に氷冷
下ＷＳＣＩ（１.０４ｇ）を加えた。この溶液を氷冷下
で２時間攪拌した後、室温で一晩攪拌した。溶媒を留去
した後、残留物を酢酸エチルに溶解し、１０％クエン酸
水溶液、水、５％炭酸水素ナトリウム水溶液そして水で
洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を留去し
た後、シリカゲルカラムクロマトグラフィーで精製して
中間体化合物１７を２.４１ｇ得た。¹ H-NMR(δ ppm, CDCl₃) : 7.76 (2H, d, J=7.8 Hz), 7.
58 (2H, d, J=7.3 Hz), 7.23-7.46 (6H, m), 6.52 (1H,
br s), 5.94 (1H, d, J=8.0 Hz), 5.09 (2H,s), 4.36-
4.55 (3H, m), 4.22 (1H, t, J=6.8 Hz), 3.15-3.29 (2
H, m), 2.90 (1H, d, J=17 Hz), 2.59 (1H, dd, J=6.4,
17 Hz), 2.37 (2H, t, J=7.3 Hz), 1.58-1.82 (2H,
m), 1.44 (9H, s), 1.35-1.58 (2H, m).4-iv) The obtained benzyl 5-aminovalerate (2.04 g), Fmoc-aspartic acid β-t-
To a solution of butyl ester (2.03 g) and HOBt monohydrate (0.83 g) in dichloromethane (30 mL) was added WSCI (1.04 g) under ice-cooling. The solution was stirred for 2 hours under ice cooling, and then stirred at room temperature overnight. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with a 10% aqueous citric acid solution, water, a 5% aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 2.41 g of intermediate compound 17. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.8 Hz), 7.
58 (2H, d, J = 7.3 Hz), 7.23-7.46 (6H, m), 6.52 (1H,
br s), 5.94 (1H, d, J = 8.0 Hz), 5.09 (2H, s), 4.36-
4.55 (3H, m), 4.22 (1H, t, J = 6.8 Hz), 3.15-3.29 (2
H, m), 2.90 (1H, d, J = 17 Hz), 2.59 (1H, dd, J = 6.4,
17 Hz), 2.37 (2H, t, J = 7.3 Hz), 1.58-1.82 (2H,
m), 1.44 (9H, s), 1.35-1.58 (2H, m).

【００６８】４−ｖ) 中間体化合物１７（Ｆｍｏｃ−
Ａｓｐ(ＯｔＢｕ)−ＮＨ−(ＣＨ₂)₄−ＣＯ₂Ｂｚｌ）
(０.６９ｇ）と５％パラジウム炭素（７０mg）のメタノ
ール（２０mL）懸濁液を水素雰囲気下（２kg／cm²）室
温で５時間反応させた。パラジウム炭素を濾別し、メタ
ノールを留去した後、得られた粗生成物をシリカゲルカ
ラムクロマトグラフィーで精製し、さらにヘキサン−ジ
エチルエーテル系により固化させて中間体化合物１８を
０.２６ｇ得た。¹ H-NMR (δ ppm, CDCl₃) : 7.76 (2H, d, J=7.3 Hz),
7.58 (2H, d, J=7.3 Hz), 7.40 (2H, t, J=7.3 Hz), 7.
31 (2H, t, J=7.6 Hz), 6.62 (1H, t, J=5.9 Hz), 6.03
(1H, d, J=8.8 Hz), 4.49 (1H, br s), 4.43 (2H, d,
J=6.8 Hz), 4.21(1H, t, J=7.1 Hz), 3.26 (2H, q, J=
6.3 Hz), 2.89 (1H, dd, J=3.9, 18 Hz),2.61 (1H, dd,
J=6.8, 17 Hz), 2.35 (2H, t, J=7.1 Hz), 1.60-1.70
(2H, m),1.50-1.59 (2H, m), 1.44 (9H, s).4-v) Intermediate compound 17 (Fmoc-
_{Asp (OtBu) -NH- (CH 2} ) 4 -CO 2 Bzl)
(0.69 g) and a suspension of 5% palladium on carbon (70 mg) in methanol (20 mL) were reacted under a hydrogen atmosphere (2 kg / cm ² ) at room temperature for 5 hours. After filtering off the palladium carbon and distilling off the methanol, the obtained crude product was purified by silica gel column chromatography and further solidified with a hexane-diethyl ether system to obtain 0.26 g of an intermediate compound 18. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.3 Hz),
7.58 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.3 Hz), 7.
31 (2H, t, J = 7.6 Hz), 6.62 (1H, t, J = 5.9 Hz), 6.03
(1H, d, J = 8.8 Hz), 4.49 (1H, br s), 4.43 (2H, d,
J = 6.8 Hz), 4.21 (1H, t, J = 7.1 Hz), 3.26 (2H, q, J =
6.3 Hz), 2.89 (1H, dd, J = 3.9, 18 Hz), 2.61 (1H, dd,
(J = 6.8, 17 Hz), 2.35 (2H, t, J = 7.1 Hz), 1.60-1.70
(2H, m), 1.50-1.59 (2H, m), 1.44 (9H, s).

【００６９】４−vi) 中間体化合物２（３−ヒドロキ
シミリスチン酸ベンジルエステル）(０.１６ｇ）、中間
体化合物１８（０.２５ｇ）、ジメチルアミノピリジン
（４mg）のジクロロメタン（５mL）溶液にＤＣＣ（０.
１５ｇ）を氷冷下加えた。この溶液を氷冷下で２時間さ
らに室温で４日間撹拌した。析出物を濾別した後、ジク
ロロメタンを留去した。残査に酢酸エチルと１０％クエ
ン酸水溶液を加えた。得られた有機層を水、５％炭酸水
素ナトリウム水溶液、水で順次洗浄した後、無水硫酸ナ
トリウムで乾燥した。溶媒を留去し、残査をシリカゲル
カラムクロマトグラフィーで精製し化合物１２を０.３
６ｇ得た。¹ H-NMR (δ ppm, CDCl₃) : 7.76 (2H, d, J=7.3 Hz),
7.58 (2H, d, J=7.3 Hz), 7.40 (2H, t, J=7.3 Hz), 7.
28-7.38 (7H, m), 6.53 (1H, br s), 5.95 (1H,d, J=8.
3 Hz), 5.22 (1H, qui., J=6.3Hz), 5.10 (2H, s), 4.4
7 (1H, br s),4.43 (2H, d, J=6.8 Hz), 4.22 (1H, t,
J=7.1 Hz), 3.22 (2H, q, J=6.5 Hz),2.90 (1H, dd, J=
4.2, 16 Hz), 2.53-2.65 (3H, m), 2.21 (2H, dt, J=2.
9, 7.3Hz), 1.44 (9H, s), 1.41-1.65 (4H, m), 1.04-
1.41 (20H, m), 0.88 (3H, t,J=6.8 Hz).4-vi) DCC was added to a solution of Intermediate Compound 2 (benzyl 3-hydroxymyristate) (0.16 g), Intermediate Compound 18 (0.25 g) and dimethylaminopyridine (4 mg) in dichloromethane (5 mL). (0.
15g) was added under ice cooling. The solution was stirred for 2 hours under ice cooling and further for 4 days at room temperature. After the precipitate was separated by filtration, dichloromethane was distilled off. Ethyl acetate and a 10% aqueous citric acid solution were added to the residue. The obtained organic layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain Compound 12 (0.3).
6 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.3 Hz),
7.58 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.3 Hz), 7.
28-7.38 (7H, m), 6.53 (1H, br s), 5.95 (1H, d, J = 8.
3 Hz), 5.22 (1H, qui., J = 6.3Hz), 5.10 (2H, s), 4.4
7 (1H, br s), 4.43 (2H, d, J = 6.8 Hz), 4.22 (1H, t,
J = 7.1 Hz), 3.22 (2H, q, J = 6.5 Hz), 2.90 (1H, dd, J =
4.2, 16 Hz), 2.53-2.65 (3H, m), 2.21 (2H, dt, J = 2.
9, 7.3Hz), 1.44 (9H, s), 1.41-1.65 (4H, m), 1.04-
1.41 (20H, m), 0.88 (3H, t, J = 6.8 Hz).

【００７０】４−vii) 化合物１２（０.３６ｇ）のＤ
ＭＦ（５mL）溶液にジエチルアミン（０.５mL）を室温
下加えた。この溶液を室温で２時間撹拌した後、減圧濃
縮した。得られたアミン体とＦｍｏｃ−Ｌ−バリン
（０.１８ｇ）およびＨＯＢｔ・１水和物（０.０８ｇ）
のジクロロメタン（１０mL）溶液に氷冷下、ＷＳＣＩ
（０.１０ｇ）を加えた。この溶液を氷冷下で２時間撹
拌した後、室温で一晩撹拌した。ジクロロメタンを留去
した後、残留物にクロロホルムと１０％クエン酸水溶液
を加えた。分液したクロロホルム層を水、５％炭酸水素
ナトリウム水溶液そして水で順番に洗浄後、無水硫酸ナ
トリウムで乾燥した。クロロホルムを留去した後、シリ
カゲルカラムクロマトグラフィーで精製し化合物１３を
０.４０ｇ得た。¹ H-NMR (δ ppm, CDCl₃) : 7.77 (2H, d, J=7.3 Hz),
7.60 (2H, dd, J=3.7,6.8 Hz), 7.40 (2H, t, J=7.1 H
z), 7.24-7.36 (8H, m), 6.74 (1H, br s), 5.30 (1H,
d, J=7.3 Hz), 5.21 (1H, qui., J=6.3 Hz), 5.10 (2H,
s), 4.66-4.74(1H, m), 4.37-4.48 (2H, m), 4.23 (1
H, t, J=6.8 Hz), 4.01 (1H, br s), 3.10-3.26 (2H,
m), 2.86-2.97 (1H, m), 2.51-2.65 (3H, m), 2.17 (2
H, dt, J=3.1, 7.3 Hz), 2.14-2.20 (1H, m), 1.35-1.6
3 (4H, m), 1.41 (9H, s), 1.04-1.35 (20H, m), 0.98
(3H, d, J=6.8 Hz), 0.93 (3H, d, J=6.3 Hz), 0.88 (3
H, t,J=6.8 Hz).4-vii) D of compound 12 (0.36 g)
Diethylamine (0.5 mL) was added to the MF (5 mL) solution at room temperature. The solution was stirred at room temperature for 2 hours and concentrated under reduced pressure. The obtained amine compound, Fmoc-L-valine (0.18 g) and HOBt monohydrate (0.08 g)
WSCI in a dichloromethane (10 mL) solution under ice-cooling
(0.10 g) was added. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. After the dichloromethane was distilled off, chloroform and a 10% aqueous citric acid solution were added to the residue. The separated chloroform layer was washed sequentially with water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. After chloroform was distilled off, the residue was purified by silica gel column chromatography to obtain 0.40 g of compound 13. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.77 (2H, d, J = 7.3 Hz),
7.60 (2H, dd, J = 3.7,6.8 Hz), 7.40 (2H, t, J = 7.1 H
z), 7.24-7.36 (8H, m), 6.74 (1H, br s), 5.30 (1H,
d, J = 7.3 Hz), 5.21 (1H, qui., J = 6.3 Hz), 5.10 (2H,
s), 4.66-4.74 (1H, m), 4.37-4.48 (2H, m), 4.23 (1
H, t, J = 6.8 Hz), 4.01 (1H, br s), 3.10-3.26 (2H,
m), 2.86-2.97 (1H, m), 2.51-2.65 (3H, m), 2.17 (2
H, dt, J = 3.1, 7.3 Hz), 2.14-2.20 (1H, m), 1.35-1.6
3 (4H, m), 1.41 (9H, s), 1.04-1.35 (20H, m), 0.98
(3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.3 Hz), 0.88 (3
(H, t, J = 6.8 Hz).

【００７１】４−viii) 化合物１３（０.４０ｇ）をメ
タノール（２０mL）に溶解し５％パラジウム炭素（４０
mg）を加え、水素雰囲気下室温で１０時間撹拌した。パ
ラジウム炭素を濾別し、メタノールを留去した後、得ら
れた粗生成物をシリカゲルカラムクロマトグラフィーで
精製し化合物１４を０.３４ｇ得た。¹ H-NMR (δ ppm, CDCl₃) : 7.76 (2H, d, J=7.3 Hz),
7.54-7.67 (3H, m), 7.40 (2H, d, J=7.6 Hz), 7.31 (2
H, t, J=7.6 Hz), 6.87-6.98 (1H, m), 5.73 (1H, br
s), 5.19-5.30 (1H, m), 4.71-4.80 (1H, m), 4.33-4.4
5 (2H, m), 4.19-4.25 (1H, m), 4.03-4.11 (1H, m),
3.06-3.34 (2H, m), 2.75-2.87 (1H, m), 2.49-2.72 (3
H, m), 2.10-2.37 (3H, m), 1.40-1.71 (4H, m), 1.40
(9H, s), 1.16-1.35 (20H, m), 0.98 (3H, d, J=6.8 H
z), 0.94 (3H, d, J=6.8 Hz), 0.88 (3H, t, J=6.8 H
z).4-viii) Compound 13 (0.40 g) was dissolved in methanol (20 mL) and 5% palladium on carbon (40
mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. After filtering off palladium carbon and distilling off methanol, the obtained crude product was purified by silica gel column chromatography to obtain 0.34 g of compound 14. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.3 Hz),
7.54-7.67 (3H, m), 7.40 (2H, d, J = 7.6 Hz), 7.31 (2
H, t, J = 7.6 Hz), 6.87-6.98 (1H, m), 5.73 (1H, br
s), 5.19-5.30 (1H, m), 4.71-4.80 (1H, m), 4.33-4.4
5 (2H, m), 4.19-4.25 (1H, m), 4.03-4.11 (1H, m),
3.06-3.34 (2H, m), 2.75-2.87 (1H, m), 2.49-2.72 (3
H, m), 2.10-2.37 (3H, m), 1.40-1.71 (4H, m), 1.40
(9H, s), 1.16-1.35 (20H, m), 0.98 (3H, d, J = 6.8 H
z), 0.94 (3H, d, J = 6.8 Hz), 0.88 (3H, t, J = 6.8 H
z).

【００７２】４−ix) 化合物１４（０.３４ｇ）とＧｌ
ｎ(Ｍｂｈ)−Ｌｅｕ−ＯｔＢｕ(０.２２ｇ）およびＨＯ
Ｂｔ・１水和物（０.０６ｇ）のＤＭＦ（１０mL）溶液
に氷冷下、ＷＳＣＩ（０.０８ｇ）を加えた。この溶液
を氷冷下で２時間撹拌した後、室温で一晩撹拌した。Ｄ
ＭＦを留去した後、残留物にクロロホルムと１０％クエ
ン酸水溶液を加えた。分液したクロロホルム層を水、５
％炭酸水素ナトリウム水溶液そして水で順番に洗浄後、
無水硫酸ナトリウムで乾燥した。クロロホルムを留去し
た後、シリカゲルカラムクロマトグラフィーで精製し化
合物１５を０.４７ｇ得た。¹ H-NMR (δ ppm, CDCl₃) :7.76 (2H, d, J=7.8 Hz), 7.
59 (2H, d, J=7.3 Hz), 7.40 (2H, t, J=7.6 Hz), 7.30
(2H, dt, J=1.1, 7.6 Hz), 7.28-7.47 (3H, m), 7.14
(2H, dd, J=2.4, 8.8 Hz), 7.16 (2H, t, J=7.6 Hz),
7.05-7.21 (1H,m), 6.85-7.04 (2H, m), 6.82 (4H, dd,
J=2.0, 8.8 Hz), 6.20 (1H, d, J=7.8Hz), 5.52, 5.47
(1H, 2d, J=8.3 Hz), 5.12-5.22 (1H, m), 4.66-4.77
(1H, m), 4.30-4.49 (4H, m), 4.21 (1H, dt, J=2.9,
6.8 Hz), 3.95-4.05 (1H, m), 3.76 (6H, 2s), 3.06-3.
27 (2H, m), 2.72-2.83 (1H, m), 2.51-2.65 (1H, m),
2.32-2.48 (4H, m), 1.99-2.27 (4H, m), 1.43 (9H,
s), 1.39 (9H, s), 1.35-1.66 (7H, m), 1.17-1.34 (20
H, m), 0.80-0.99 (15H, m).4-ix) Compound 14 (0.34 g) and Gl
n (Mbh) -Leu-OtBu (0.22 g) and HO
To a solution of Bt monohydrate (0.06 g) in DMF (10 mL) was added WSCI (0.08 g) under ice-cooling. The solution was stirred under ice cooling for 2 hours, and then stirred at room temperature overnight. D
After the MF was distilled off, chloroform and a 10% aqueous citric acid solution were added to the residue. The separated chloroform layer was washed with water, 5
% Aqueous sodium hydrogen carbonate solution and water,
Dry over anhydrous sodium sulfate. After chloroform was distilled off, the residue was purified by silica gel column chromatography to obtain 0.47 g of compound 15. ¹ H-NMR (δ ppm, CDCl ₃ ): 7.76 (2H, d, J = 7.8 Hz), 7.
59 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.6 Hz), 7.30
(2H, dt, J = 1.1, 7.6 Hz), 7.28-7.47 (3H, m), 7.14
(2H, dd, J = 2.4, 8.8 Hz), 7.16 (2H, t, J = 7.6 Hz),
7.05-7.21 (1H, m), 6.85-7.04 (2H, m), 6.82 (4H, dd,
J = 2.0, 8.8 Hz), 6.20 (1H, d, J = 7.8Hz), 5.52, 5.47
(1H, 2d, J = 8.3 Hz), 5.12-5.22 (1H, m), 4.66-4.77
(1H, m), 4.30-4.49 (4H, m), 4.21 (1H, dt, J = 2.9,
6.8 Hz), 3.95-4.05 (1H, m), 3.76 (6H, 2s), 3.06-3.
27 (2H, m), 2.72-2.83 (1H, m), 2.51-2.65 (1H, m),
2.32-2.48 (4H, m), 1.99-2.27 (4H, m), 1.43 (9H,
s), 1.39 (9H, s), 1.35-1.66 (7H, m), 1.17-1.34 (20
H, m), 0.80-0.99 (15H, m).

【００７３】４−ｘ) 化合物１５（０.４７ｇ）をＴＦ
Ａ（５mL）に溶解した。この溶液を室温で２時間撹拌し
た後、減圧濃縮した。残査にクロロホルムを加えた後、
飽和炭酸水素ナトリウム水溶液を加えて約ｐＨ７にし
た。得られた固体を濾取した後、クロロホルムで洗浄
し、乾燥させて化合物１６を０.２９ｇ得た。¹ H-NMR (δ ppm, DMSO-d6) : 8.10-8.30 (1H, m), 7.97
-8.07 (1H, m), 7.86(2H, d, J=7.8 Hz), 7.68-7.89 (3
H, m), 7.40 (2H, t, J=7.3 Hz), 7.31 (2H,t, J=7.3 H
z), 7.28-7.43 (1H, m), 7.15-7.24 (1H, m), 6.78-6.8
4 (1H, m), 6.62 (1H, br s), 5.04-5.12 (1H, m), 4.4
8-4.56 (1H, m), 4.11-4.34 (5H, m),3.82-3.88 (1H,
m), 3.66-3.75 (1H, m), 2.95-2.98 (2H, m), 2.31-2.6
8 (4H,m), 2.15-2.23 (2H, m), 1.83-2.12 (4H, m), 1.
59-1.76 (2H, m), 1.33-1.57(7H, m), 1.16-1.30 (20H,
m), 0.79-0.92 (15H, m).4-x) Compound 15 (0.47 g) was converted to TF
A (5 mL). The solution was stirred at room temperature for 2 hours and concentrated under reduced pressure. After adding chloroform to the residue,
A saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to about 7. The obtained solid was collected by filtration, washed with chloroform, and dried to obtain 0.29 g of compound 16. ¹ H-NMR (δ ppm, DMSO-d6): 8.10-8.30 (1H, m), 7.97
-8.07 (1H, m), 7.86 (2H, d, J = 7.8 Hz), 7.68-7.89 (3
H, m), 7.40 (2H, t, J = 7.3 Hz), 7.31 (2H, t, J = 7.3 H
z), 7.28-7.43 (1H, m), 7.15-7.24 (1H, m), 6.78-6.8
4 (1H, m), 6.62 (1H, br s), 5.04-5.12 (1H, m), 4.4
8-4.56 (1H, m), 4.11-4.34 (5H, m), 3.82-3.88 (1H,
m), 3.66-3.75 (1H, m), 2.95-2.98 (2H, m), 2.31-2.6
8 (4H, m), 2.15-2.23 (2H, m), 1.83-2.12 (4H, m), 1.
59-1.76 (2H, m), 1.33-1.57 (7H, m), 1.16-1.30 (20H,
m), 0.79-0.92 (15H, m).

【００７４】実施例５ ５−ｉ) 中間体化合物２（３.１８ｇ）、Ｆｍｏｃ−Ｌ
−イソロイシン（３.７０ｇ）およびジメチルアミノピ
リジン（０.１０ｇ）のジクロロメタン（２５０mL）溶
液に氷冷下、ＤＣＣ（３.１４ｇ）を加え、氷冷下で１
時間、続いて室温で一晩撹拌した。析出物を濾別した
後、ジクロロメタンを留去した。残留物に酢酸エチル
（３０mL）を加え、不溶物を濾別した後、酢酸エチルを
留去した。残留物をシリカゲルカラムクロマトグラフィ
ーで精製し、中間体化合物１９を７.１４ｇ得た。¹ H-NMR (δ ppm, CDCl₃) 7.29-7.77 (13H, m), 5.27-5.
33 (2H, m), 5.11 (2H, s), 4.29-4.34 (3H, m), 4.23
(1H, t, J=6.8 Hz), 2.57-2.72 (2H, m), 1.07-1.90 (2
3H, m), 0.86-0.95 (9H, m).Example 5 5-i) Intermediate compound 2 (3.18 g), Fmoc-L
DCC (3.14 g) was added to a solution of isoleucine (3.70 g) and dimethylaminopyridine (0.10 g) in dichloromethane (250 mL) under ice-cooling.
Stirred for hours, then overnight at room temperature. After the precipitate was separated by filtration, dichloromethane was distilled off. Ethyl acetate (30 mL) was added to the residue, and the insolubles were removed by filtration. The residue was purified by silica gel column chromatography to obtain 7.14 g of intermediate compound 19. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.29-7.77 (13H, m), 5.27-5.
33 (2H, m), 5.11 (2H, s), 4.29-4.34 (3H, m), 4.23
(1H, t, J = 6.8 Hz), 2.57-2.72 (2H, m), 1.07-1.90 (2
3H, m), 0.86-0.95 (9H, m).

【００７５】５−ii) 中間体化合物１９（７.１４ｇ）
をＤＭＦ（７０mL）に溶解し、ジエチルアミン（７mL）
を加え，室温で５時間撹拌した。溶媒を留去した後、シ
リカゲルカラムクロマトグラフィーで精製し、中間体化
合物２０を４.３３ｇ得た。¹ H-NMR (δppm, CDCl₃) 7.33-7.36 (5H, m), 5.24-5.31
(1H, m), 5.11 (2H,s), 3.19 (1H, d, J=4.9 Hz), 2.5
7-2.66 (2H, m), 1.05-1.75 (25H, m), 0.86-0.94 (9H,
m).5-ii) Intermediate compound 19 (7.14 g)
Was dissolved in DMF (70 mL) and diethylamine (7 mL)
Was added and stirred at room temperature for 5 hours. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 4.33 g of intermediate compound 20. ¹ H-NMR (δppm, CDCl ₃ ) 7.33-7.36 (5H, m), 5.24-5.31
(1H, m), 5.11 (2H, s), 3.19 (1H, d, J = 4.9 Hz), 2.5
7-2.66 (2H, m), 1.05-1.75 (25H, m), 0.86-0.94 (9H,
m).

【００７６】５−iii) Ｆｍｏｃ−Ｌ−アスパラギン酸
ｔ−ブチルエステル（９.０５ｇ）、Ｄ−ロイシンベン
ジルエステル（４.４３ｇ）およびＨＯＢｔ・１水和物
（３.３７ｇ）のジクロロメタン（８０mL）溶液に、Ｗ
ＳＣＩ（４.２２ｇ）を氷冷下に加え、この温度で２時
間さらに室温で一晩撹拌した。ジクロロメタンを留去し
た後、酢酸エチルを加え１０％クエン酸水溶液、水、５
％炭酸水素ナトリウム水溶液および水で洗浄後、無水硫
酸ナトリウムで乾燥した。溶媒を留去した後、得られた
粗生成物をヘキサン−酢酸エチルから結晶化して精製
し、中間体化合物２１を８.３６ｇ得た。¹ H-NMR (δ ppm, CDCl₃) 7.77(2H, d, J=7.3Hz), 7.59
(2H, d, J=7.8Hz), 7.40(2H, t, J=7.3Hz), 7.28-7.37
(7H, m), 6.94(1H, d, J=7.8Hz), 5.96(1H, d, J=7.8H
z), 5.17(1H, d, J=12Hz), 5.13(1H, d, J=12Hz), 4.53
-4.67(2H, m), 4.39(2H, d, J=6.8Hz), 4.23(1H, t, J=
7.1Hz), 2.89(1H, dd, J=3.2, 17Hz), 2.62(1H, dd, J=
6.8, 17Hz), 1.51-1.70(3H, m), 1.44(9H, s), 0.90(3
H, d, J=2.4Hz), 0.88(3H, d, J=2.4Hz).5-iii) Fmoc-L-aspartic acid t-butyl ester (9.05 g), D-leucine benzyl ester (4.43 g) and HOBt monohydrate (3.37 g) in dichloromethane (80 mL) In solution, W
SCI (4.22 g) was added under ice cooling, and the mixture was stirred at this temperature for 2 hours and further at room temperature overnight. After the dichloromethane was distilled off, ethyl acetate was added, and a 10% aqueous citric acid solution, water,
After washing with a 5% aqueous sodium hydrogen carbonate solution and water, the resultant was dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained crude product was crystallized from hexane-ethyl acetate and purified to obtain 8.36 g of an intermediate compound 21. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.77 (2H, d, J = 7.3 Hz), 7.59
(2H, d, J = 7.8Hz), 7.40 (2H, t, J = 7.3Hz), 7.28-7.37
(7H, m), 6.94 (1H, d, J = 7.8Hz), 5.96 (1H, d, J = 7.8H
z), 5.17 (1H, d, J = 12Hz), 5.13 (1H, d, J = 12Hz), 4.53
-4.67 (2H, m), 4.39 (2H, d, J = 6.8Hz), 4.23 (1H, t, J =
7.1Hz), 2.89 (1H, dd, J = 3.2, 17Hz), 2.62 (1H, dd, J =
6.8, 17Hz), 1.51-1.70 (3H, m), 1.44 (9H, s), 0.90 (3
H, d, J = 2.4Hz), 0.88 (3H, d, J = 2.4Hz).

【００７７】５−iv) 中間体化合物２１（６.１５ｇ）
をＤＭＦ（１００mL）に溶解し、ジエチルアミン（１０
mL）を加え、室温で３時間撹拌した。溶媒を留去して中
間体化合物２２を３.９３ｇ得た。¹ H-NMR (δ ppm, d₆-DMSO) 7.86(1H, d, J=7.8Hz), 7.6
8-7.75(3H, m), 7.49(1H, d, J=8.3Hz), 7.38-7.42(2H,
m), 7.29-7.33(2H, m), 4.18-4.41(5H, m), 2.64-2.69
(1H, m), 2.43-2.49(1H, m), 1.69-1.73(1H, m), 1.42-
1.48(1H, m), 1.37(9H, s), 0.86(9H, s).5-iv) Intermediate compound 21 (6.15 g)
Was dissolved in DMF (100 mL) and diethylamine (10 mL) was added.
mL) and stirred at room temperature for 3 hours. The solvent was distilled off to obtain 3.93 g of an intermediate compound 22. ¹ H-NMR (δ ppm, d ₆ -DMSO) 7.86 (1H, d, J = 7.8 Hz), 7.6
8-7.75 (3H, m), 7.49 (1H, d, J = 8.3Hz), 7.38-7.42 (2H,
m), 7.29-7.33 (2H, m), 4.18-4.41 (5H, m), 2.64-2.69
(1H, m), 2.43-2.49 (1H, m), 1.69-1.73 (1H, m), 1.42-
1.48 (1H, m), 1.37 (9H, s), 0.86 (9H, s).

【００７８】５−ｖ) 中間体化合物２２（３.９３
ｇ）、Ｆｍｏｃ−Ｌ−バリン（３.３９ｇ）およびＨＯ
Ｂｔ・１水和物（１.５３ｇ）のＤＭＦ（７０mL）溶液
に、ＷＳＣＩ（１.９２ｇ）を氷冷下に加え、この温度
で２時間さらに室温で一晩撹拌した。ＤＭＦを留去した
後、クロロホルムを加え１０％クエン酸水溶液、水、５
％炭酸水素ナトリウム水溶液および水で洗浄後、無水硫
酸ナトリウムで乾燥した。溶媒を留去した後、得られた
粗生成物をクロロホルム−ジエチルエーテルから固化し
て中間体化合物２３を６.１９ｇ得た。¹ H-NMR (δ ppm, CDCl₃) 7.77(2H, d, J=7.3Hz), 7.60
(2H, d, J=8.3Hz), 7.40(2H, dt, J=3.4, 7.3Hz), 7.27
-7.37(7H, m), 7.22(1H, d, J=7.8Hz), 7.08(1H, d, J=
7.3Hz), 5.29(1H, d, J=6.8Hz), 5.09(2H, s), 4.79-4.
86(1H, m), 4.56-4.63(1H, m), 4.41(2H, d, J=7.3Hz),
4.23(1H, t, J=6.8Hz), 4.01(1H, t, J=6.3Hz), 2.90
(1H, dd, J=4.4, 17Hz), 2.58(1H, dd, J=6.5, 17Hz),
2.10-2.20(1H, m), 1.56-1.68(3H, m), 1.42(9H, s),
0.98(3H, d, J=6.8Hz), 0.93(3H, d,J=6.8Hz), 0.85-0.
91(6H, m).5-v) Intermediate compound 22 (3.93)
g), Fmoc-L-valine (3.39 g) and HO
To a solution of Bt monohydrate (1.53 g) in DMF (70 mL) was added WSCI (1.92 g) under ice-cooling, and the mixture was stirred at this temperature for 2 hours and further at room temperature overnight. After distilling off DMF, chloroform was added and a 10% aqueous citric acid solution, water,
After washing with a 5% aqueous sodium hydrogen carbonate solution and water, the resultant was dried over anhydrous sodium sulfate. After evaporating the solvent, the obtained crude product was solidified from chloroform-diethyl ether to obtain 6.19 g of an intermediate compound 23. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.77 (2H, d, J = 7.3 Hz), 7.60
(2H, d, J = 8.3Hz), 7.40 (2H, dt, J = 3.4, 7.3Hz), 7.27
-7.37 (7H, m), 7.22 (1H, d, J = 7.8Hz), 7.08 (1H, d, J =
7.3Hz), 5.29 (1H, d, J = 6.8Hz), 5.09 (2H, s), 4.79-4.
86 (1H, m), 4.56-4.63 (1H, m), 4.41 (2H, d, J = 7.3Hz),
4.23 (1H, t, J = 6.8Hz), 4.01 (1H, t, J = 6.3Hz), 2.90
(1H, dd, J = 4.4, 17Hz), 2.58 (1H, dd, J = 6.5, 17Hz),
2.10-2.20 (1H, m), 1.56-1.68 (3H, m), 1.42 (9H, s),
0.98 (3H, d, J = 6.8Hz), 0.93 (3H, d, J = 6.8Hz), 0.85-0.
91 (6H, m).

【００７９】５−vi) ５−アミノ−３−ペンテン酸
（０.５７ｇ）のジオキサン（２０mL）溶液に氷冷下、
濃硫酸（０.６mL）とイソブチレン（１.５mL）を含むジ
クロロメタン（２.５mL）溶液を順次加え、密栓して室
温で１４時間撹拌した。反応容器を氷冷してから開栓
し、反応液に水酸化ナトリウム（１.７ｇ）を含む水
（３０mL）溶液を加え、ジエチルエーテルおよびクロロ
ホルムで抽出した。有機層を分離し、無水硫酸ナトリウ
ムで乾燥した。溶媒を留去し、中間体化合物２５を０.
１４ｇ得た。¹ H-NMR (δ pm, CDCl₃) 5.68-5.66(2H, m), 3.32(2H, b
r s), 2.97-2.99(2H,m), 1.87(2H, br s), 1.45(9H,
s).5-vi) A solution of 5-amino-3-pentenoic acid (0.57 g) in dioxane (20 mL) was added under ice-cooling.
A solution of concentrated sulfuric acid (0.6 mL) and a solution of isobutylene (1.5 mL) in dichloromethane (2.5 mL) were sequentially added, and the mixture was sealed and stirred at room temperature for 14 hours. The reaction vessel was cooled with ice and opened, and a water (30 mL) solution containing sodium hydroxide (1.7 g) was added to the reaction solution, followed by extraction with diethyl ether and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off, and the intermediate compound 25 was dissolved in 0.1%.
14 g were obtained. ¹ H-NMR (δ pm, CDCl ₃ ) 5.68-5.66 (2H, m), 3.32 (2H, b
rs), 2.97-2.99 (2H, m), 1.87 (2H, br s), 1.45 (9H,
s).

【００８０】５−vii) 中間体化合物２３（５.１２
ｇ）をＤＭＦ（１５mL）に溶解し、メタノール（２５０
mL）で希釈した。この溶液に１０％パラジウム炭素
（０.９６ｇ）を加え、得られた懸濁液を水素雰囲気下
（１気圧）に室温で２時間撹拌した。パラジウム炭素を
濾別し、濾液のメタノールを留去して、中間体化合物２
４を４．８７ｇ得た。このうち３.８４ｇをＤＭＦ（１
０mL）に溶解し、ジクロロメタン（２０mL）で希釈し
た。この溶液に中間体化合物２０（２.６８ｇ）、HOBt
・１水和物（１.０４ｇ）を室温で加えた後、氷冷し、
ＷＳＣＩ（１.７７ｇ）を加え、氷冷下で２時間、続い
て室温で一晩撹拌した。反応液をクロロホルム（５０m
L）で希釈し、飽和食塩水で洗浄し、無水硫酸ナトリウ
ムで乾燥した。溶媒を留去した後、シリカゲルカラムク
ロマトグラフィーで精製し、化合物１７を４.８８ｇ得
た。¹ H-NMR (δ ppm, CDCl₃) 7.27-7.76(13H, m), 6.99(1H,
br), 6.91(2H, br),6.83(1H, br), 5.57(1H, br), 5.1
9-5.24(1H, m), 5.02-5.10(2H, m), 3.95-4.85(7H, m),
2.46-2.86(4H, m), 1.08-2.11(36H, m), 0.85-0.95(21
H, m).5-vii) Intermediate compound 23 (5.12)
g) was dissolved in DMF (15 mL), and methanol (250
mL). To this solution was added 10% palladium on carbon (0.96 g) and the resulting suspension was stirred under a hydrogen atmosphere (1 atm) at room temperature for 2 hours. The palladium carbon was removed by filtration, and methanol in the filtrate was distilled off to obtain an intermediate compound 2
4.87 g of 4 was obtained. 3.84 g of this was added to DMF (1
0 mL) and diluted with dichloromethane (20 mL). To this solution was added intermediate compound 20 (2.68 g), HOBt
・ After adding monohydrate (1.04 g) at room temperature, the mixture was cooled on ice,
WSCI (1.77 g) was added, and the mixture was stirred under ice cooling for 2 hours, and then at room temperature overnight. The reaction solution was chloroform (50m
L), washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 4.88 g of compound 17. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.27-7.76 (13H, m), 6.99 (1H,
br), 6.91 (2H, br), 6.83 (1H, br), 5.57 (1H, br), 5.1
9-5.24 (1H, m), 5.02-5.10 (2H, m), 3.95-4.85 (7H, m),
2.46-2.86 (4H, m), 1.08-2.11 (36H, m), 0.85-0.95 (21
H, m).

【００８１】５−viii) 化合物１７（４.８８ｇ）をメ
タノール（３５０mL）に溶解し、１０％パラジウム炭素
（０.９８ｇ）を加え、得られた懸濁液を水素雰囲気下
に室温で２時間撹拌した。パラジウム炭素を濾別し、濾
液のメタノールを留去した後、シリカゲルカラムクロマ
トグラフィーで精製し、化合物１８を３.５８ｇ得た。¹ H-NMR (δ ppm, d₆-DMSO) 12.25(1H, br), 7.28-8.27
(12H, m), 5.04-5.09(1H, m), 4.56-4.58(1H, m), 4.14
-4.31(5H, m), 3.81-3.84(1H, m), 2.38-2.70(4H, m),
1.87-2.01(1H, m), 1.74-1.78(1H, m), 1.09-1.53(34H,
m), 0.78-0.87(21H, m).5-viii) Compound 17 (4.88 g) was dissolved in methanol (350 mL), 10% palladium on carbon (0.98 g) was added, and the resulting suspension was placed under a hydrogen atmosphere at room temperature for 2 hours. Stirred. After filtering off the palladium carbon and evaporating the methanol from the filtrate, the residue was purified by silica gel column chromatography to obtain 3.58 g of compound 18. ¹ H-NMR (δ ppm, d ₆ -DMSO) 12.25 (1H, br), 7.28-8.27
(12H, m), 5.04-5.09 (1H, m), 4.56-4.58 (1H, m), 4.14
-4.31 (5H, m), 3.81-3.84 (1H, m), 2.38-2.70 (4H, m),
1.87-2.01 (1H, m), 1.74-1.78 (1H, m), 1.09-1.53 (34H,
m), 0.78-0.87 (21H, m).

【００８２】５−ix) 中間体化合物２５（０.１９
ｇ）、化合物１８（０.５２ｇ）およびＨＯＢｔ・１水
和物（０.１９ｇ）のジクロロメタン（２０mL）溶液
に、ＷＳＣＩ（０.３２ｇ）を室温で加え、２２時間撹
拌した。ジクロロメタンを留去した後、シリカゲルカラ
ムクロマトグラフィーで精製し、化合物１９を０.５６
ｇ得た。¹ H-NMR (δ ppm, d₆-DMSO) 7.76(2H, d, J=7.3Hz), 7.5
9-7.64(3H, m), 6.90-7.42(8H, m), 6.20-6.27(1H, m),
5.64-5.72(1H, m), 5.50-5.54(1H, m), 5.14-5.21(1H,
m), 4.81-4.88(1H, m), 4.21-4.51(6H, m), 3.71-3.98
(4H, m), 2.73-2.99(2H, m), 2.15-2.51(2H, m), 1.08-
1.92(45H, m), 0.86-0.99(21H, m).5-ix) Intermediate compound 25 (0.19
g), compound 18 (0.52 g) and HOBt monohydrate (0.19 g) in dichloromethane (20 mL) were added with WSCI (0.32 g) at room temperature and stirred for 22 hours. After the dichloromethane was distilled off, the residue was purified by silica gel column chromatography to give compound 19 (0.56).
g was obtained. ¹ H-NMR (δ ppm, d ₆ -DMSO) 7.76 (2H, d, J = 7.3Hz), 7.5
9-7.64 (3H, m), 6.90-7.42 (8H, m), 6.20-6.27 (1H, m),
5.64-5.72 (1H, m), 5.50-5.54 (1H, m), 5.14-5.21 (1H, m
m), 4.81-4.88 (1H, m), 4.21-4.51 (6H, m), 3.71-3.98
(4H, m), 2.73-2.99 (2H, m), 2.15-2.51 (2H, m), 1.08-
1.92 (45H, m), 0.86-0.99 (21H, m).

【００８３】５−ｘ) 化合物１９（０.５６ｇ）をＴＦ
Ａ（３mL）に溶解し、溶液を室温で９０分間撹拌した。
クロロホルム（３０mL）で希釈し、水洗した。有機層を
分離し、溶媒を留去した。残留物（０.３３ｇ）にジエ
チルエーテルとヘキサンを加え、析出した沈殿物を濾取
し、減圧乾燥して化合物２０を０.３３ｇ得た。¹ H-NMR (δ ppm, d₆-DMSO) 12.18(1H, br), 8.27(1H, b
r), 7.68-8.00(7H, m), 7.29-7.42(6H, m), 5.44-5.65
(2H, m), 5.08-5.15(1H, m), 4.54-4.56(1H, m), 4.12-
4.31(5H, m), 3.83-3.89(1H, m), 3.57-3.69(2H, m),
2.96(2H, d, J=6.6Hz), 2.28-2.67(4H, m), 1.01-2.00
(27H, m), 0.82-0.87(21H, m).5-x) Compound 19 (0.56 g) was converted to TF
A (3 mL) and the solution was stirred at room temperature for 90 minutes.
Diluted with chloroform (30 mL) and washed with water. The organic layer was separated and the solvent was distilled off. Diethyl ether and hexane were added to the residue (0.33 g), and the deposited precipitate was collected by filtration and dried under reduced pressure to obtain 0.33 g of compound 20. ¹ H-NMR (δ ppm, d ₆ -DMSO) 12.18 (1H, br), 8.27 (1H, b
r), 7.68-8.00 (7H, m), 7.29-7.42 (6H, m), 5.44-5.65
(2H, m), 5.08-5.15 (1H, m), 4.54-4.56 (1H, m), 4.12-
4.31 (5H, m), 3.83-3.89 (1H, m), 3.57-3.69 (2H, m),
2.96 (2H, d, J = 6.6Hz), 2.28-2.67 (4H, m), 1.01-2.00
(27H, m), 0.82-0.87 (21H, m).

【００８４】実施例６ ６−ｉ) オキサリルクロライド（０.４０mL）を含むジ
クロロメタン（５mL）溶液に、ＤＭＳＯ（０.７０mL）
を含むジクロロメタン（３mL）溶液を−６０℃で滴下
し、１０分間撹拌した後、Ｆｍｏｃ−Ｌ−バリノール
（１.００ｇ）を含むジクロロメタン（１５mL）溶液を
１５分間で滴下し、−６０℃で３０分間撹拌した。反応
液にジイソプロピルエチルアミン（２.６mL）を加え、
室温下で３０分間撹拌した後、飽和食塩水を加えた。ジ
クロロメタン層を分離し、無水硫酸ナトリウムで乾燥し
た。ジクロロメタンを留去した後、シリカゲルカラムク
ロマトグラフィーで精製し、中間体化合物２６を１.２
５ｇ得た。¹ H-NMR (δ ppm, CDCl₃) 9.66(1H, s), 7.76(2H, d, J=
7.3Hz), 7.60(2H, d,J=7.3Hz), 7.41(2H, t, J=7.3Hz),
7.30-7.34(2H, m), 5.36(1H, d, J=7.8Hz),4.17-4.62
(4H, m), 2.30-2.35(1H, m), 1.04(3H, d, J=6.8Hz),
0.96(3H, d, J=7.3Hz).Example 6 6-i) DMSO (0.70 mL) was added to a dichloromethane (5 mL) solution containing oxalyl chloride (0.40 mL).
A solution of Fmoc-L-valinol (1.00 g) in dichloromethane (15 mL) was added dropwise over 15 minutes, and a solution of Fmoc-L-valinol (1.00 g) was added dropwise over 15 minutes. Stirred for minutes. Diisopropylethylamine (2.6 mL) was added to the reaction solution,
After stirring at room temperature for 30 minutes, saturated saline was added. The dichloromethane layer was separated and dried over anhydrous sodium sulfate. After the dichloromethane was distilled off, the residue was purified by silica gel column chromatography to obtain an intermediate compound 26 of 1.2.
5 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 9.66 (1H, s), 7.76 (2H, d, J =
7.3Hz), 7.60 (2H, d, J = 7.3Hz), 7.41 (2H, t, J = 7.3Hz),
7.30-7.34 (2H, m), 5.36 (1H, d, J = 7.8Hz), 4.17-4.62
(4H, m), 2.30-2.35 (1H, m), 1.04 (3H, d, J = 6.8Hz),
0.96 (3H, d, J = 7.3Hz).

【００８５】６−ii) 中間体化合物２６（１.２５
ｇ）、Ｌ−アスパラギン酸 α−ベンジルβ−ｔ−ブチ
ルエステル（０.８６ｇ）を１,２−ジクロロエタン（１
５mL）に溶解し、室温で撹拌しながらナトリウムトリア
セトキシボロヒドリド（０.８９ｇ）を加え、１３時間
撹拌した。反応液に５％炭酸水素ナトリウム水溶液を加
え、分離した有機層を飽和食塩水で洗浄し、無水硫酸ナ
トリウムで乾燥した。１,２−ジクロロエタンを留去し
た後、シリカゲルカラムクロマトグラフィーで精製し、
中間体化合物２７を１.５５ｇ得た。¹ H-NMR (δ ppm, CDCl₃) 7.75(2H, d, J=7.3Hz), 7.59-
7.62(2H, m), 7.27-7.52(10H, m), 5.17(1H, d, J=12H
z), 5.13(1H, d, J=12Hz), 4.84(1H, d, J=7.8Hz), 4.3
5-4.45(2H, m), 4.22(1H, t, J=6.8Hz), 3.65(1H, br),
3.46(1H, br),2.51-2.76(3H, m), 1.87(1H, br), 1.40
(9H, s), 0.84-0.88(6H, m).6-ii) Intermediate compound 26 (1.25
g), L-aspartic acid α-benzyl β-t-butyl ester (0.86 g) was converted to 1,2-dichloroethane (1
5 mL), sodium triacetoxyborohydride (0.89 g) was added with stirring at room temperature, and the mixture was stirred for 13 hours. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the separated organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After 1,2-dichloroethane was distilled off, the residue was purified by silica gel column chromatography.
1.55 g of intermediate compound 27 were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.75 (2H, d, J = 7.3 Hz), 7.59-
7.62 (2H, m), 7.27-7.52 (10H, m), 5.17 (1H, d, J = 12H
z), 5.13 (1H, d, J = 12Hz), 4.84 (1H, d, J = 7.8Hz), 4.3
5-4.45 (2H, m), 4.22 (1H, t, J = 6.8Hz), 3.65 (1H, br),
3.46 (1H, br), 2.51-2.76 (3H, m), 1.87 (1H, br), 1.40
(9H, s), 0.84-0.88 (6H, m).

【００８６】６−iii) 中間体化合物２７（０.８１
ｇ）をメタノール（５０mL）に溶解し、５％パラジウム
炭素（０.２０ｇ）を加え、得られた懸濁液を水素雰囲
気下に室温で３０分間撹拌した。パラジウム炭素を濾別
し、メタノールを留去して、中間体化合物２８を０.５
９ｇ得た。¹ H-NMR (δ ppm, d₆-DMSO) 7.86(2H, d, J=7.3Hz), 7.6
7-7.71(2H, m), 7.30-7.42(4H, m), 7.05(1H, d, J=8.3
Hz), 4.21-4.36(3H, m), 3.44(2H, brs), 2.44-2.78(4
H, m), 1.78(1H, br), 1.39(9H, s), 0.80-0.84(6H,
m).6-iii) Intermediate compound 27 (0.81
g) was dissolved in methanol (50 mL), 5% palladium on carbon (0.20 g) was added, and the resulting suspension was stirred under a hydrogen atmosphere at room temperature for 30 minutes. The palladium carbon was removed by filtration, and methanol was distilled off.
9 g were obtained. ¹ H-NMR (δ ppm, d ₆ -DMSO) 7.86 (2H, d, J = 7.3 Hz), 7.6
7-7.71 (2H, m), 7.30-7.42 (4H, m), 7.05 (1H, d, J = 8.3
Hz), 4.21-4.36 (3H, m), 3.44 (2H, brs), 2.44-2.78 (4
H, m), 1.78 (1H, br), 1.39 (9H, s), 0.80-0.84 (6H,
m).

【００８７】６−iv) (Ｒ)−３−ヒドロキシミリスチ
ン酸（２.５０ｇ）とトリエチルアミン（１.４３mL）の
ＤＭＦ（２５mL）溶液にフェナシルブロマイド（２.０
４ｇ）を室温で加え一晩撹拌した。溶媒を除いた後、酢
酸エチルを加え水で３回洗浄した。無水硫酸ナトリウム
で乾燥後、酢酸エチルを留去して、シリカゲルカラムク
ロマトグラフィーで精製し，中間体化合物２９を３.５
３ｇ得た。¹ H-NMR (δ ppm, CDCl₃) 7.92 (2H, d, J=6.8Hz), 7.63
(1H, d, J=7.3Hz),7.50 (2H, d, J=7.6Hz), 5.48 (1
H, d, J=17Hz), 5.37 (1H, d, J=17Hz), 4.09-4.18
(1H, m), 3.41 (1H, br s), 2.70 (1H, dd, J=2.9, 15
Hz), 2.57 (1H, dd, J=9.3, 15Hz), 1.19-1.67 (20H,
m), 0.88 (3H, t, J=6.8Hz).6-iv) Phenacyl bromide (2.0) was added to a solution of (R) -3-hydroxymyristic acid (2.50 g) and triethylamine (1.43 mL) in DMF (25 mL).
4g) at room temperature and stirred overnight. After removing the solvent, ethyl acetate was added and the mixture was washed three times with water. After drying over anhydrous sodium sulfate, the ethyl acetate was distilled off and the residue was purified by silica gel column chromatography to obtain an intermediate compound 29 of 3.5.
3 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.92 (2H, d, J = 6.8Hz), 7.63
(1H, d, J = 7.3Hz), 7.50 (2H, d, J = 7.6Hz), 5.48 (1
(H, d, J = 17Hz), 5.37 (1H, d, J = 17Hz), 4.09-4.18
(1H, m), 3.41 (1H, br s), 2.70 (1H, dd, J = 2.9, 15
Hz), 2.57 (1H, dd, J = 9.3, 15Hz), 1.19-1.67 (20H,
m), 0.88 (3H, t, J = 6.8Hz).

【００８８】６−ｖ) ５−アミノ−３−ペンテン酸
（１.００ｇ）の１０％炭酸ナトリウム水溶液（２０m
L）及びジオキサン（１０mL）溶液に氷冷下、Ｆｍｏｃ
−Ｃｌ（２.２０ｇ）のジオキサン（１０mL）溶液を加
え，一夜撹拌した。反応液を酢酸エチルで希釈し、１０
％炭酸ナトリウム水溶液で３回抽出した。水層を１Ｎ塩
酸で酸性とした後，酢酸エチルで抽出した。有機層を
水、飽和食塩水で順に洗浄し、無水硫酸ナトリウムで乾
燥した。酢酸エチルを留去し、中間体化合物３０を２.
４４ｇ得た。¹ H-NMR (δ ppm, CDCl₃) 7.75-7.76 (2H, m), 7.57-7.5
9 (2H, m), 7.37-7.41(2H, m), 7.28-7.32 (2H, m), 5.
50-5.70 (2H, m), 4.88 (1H, m), 4.40-4.43(2H, m),
4.20-4.30 (1H, m), 3.60-3.82 (2H, m), 3.00-3.12 (2
H, m).6-v) 5-amino-3-pentenoic acid (1.00 g) in 10% aqueous sodium carbonate solution (20 m
L) and dioxane (10 mL) solution under ice-cooling, Fmoc
A solution of -Cl (2.20 g) in dioxane (10 mL) was added and stirred overnight. The reaction was diluted with ethyl acetate and
The mixture was extracted three times with a 10% aqueous sodium carbonate solution. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off to give the intermediate compound 30 as 2.
44 g were obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.75-7.76 (2H, m), 7.57-7.5
9 (2H, m), 7.37-7.41 (2H, m), 7.28-7.32 (2H, m), 5.
50-5.70 (2H, m), 4.88 (1H, m), 4.40-4.43 (2H, m),
4.20-4.30 (1H, m), 3.60-3.82 (2H, m), 3.00-3.12 (2
H, m).

【００８９】６−vi) 中間体化合物２９（０.８６
ｇ）、中間体化合物３０（０.９３ｇ）およびＤＭＡＰ
（６１mg）のジクロロメタン（３０mL）溶液に氷冷下、
ＤＣＣ（０.７７ｇ）を加え、氷冷下で２時間、続いて
室温で一晩撹拌した。析出物を濾別した後、ジクロロメ
タンを留去した。残留物に酢酸エチル（３０mL）を加
え、１０％クエン酸水溶液、水、５％炭酸水素ナトリウ
ム水溶液および水で洗浄後、無水硫酸ナトリウムで乾燥
した。溶媒を留去し、得られた粗生成物をシリカゲルカ
ラムクロマトグラフィーで精製し、中間体化合物３１を
１.５４ｇ得た。¹ H-NMR (δ ppm, CDCl₃) 7.88 (2H, d, J=6.8Hz), 7.75
(2H, d, J=7.8Hz),7.58 (2H, d, J=7.3Hz),7.58 (1H,
t, J=7.6Hz), 7.45 (2H, t, J=7.6Hz), 7.39(2H, t,
J=7.6Hz), 7.30 (2H, t, J=7.3Hz), 5.69-5.80 (1H,
m), 5.57-5.68(1H, m), 5.27-38 (3H, m), 4.99 (1H, b
r s), 4.36 (2H, d, J=6.8 Hz), 4.19(1H, t, J=6.6 H
z), 3.81 (2H, br s), 3.05-3.17 (2H, m), 2.77 (1H,
dd, J=3.4Hz), 2.75 (1H, d, J=1.5Hz), 1.53-1.76 (2
H, m), 1.18-1.41 (18H, m), 0.88 (3H, t, J=6.8Hz).6-vi) Intermediate compound 29 (0.86
g), intermediate compound 30 (0.93 g) and DMAP
(61 mg) in dichloromethane (30 mL) solution under ice-cooling,
DCC (0.77 g) was added, and the mixture was stirred under ice cooling for 2 hours, and then at room temperature overnight. After the precipitate was separated by filtration, dichloromethane was distilled off. Ethyl acetate (30 mL) was added to the residue, and the mixture was washed with a 10% aqueous citric acid solution, water, a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained crude product was purified by silica gel column chromatography to obtain 1.54 g of an intermediate compound 31. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.88 (2H, d, J = 6.8Hz), 7.75
(2H, d, J = 7.8Hz), 7.58 (2H, d, J = 7.3Hz), 7.58 (1H,
t, J = 7.6Hz), 7.45 (2H, t, J = 7.6Hz), 7.39 (2H, t,
J = 7.6Hz), 7.30 (2H, t, J = 7.3Hz), 5.69-5.80 (1H,
m), 5.57-5.68 (1H, m), 5.27-38 (3H, m), 4.99 (1H, b
rs), 4.36 (2H, d, J = 6.8 Hz), 4.19 (1H, t, J = 6.6 H
z), 3.81 (2H, br s), 3.05-3.17 (2H, m), 2.77 (1H,
(dd, J = 3.4Hz), 2.75 (1H, d, J = 1.5Hz), 1.53-1.76 (2
H, m), 1.18-1.41 (18H, m), 0.88 (3H, t, J = 6.8Hz).

【００９０】６−vii) 中間体化合物３１（０.３３
ｇ）をＤＭＦ（５mL）に溶解し、ジエチルアミン（０.
４mL）を加え室温で９０分間撹拌した。反応液を減圧濃
縮し、中間体化合物３２を得た。得られた中間体化合物
３２（０.３１ｇ）にＤＭＦ（３０mL）を加えて溶解
し、室温で撹拌しながら中間体化合物２８（０.２５
ｇ)、ＨＯＢｔ・１水和物（９０mg）を加えた。この溶液
を氷冷し、ＷＳＣＩ（０.１４ｇ）を加え、室温で一晩
撹拌した。不溶物を濾別し、濾液の溶媒を留去した後、
シリカゲルカラムクロマトグラフィーで精製して化合物
２１を０.１０ｇ得た。¹ H-NMR (δppm, CDCl₃) 7.87(2H, d, J=7.3Hz), 7.75(2
H, d, J=7.3Hz), 7.28-7.61(11H, m), 5.66-5.74(1H,
m), 5.52-5.59(1H, m), 5.25-5.31(3H, m), 4.86(1H,
d, J=9.8Hz), 4.47-4.51(1H, m), 4.33-4.37(1H, m),
4.19-4.22(1H, m),3.76-3.88(2H, m), 3.57(1H, br),
3.34-3.37(1H, m), 3.00-3.11(2H, m), 2.46-2.77(5H,
m), 1.74-1.79(1H, m), 1.65(2H, br s), 1.41(9H, s),
1.24-1.28(18H, m), 0.86-0.92(9H, m).6-vii) Intermediate compound 31 (0.33
g) was dissolved in DMF (5 mL) and diethylamine (0.5 mL) was added.
4 mL) and stirred at room temperature for 90 minutes. The reaction solution was concentrated under reduced pressure to obtain an intermediate compound 32. DMF (30 mL) was added to and dissolved in the obtained intermediate compound 32 (0.31 g).
g), HOBt monohydrate (90 mg) was added. This solution was ice-cooled, WSCI (0.14 g) was added, and the mixture was stirred at room temperature overnight. After filtering off the insoluble matter and evaporating the solvent of the filtrate,
Purification by silica gel column chromatography gave 0.10 g of compound 21. ^{1 H-NMR (δppm, CDCl} 3) 7.87 (2H, d, J = 7.3Hz), 7.75 (2
H, d, J = 7.3Hz), 7.28-7.61 (11H, m), 5.66-5.74 (1H,
m), 5.52-5.59 (1H, m), 5.25-5.31 (3H, m), 4.86 (1H,
d, J = 9.8Hz), 4.47-4.51 (1H, m), 4.33-4.37 (1H, m),
4.19-4.22 (1H, m), 3.76-3.88 (2H, m), 3.57 (1H, br),
3.34-3.37 (1H, m), 3.00-3.11 (2H, m), 2.46-2.77 (5H,
m), 1.74-1.79 (1H, m), 1.65 (2H, br s), 1.41 (9H, s),
1.24-1.28 (18H, m), 0.86-0.92 (9H, m).

【００９１】６−viii) 化合物２１（７７mg）を酢酸
（３mL）に溶解し、亜鉛粉末（１５０mg）を加え、５０
℃で４時間撹拌した。不溶物を濾別し、濾液の溶媒を留
去した後、シリカゲルカラムクロマトグラフィーで精製
して化合物２２を４１mg得た。¹ H-NMR (δ ppm, CDCl₃) 7.75(2H, d, J=7.3Hz), 7.54-
7.61(2H, m), 7.29-7.41(5H, m), 6.46(1H, d, J=8.8H
z), 5.53-5.67(2H, m), 5.09-5.20(2H, m), 4.32-4.55
(3H, m), 3.81(2H, br s), 3.51-3.60(2H, m), 2.31-3.
02(7H, m), 1.03-1.81(30H, m), 0.78-0.94(9H, m).6-viii) Compound 21 (77 mg) was dissolved in acetic acid (3 mL), and zinc powder (150 mg) was added.
Stirred at C for 4 hours. The insoluble material was separated by filtration, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography to obtain 41 mg of compound 22. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.75 (2H, d, J = 7.3 Hz), 7.54-
7.61 (2H, m), 7.29-7.41 (5H, m), 6.46 (1H, d, J = 8.8H
z), 5.53-5.67 (2H, m), 5.09-5.20 (2H, m), 4.32-4.55
(3H, m), 3.81 (2H, br s), 3.51-3.60 (2H, m), 2.31-3.
02 (7H, m), 1.03-1.81 (30H, m), 0.78-0.94 (9H, m).

【００９２】６−ix) 化合物２２（４１mg）をＴＦＡ
（１mL）に溶解し、溶液を室温で１時間撹拌した。ＴＦ
Ａを留去した後、シリカゲルカラムクロマトグラフィー
で精製して化合物２３を３１mg得た。¹ H-NMR (δ ppm, CD₃OD) 7.78(2H, d, J=7.3Hz), 7.64-
7.67(2H, m), 7.28-7.40(4H, m), 5.55(2H, br s), 5.3
6(1H, br s), 4.50-4.54(1H, m), 4.20-4.34(2H, m),
3.90-3.95(1H, m), 3.56(1H, br s), 3.42(1H, br s),
2.92-3.05(2H, m), 2.39-2.67(7H, m), 1.71(1H, br
s), 1.26-1.29(20H, m), 0.87-0.94(9H, m).6-ix) Compound 22 (41 mg) was converted to TFA
(1 mL) and the solution was stirred at room temperature for 1 hour. TF
After evaporating A, the residue was purified by silica gel column chromatography to obtain 31 mg of compound 23. ¹ H-NMR (δ ppm, CD ₃ OD) 7.78 (2H, d, J = 7.3 Hz), 7.64-
7.67 (2H, m), 7.28-7.40 (4H, m), 5.55 (2H, br s), 5.3
6 (1H, br s), 4.50-4.54 (1H, m), 4.20-4.34 (2H, m),
3.90-3.95 (1H, m), 3.56 (1H, br s), 3.42 (1H, br s),
2.92-3.05 (2H, m), 2.39-2.67 (7H, m), 1.71 (1H, br
s), 1.26-1.29 (20H, m), 0.87-0.94 (9H, m).

【００９３】[0093]

【試験例】次に本発明のデプシペプチドがＨｅｐ Ｇ２
細胞において、アポリポプロテインＥ産生能およびアポ
リポプロテインＢ産生能に与える影響を、試験方法とと
もに記す。まず、Ｈｅｐ Ｇ２細胞１×１０⁵個／ml（ダ
ルベッコ変法イーグル培地（日水製薬社製；以後「Ｄ−
ＭＥＭ培地」と呼ぶ）に１０％の牛胎児血清を加えたも
のに懸濁）を２４穴組織培養用プレートに１mlずつ注入
し、３７℃で炭酸ガス５％および空気９５％の混合ガス
雰囲気下で培養した。３日後に、培地をピペッターにて
除去し、新たにＤ−ＭＥＭ培地１mlを加え、さらに表１
に示す濃度の、本発明のデプシペプチドである化合物
５、化合物７、化合物１１、化合物１６、化合物２０お
よび化合物２３のＭｅＯＨ溶液１０μlを加えた。１８
時間後、培地を再び交換（Ｄ−ＭＥＭ培地）し、このペ
デプシペプチドのメタノール溶液１０μlを加え、さら
に３７℃で８時間培養し、その上澄み液をサンプル溶液
とした。培地中に生成したアポリポプロテインＥおよび
アポリポプロテインＢを以下に示すエンザイムイムノア
ッセイ法によって定量した。なお、エンザイムイムノア
ッセイ法で使用した緩衝液の組成を以下に示す。なお、
ＰＢＳとはリン酸緩衝液を、ＰＢＳ−ＴはＴｗｅｅｎ
２０を添加したリン酸緩衝液を、ブロッキング液は大日
本製薬社製の乳タンパク質由来の免疫用ブロック剤「Bl
ock Ace」を含むリン酸緩衝液を示す。[Test Example] Next, the depsipeptide of the present invention is Hep G2
The effects on apolipoprotein E-producing ability and apolipoprotein B-producing ability of cells are described together with test methods. First, 1 × 10 ⁵ Hep G2 cells / ml (Dulbecco's modified Eagle's medium (manufactured by Nissui Pharmaceutical Co., Ltd .; hereinafter, “D-
MEM medium) and 10% fetal bovine serum added thereto), and inject 1 ml each into a 24-well tissue culture plate at 37 ° C. in a mixed gas atmosphere of 5% carbon dioxide and 95% air. And cultured. Three days later, the medium was removed with a pipettor, and 1 ml of D-MEM medium was newly added.
10 μl of a MeOH solution of the depsipeptide of the present invention, Compound 5, Compound 7, Compound 11, Compound 16, Compound 20, and Compound 23, was added at the concentration shown in FIG. 18
After a lapse of time, the medium was replaced again (D-MEM medium), 10 μl of this methanol solution of pedepsi peptide was added, and the mixture was further cultured at 37 ° C. for 8 hours, and the supernatant was used as a sample solution. Apolipoprotein E and apolipoprotein B produced in the medium were quantified by the enzyme immunoassay shown below. The composition of the buffer used in the enzyme immunoassay is shown below. In addition,
PBS is phosphate buffer, PBS-T is Tween
20 was added to the phosphate buffer, and the blocking solution was a milk protein-derived immunization blocking agent “Bl
5 shows a phosphate buffer containing "ock Ace".

【００９４】 ＰＢＳ（pH７.２） ＫＨ₂ＰＯ₄ ０.２ｇ Ｎａ₂ＨＰＯ₄・１２Ｈ₂Ｏ ２.９ｇ ＮａＣｌ ８.０ｇ ＫＣｌ ０.２ｇ 蒸留水 適量 全量 １０００mlPBS (pH 7.2) KH ₂ PO ₄ 0.2 g Na ₂ HPO ₄ .12H ₂ O 2.9 g NaCl 8.0 g KCl 0.2 g Distilled water qs 1000 ml

【００９５】 ＰＢＳ−Ｔ（pH７.２） ＫＨ₂ＰＯ₄ ０.２ｇ Ｎａ₂ＨＰＯ₄・１２Ｈ₂Ｏ ２.９ｇ ＮａＣｌ ８.０ｇ ＫＣｌ ０.２ｇ Ｔｗｅｅｎ ２０ ０.５ｇ 蒸留水 適量 全量 １０００ml[0095] _{PBS-T (pH7.2) KH 2} PO 4 0.2g Na 2 HPO 4 · 12H 2 O 2.9g NaCl 8.0g KCl 0.2g Tween 20 0.5g Distilled water qs Total 1000ml

【００９６】ブロッキング液（pH７.２） Ｂｌｏｃｋ Ａｃｅ ２５０ml ＫＨ₂ＰＯ₄ ０.２ｇ Ｎａ₂ＨＰＯ₄・１２Ｈ₂Ｏ ２.９ｇ ＮａＣｌ ８.０ｇ ＫＣｌ ０.２ｇ 蒸留水 適量 全量 １０００ml[0096] Blocking solution _{(pH7.2) Block Ace 250ml KH 2} PO 4 0.2g Na 2 HPO 4 · 12H 2 O 2.9g NaCl 8.0g KCl 0.2g Distilled water qs Total 1000ml

【００９７】１) アポリポプロテインＥの測定 マウス抗ヒトアポリポプロテインＥモノクローナル抗体
（仏国BYOSIS，S.A.社製）を０.０５Ｍ炭酸水素ナトリ
ウム水溶液（pH９.５）に５μｇ／mlの濃度で溶解し
た。この５０μｌをヌンクイムノプレートに分注し、４
℃で１６時間静置した。ＰＢＳ ３００μｌで３回洗浄
後、ブロッキング液３００μｌを加え、３７℃で２時間
静置し、その後４℃で１６時間静置した。再びＰＢＳ
３００μｌで３回洗浄し、サンプル溶液５０μｌ（Ｈｅ
ｐ Ｇ２細胞の培地）を加え、室温で２時間静置した。
ＰＢＳ−Ｔ ３００μｌで３回洗浄後、ヤギ抗アポリポ
プロテインＥポリクローナル抗体（米国ケミコン社製）
の３０００倍希釈液（１０％ Block Ace水溶液）５０μ
ｌを加え、室温で２時間静置した。ＰＢＳ−Ｔ ３００
μｌで３回洗浄し、ペルオキシダーゼ標識抗ヤギＩｇＧ
ポリクローナル抗体（英国バインディングサイト社製）
の５０００倍希釈液（１０％ Block Ace水溶液）を加
え、室温で２時間静置した。ＰＢＳ−Ｔ ３００μｌで
５回洗浄後、発色液（組成：０.１Ｍクエン酸カリウムp
H４.５ １ml、３０％過酸化水素水０.４μｌ、オルトフ
ェニレンジアミン１mg）１００μｌを加え、そのまま２
分間放置した。２Ｎ硫酸１００μｌを加え反応を止め、
６５０nmを対照としたときの４９０nmの吸光度を測定し
た。市販のアポリポプロテインＥ（米国ケミコン社製）
を標品とした場合の検量線より本発明のデプシペプチド
のアポリポプロテインＥの量を求めた。1) Measurement of Apolipoprotein E A mouse anti-human apolipoprotein E monoclonal antibody (manufactured by BYOSIS, SA, France) was dissolved in a 0.05 M aqueous sodium hydrogen carbonate solution (pH 9.5) at a concentration of 5 μg / ml. This 50 μl was dispensed into a Nunc immunoplate, and
The mixture was allowed to stand at 16 ° C. for 16 hours. After washing three times with 300 μl of PBS, 300 μl of blocking solution was added, and the mixture was allowed to stand at 37 ° C. for 2 hours and then at 4 ° C. for 16 hours. Again PBS
After washing three times with 300 μl, 50 μl of sample solution (He
pG2 cell culture medium) and allowed to stand at room temperature for 2 hours.
After washing three times with 300 μl of PBS-T, goat anti-apolipoprotein E polyclonal antibody (manufactured by Chemicon, USA)
3000 times dilution (10% Block Ace aqueous solution) 50μ
was added and left at room temperature for 2 hours. PBS-T 300
Washed three times with μl and peroxidase-labeled anti-goat IgG
Polyclonal antibody (manufactured by UK Binding Site)
And a 5000-fold diluted solution (10% aqueous solution of Block Ace) was added, and the mixture was allowed to stand at room temperature for 2 hours. After washing 5 times with 300 μl of PBS-T, a color developing solution (composition: 0.1 M potassium citrate p
H4.5 (1 ml), 30% hydrogen peroxide (0.4 μl, orthophenylenediamine (1 mg), 100 μl) were added and
Let stand for minutes. 100 μl of 2N sulfuric acid was added to stop the reaction,
The absorbance at 490 nm was measured using 650 nm as a control. Commercially available apolipoprotein E (manufactured by Chemicon, USA)
Was used to determine the amount of apolipoprotein E of the depsipeptide of the present invention from a calibration curve.

【００９８】本試験例において、本発明のデプシペプチ
ドのメタノール溶液のかわりに単にメタノールを加えた
以外は本試験例と同様に行ない、アポリポプロテインＥ
量を測定し、これをコントロールとした。本発明のデプ
シペプチドの相対アポリポプロテインＥ量はコントロー
ルを１００とした場合の相対値（％）で表した。表１に
示すように、本発明のデプシペプチドは、１ないし５μ
Ｍの濃度でアポリポプロテインＥの産生能を強力に促進
することが認められた。In this test example, apolipoprotein E was prepared in the same manner as in this test example except that methanol was simply added instead of the methanol solution of the depsipeptide of the present invention.
The amount was measured and used as a control. The relative amount of apolipoprotein E of the depsipeptide of the present invention was expressed as a relative value (%) when the control was taken as 100. As shown in Table 1, the depsipeptide of the present invention contained 1 to 5 μm.
It was found that the concentration of M strongly promotes the production of apolipoprotein E.

【００９９】[0099]

【表１】 [Table 1]

【０１００】[0100]

【製剤例】次に本発明のデプシペプチドを有効成分とす
る製剤の製剤例を示す。 化合物２０、けい酸マグネシウム及び乳糖を混合し、こ
れをヒドロキシプロピルセルロースを溶解したアルコー
ル液で練合し、次いで適当な粒度に造粒し、乾燥、整粒
後さらにステアリン酸マグネシウム及び植物硬化油を添
加混合し均一な顆粒とする。次いでロータリー式打錠機
により直径７.０mm、重量１５０mgおよび硬度６kgの錠
剤を調製した。[Preparation Examples] Next, preparation examples of preparations containing the depsipeptide of the present invention as an active ingredient are shown. Compound 20, magnesium silicate and lactose are mixed, kneaded with an alcohol solution in which hydroxypropylcellulose is dissolved, then granulated to an appropriate particle size, dried and sized, and then magnesium stearate and vegetable hydrogenated oil are further added. Add and mix to make uniform granules. Next, tablets having a diameter of 7.0 mm, a weight of 150 mg and a hardness of 6 kg were prepared by a rotary tableting machine.

【０１０１】 上記処方例中ヒドロキシプロピルセルロースを除いた各
原料を均一に混合し、これにヒドロキシプロピルセルロ
ースを溶解したアルコール溶液を加えて練合した後押出
造粒機により造粒し、乾燥して顆粒を得た。この顆粒を
整粒して１２メッシュの篩を通過し４８メッシュの篩上
に残留するものを顆粒剤とした。[0101] The raw materials except for hydroxypropylcellulose in the above formulation examples were uniformly mixed, and an alcoholic solution in which hydroxypropylcellulose was dissolved was added and kneaded, followed by granulation by an extrusion granulator and drying to obtain granules. Was. The granules were sized, passed through a 12-mesh sieve, and remained on the 48-mesh sieve as granules.

【０１０２】 白糖、Ｄ−ソルビトール、パラオキシ安息香酸エチル、
パラオキシ安息香酸プロピル及び化合物２０を精製水
（温水）６０ｇに溶解する。冷却後香味料を溶解したグ
リセリン及びエタノールの溶液を加える。次にこの混合
物に精製水を加えて１００mlにする。[0102] Sucrose, D-sorbitol, ethyl paraoxybenzoate,
Dissolve propyl paraoxybenzoate and Compound 20 in 60 g of purified water (warm water). After cooling, a solution of glycerin and ethanol in which the flavor is dissolved is added. The mixture is then made up to 100 ml with purified water.

【０１０３】 炭酸水素ナトリウム、塩化ナトリウム及びこの化合物２
０のナトリウム塩を蒸留水に加えて溶解し、全量を１
０.０mlとする。[0103] Sodium bicarbonate, sodium chloride and this compound 2
0 sodium salt was added to distilled water and dissolved, and the total amount was 1
Make up to 0.0 ml.

【０１０４】 化合物２０にグリセリンを加えて溶解する。そこへ、マ
クロゴール４０００を加えて加温し溶解後、坐剤型に注
入して冷却固化し１個あたり１.５ｇの坐剤を製造す
る。[0104] Glycerin is added to compound 20 and dissolved. Macrogol 4000 is added thereto, heated and dissolved, and then poured into a suppository mold, cooled and solidified to produce suppositories of 1.5 g per piece.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.⁶ 識別記号 ＦＩ Ｃ０７Ｃ 237/12 Ｃ０７Ｋ 5/06 Ｃ０７Ｋ 5/06 Ａ６１Ｋ 37/02 (72)発明者 川村 恒二 埼玉県入間郡大井町鶴ヶ岡５丁目３番１号 日清製粉株式会社創薬研究所内 (72)発明者 平本 茂 埼玉県入間郡大井町鶴ヶ岡５丁目３番１号 日清製粉株式会社創薬研究所内 (72)発明者 保田 織恵 埼玉県入間郡大井町鶴ヶ岡５丁目３番１号 日清製粉株式会社創薬研究所内 (72)発明者 木下 宣祐 埼玉県入間郡大井町鶴ヶ岡５丁目３番１号 日清製粉株式会社創薬研究所内 (72)発明者 真貝 明子 埼玉県入間郡大井町鶴ヶ岡５丁目３番１号 日清製粉株式会社創薬研究所内 (72)発明者 高須 雅子 埼玉県入間郡大井町鶴ヶ岡５丁目３番１号 日清製粉株式会社創薬研究所内────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 237/12 C07K 5/06 C07K 5/06 A61K 37/02 (72) Inventor Tsuneji Kawamura Tsuruga Oimachi, Iruma-gun, Saitama 5-3-1 Oka, Nisshin Flour Milling Co., Ltd. Drug Discovery Research Laboratory (72) Inventor Shigeru Hiramoto 5-3-1, Tsurugaoka, Oi-machi, Iruma-gun, Saitama Prefecture Nisshin Flour Milling Co., Ltd. Drug Discovery Research Laboratory (72 ) Inventor Orie Yasuda 5-3-1 Tsurugaoka, Oi-machi, Iruma-gun, Saitama Prefecture Inside the drug discovery laboratory of Nisshin Flour Milling Co., Ltd. No. 1 Inside the Drug Discovery Research Laboratory of Nisshin Flour Milling Co., Ltd. (72) Inventor Akiko Makai 5-3-1, Tsurugaoka, Oimachi, Iruma-gun, Saitama Prefecture Inside the Drug Discovery Research Laboratory of Nisshin Flour Milling Co., Ltd. Tsuru, Oimachi, Iruma-gun, Prefecture Oka 5-chome third No. 1 Nisshin Flour Milling Co., Ltd. drug discovery within the Institute

Claims (14)

【特許請求の範囲】[Claims] 【請求項１】 一般式（１） 【化１】 ［式中、Ｒ¹は、直鎖状もしくは有枝鎖状のＣ₅〜Ｃ₂₀ア
ルキル基または直鎖状もしくは有枝鎖状のＣ₅〜Ｃ₁₅ア
ルコキシメチル基を示し、 Ｒ²は、 −Ｏ−ＣＯ−ＣＨ(Ｒ⁵)−Ｘ−ＣＨ(Ｒ⁶)−ＮＨ− （式中、Ｘは、Ｎ（Ｒ⁷）−ＣＯ、Ｎ(Ｒ⁸)−ＣＨ₂、Ｃ
Ｈ₂−ＣＯ、ＣＨ₂−ＣＨ₂、ＣＨ＝ＣＨ、ＣＨ₂−ＣＨ
(ＯＨ)、ＣＨ(ＯＨ)−ＣＨ(ＯＨ)を示し、Ｒ⁵、Ｒ⁶、Ｒ
⁷、Ｒ⁸は、水素または直鎖状もしくは有枝鎖状のＣ₁〜
Ｃ₆アルキル基を示す）を示し、 Ｒ³は、 【化２】 （式中、Ｙは、Ｎ(Ｒ¹²)−ＣＯ、Ｎ(Ｒ¹³)−ＣＨ₂、Ｃ
Ｈ₂−ＣＯ、ＣＨ₂−ＣＨ₂、ＣＨ＝ＣＨ、ＣＨ₂−ＣＨ
(ＯＨ)、ＣＨ(ＯＨ)−ＣＨ(ＯＨ)を示し、ｎは１〜３の
整数を示し、Ｒ⁹、Ｒ¹⁰、Ｒ¹²、Ｒ¹³は、水素または直
鎖状もしくは有枝鎖状のＣ₁〜Ｃ₆アルキル基を示し、Ｒ
¹¹はアミンの保護基としてペプチド化学で通常用いられ
る保護基を示す）を示し、 Ｒ⁴は、水酸基、直鎖状もしくは有枝鎖状のＣ₁〜Ｃ₆ア
ルコキシ基、ベンジルオキシ基、Ａ、Ａ−Ｂ、または −ＮＨ−ＣＨ(Ｒ¹⁴)−Ｚ−ＣＨ(Ｒ¹⁵)−ＣＯＲ¹⁶ （式中、Ｚは、ＣＨ₂−Ｎ(Ｒ¹⁷)、ＣＯ−ＣＨ₂、ＣＯ−
Ｎ(Ｒ¹⁸)、ＣＨ₂−ＣＨ₂、ＣＨ＝ＣＨ、ＣＨ(ＯＨ)−Ｃ
Ｈ₂、ＣＨ(ＯＨ)−ＣＨ(ＯＨ)を示し、Ｒ¹⁴は水素、Ｃ₁
〜Ｃ₆アルキル基または−(ＣＨ₂)_m−ＣＯＲ¹⁹を示し、
Ｒ¹⁵、Ｒ¹⁷、Ｒ¹⁸は、水素または直鎖状もしくは有枝鎖
状のＣ₁〜Ｃ₆アルキル基を示し、Ｒ¹⁶は、水酸基、直鎖
状もしくは有枝鎖状のＣ₁〜Ｃ₆アルコキシ基またはベン
ジルオキシ基を示し、Ｒ¹⁹は水酸基、アミノ基またはＣ
₁〜Ｃ₆アルコキシ基を示し、ｍは１〜３の整数を示す）
を示し、 Ａは、アラニン、バリン、ロイシン、イソロイシン、フ
ェニルアラニン、チロシン、プロリン、アスパラギン
酸、アスパラギン、グルタミン酸、グルタミン、セリ
ン、リシンおよびβ−ｔ−ブチルアラニンからなるアミ
ノ酸残基またはこれらのアミノ酸残基のＮ−メチル体を
示し、 Ｂは、アラニン、バリン、ロイシン、イソロイシン、セ
リン、トレオニン、リシン、ヒドロキシリシン、アルギ
ニン、システイン、メチオニン、フェニルアラニン、チ
ロシン、トリプトファン、ヒスチジン、プロリン、４−
ヒドロキシプロリン、アスパラギン酸、アスパラギン、
グルタミン酸、グルタミン、ピペリジン−４−カルボン
酸、ホモプロリン、オクタヒドロインドール−２−カル
ボン酸、ノルバリン、ノルロイシン、α−ｔ−ブチルグ
リシン、シクロヘキシルグリシン、アゼチジン−２−カ
ルボン酸、３−（３−ピリジル）アラニン、（３−Ｎ−
メチル）ピペリジルアラニン、３−（２−ナフチル）ア
ラニン、β−シクロヘキシルアラニン、β−ｔ−ブチル
アラニン、９−アントラセニルアラニン、α−メチルア
ラニンおよび２−アミノブタン酸から選ばれるアミノ酸
残基またはこれらのアミノ酸残基のＮ−メチル体を示
し、 ＡまたはＢにおける遊離のアミノ基、遊離のカルボキシ
ル基、遊離のω−カルバミド基、遊離の水酸基、遊離の
メルカプト基および／またはＮ−末端のアミノ基はそれ
らの保護基としてペプチド化学で通常用いられる保護基
でそれぞれ保護されていてもよく、そして上記Ａまたは
Ｂにおけるアミノ酸残基がリシン、ヒドロキシリシン、
グルタミン酸またはアスパラギン酸である場合は、隣接
するアミノ酸とペプチド結合するアミノ基またはカルボ
キシル基はα−位にあるものでもまたはω−位にあるも
のでもよい。ただし、ＸがＮ(Ｒ⁷)−ＣＯであり、Ｙが
Ｎ(Ｒ¹²)−ＣＯであり、Ｒ⁴が水酸基、直鎖状もしくは
有枝鎖状のＣ₁〜Ｃ₆アルコキシ基、ベンジルオキシ基、
Ａ、Ａ−Ｂまたは−ＮＨ−ＣＨ(Ｒ¹⁴)−Ｚ−ＣＨ(Ｒ¹⁵)
−ＣＯＲ¹⁶｛ＺはＣＯ−Ｎ(Ｒ^{1 8})である｝である場合を
除く。］で示される非天然アミノ酸を含有するデプシペ
プチドまたはその薬理学的に許容される塩。1. A compound of the general formula (1)[Wherein, R¹Is a linear or branched C_Five~ C₂₀A
Alkyl group or linear or branched C_Five~ C_FifteenA
A alkoxymethyl group;^TwoIs -O-CO-CH (R^Five) -X-CH (R⁶) -NH- (where X is N (R⁷) -CO, N (R⁸) -CH_Two, C
H_Two-CO, CH_Two-CH_Two, CH = CH, CH_Two-CH
(OH), CH (OH) -CH (OH), R^Five, R⁶, R
⁷, R⁸Is hydrogen or a linear or branched C₁~
C₆R represents an alkyl group);^ThreeIs(Where Y is N (R¹²) -CO, N (R¹³) -CH_Two, C
H_Two-CO, CH_Two-CH_Two, CH = CH, CH_Two-CH
(OH), CH (OH) -CH (OH), wherein n is 1 to 3
Represents an integer;⁹, R^Ten, R¹², R¹³Is hydrogen or direct
Chain or branched C₁~ C₆Represents an alkyl group;
¹¹Is commonly used in peptide chemistry as an amine protecting group.
R represents a protecting group).^FourIs a hydroxyl group, a linear or branched C₁~ C₆A
Alkoxy group, benzyloxy group, A, AB, or -NH-CH (R¹⁴) -Z-CH (R^Fifteen) -COR¹⁶  (Where Z is CH_Two−N (R¹⁷), CO-CH_Two, CO-
N (R¹⁸), CH_Two-CH_Two, CH = CH, CH (OH) -C
H_Two, CH (OH) -CH (OH), R¹⁴Is hydrogen, C₁
~ C₆Alkyl group or-(CH_Two)_m-COR¹⁹Indicates that
R^Fifteen, R¹⁷, R¹⁸Is hydrogen or a linear or branched chain
C₁~ C₆Represents an alkyl group;¹⁶Is a hydroxyl group, straight chain
Or branched C₁~ C₆Alkoxy group or ben
Represents a zyloxy group;¹⁹Is a hydroxyl group, an amino group or C
₁~ C₆Represents an alkoxy group, and m represents an integer of 1 to 3)
A represents alanine, valine, leucine, isoleucine,
Enylalanine, tyrosine, proline, asparagine
Acid, asparagine, glutamic acid, glutamine, seri
Amino-, lysine and β-t-butylalanine
No acid residues or N-methyl forms of these amino acid residues
B represents alanine, valine, leucine, isoleucine,
Phosphorus, threonine, lysine, hydroxylysine, argi
Nin, cysteine, methionine, phenylalanine, thi
Rosin, tryptophan, histidine, proline, 4-
Hydroxyproline, aspartic acid, asparagine,
Glutamic acid, glutamine, piperidine-4-carboxyl
Acid, homoproline, octahydroindole-2-cal
Boric acid, norvaline, norleucine, α-t-butyl group
Lysine, cyclohexylglycine, azetidine-2-ca
Rubonic acid, 3- (3-pyridyl) alanine, (3-N-
Methyl) piperidylalanine, 3- (2-naphthyl) a
Lanine, β-cyclohexylalanine, β-t-butyl
Alanine, 9-anthracenylalanine, α-methyla
Amino acids selected from lanine and 2-aminobutanoic acid
Residues or the N-methyl form of these amino acid residues
A free amino group in A or B, a free carboxy
Group, free ω-carbamide group, free hydroxyl group, free
The mercapto group and / or the N-terminal amino group
Protecting groups commonly used in peptide chemistry
And each may be protected by A or
The amino acid residue in B is lysine, hydroxylysine,
Adjacent if glutamic or aspartic acid
Amino groups or carbohydrates that bind to amino acids
The xyl group may be in the α-position or in the ω-position
May be. Where X is N (R⁷) -CO and Y is
N (R¹²) -CO and R^FourIs a hydroxyl group, linear or
Branched C₁~ C₆Alkoxy group, benzyloxy group,
A, AB or -NH-CH (R¹⁴) -Z-CH (R^Fifteen)
-COR¹⁶｛Z is CO-N (R^{1 8}) Is｝
except. ] Containing the unnatural amino acid represented by
Peptide or a pharmacologically acceptable salt thereof. 【請求項２】 ＸがＣＨ＝ＣＨである請求項１記載のデ
プシペプチドまたはその薬理学的に許容される塩。2. The depsipeptide according to claim 1, wherein X is CH ＝ CH, or a pharmaceutically acceptable salt thereof. 【請求項３】 ＸがＣＨ＝ＣＨであり、ＹがＮ(Ｒ¹²)−
ＣＯまたはＮ(Ｒ¹³)−ＣＨ₂である請求項２記載のデプ
シペプチドまたはその薬理学的に許容される塩。3. X is CH = CH and Y is N (R ¹² )-
CO or N (R ¹³⁾ depsipeptide or a pharmacologically acceptable salt thereof according to claim 2, wherein a -CH _2. 【請求項４】 ＸがＣＨ＝ＣＨであり、ＹがＮ(Ｒ¹²)−
ＣＯまたはＮ(Ｒ¹³)−ＣＨ₂であり、Ｒ⁴が水酸基、Ａ、
Ａ−Ｂまたは−ＮＨ−ＣＨ(Ｒ¹⁴)−Ｚ−ＣＨ(Ｒ¹⁵)−Ｃ
ＯＲ¹⁶（ＺはＣＨ＝ＣＨである）である請求項３記載の
デプシペプチドまたはその薬理学的に許容される塩。4. X is CH = CH and Y is N (R ¹² )-
CO or N (R ¹³⁾ is -CH _2, R ⁴ is hydroxyl, A,
A-B or ^{-NH-CH (R 14) -Z} -CH (R 15) -C
The depsipeptide according to claim 3, which is OR ¹⁶ (Z is CH = CH), or a pharmacologically acceptable salt thereof. 【請求項５】 ＸがＣＨ＝ＣＨであり、ＹがＮ(Ｒ¹²)−
ＣＯであり、Ｒ⁴が水酸基、ＡまたはＡ−Ｂである請求
項３記載のデプシペプチドまたはその薬理学的に許容さ
れる塩。5. X is CH = CH and Y is N (R ¹² )-
^4. The depsipeptide or a pharmaceutically acceptable salt thereof according to claim 3, which is CO and R ⁴ is a hydroxyl group, A or AB. 【請求項６】 ＸがＣＨ＝ＣＨであり、ＹがＮ(Ｒ¹³)−
ＣＨ₂であり、Ｒ⁴が水酸基である請求項３記載のデプシ
ペプチドまたはその薬理学的に許容される塩。6. X is CH = CH and Y is N (R ¹³ )-
The depsipeptide according to claim 3, which is CH ₂ and R ⁴ is a hydroxyl group, or a pharmaceutically acceptable salt thereof. 【請求項７】 ＸがＣＨ₂−ＣＨ₂である請求項１記載の
デプシペプチドまたはその薬理学的に許容される塩。7. The depsipeptide according to claim 1, wherein X is CH ₂ —CH ₂ or a pharmaceutically acceptable salt thereof. 【請求項８】 ＸがＣＨ₂−ＣＨ₂であり、ＹがＮ(Ｒ¹²)
−ＣＯである請求項７記載のデプシペプチドまたはその
薬理学的に許容される塩。8. X is CH ₂ —CH ₂ and Y is N (R ¹² )
The depsipeptide according to claim 7, which is -CO, or a pharmacologically acceptable salt thereof. 【請求項９】 ＸがＣＨ₂−ＣＨ₂であり、ＹがＮ(Ｒ¹²)
−ＣＯであり、Ｒ⁴がＡ−Ｂである請求項７記載のデプ
シペプチドまたはその薬理学的に許容される塩。9. X is CH ₂ —CH ₂ and Y is N (R ¹² )
8. The depsipeptide or a pharmaceutically acceptable salt thereof according to claim 7, wherein the compound is -CO and R ⁴ is AB. 【請求項１０】 請求項１に記載の非天然アミノ酸を含
有するデプシペプチドまたはその薬理学的に許容される
塩を有効成分とする医薬。10. A medicament comprising the depsipeptide containing the unnatural amino acid according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 【請求項１１】 請求項１０に記載の医薬がアポリポプ
ロテインＥ産生促進薬である医薬。11. A medicament according to claim 10, which is an apolipoprotein E production enhancer. 【請求項１２】 請求項１０に記載の医薬が神経損傷治
療薬である医薬。12. A drug according to claim 10, which is a drug for treating nerve damage. 【請求項１３】 請求項１０に記載の医薬が痴呆症治療
薬である医薬。13. A medicament according to claim 10, which is a therapeutic drug for dementia. 【請求項１４】 請求項１０に記載の医薬が高脂血症治
療薬である医薬。14. A medicament according to claim 10, which is a therapeutic drug for hyperlipidemia.