JP2697495B2 - Aldehyde derivatives - Google Patents
Aldehyde derivativesInfo
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- JP2697495B2 JP2697495B2 JP18474592A JP18474592A JP2697495B2 JP 2697495 B2 JP2697495 B2 JP 2697495B2 JP 18474592 A JP18474592 A JP 18474592A JP 18474592 A JP18474592 A JP 18474592A JP 2697495 B2 JP2697495 B2 JP 2697495B2
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Description
【0001】[0001]
【産業上の利用分野】本発明は、一般式The present invention relates to a compound of the general formula
【0002】[0002]
【化2】 Embedded image
【0003】(式中、R1 は芳香族炭化水素基、複素環
基、置換アルキル基又は環状アルキル基、R2 は、水素
原子、アルキル基又は芳香族炭化水素基、R3 は、水素
原子又はアルキル基、R4 は、アルコキシカルボニル
基、アシル基、カルバモイル基又はスルホニル基、X
は、酸素原子又は−S(O)m −で表される基、ここで
mは0,1又は2であり、nは、1〜5である。)で表
されるアルデヒド誘導体に関する。前記一般式(1)で
表されるアルデヒド誘導体は、カルパイン阻害活性及び
血小板凝集抑制作用を有し虚血性疾患治療剤として用い
ることのできる化合物である。Wherein R 1 is an aromatic hydrocarbon group, a heterocyclic group, a substituted alkyl group or a cyclic alkyl group, R 2 is a hydrogen atom, an alkyl group or an aromatic hydrocarbon group, and R 3 is a hydrogen atom Or an alkyl group, R 4 is an alkoxycarbonyl group, an acyl group, a carbamoyl group or a sulfonyl group, X
Is an oxygen atom or a group represented by —S (O) m —, wherein m is 0, 1 or 2, and n is 1 to 5. )). The aldehyde derivative represented by the general formula (1) is a compound having a calpain inhibitory activity and a platelet aggregation inhibitory activity and can be used as a therapeutic agent for ischemic disease.
【0004】[0004]
【従来の技術】カルパインは、広く生体内組織の細胞内
に存在し、カルシウムによって活性化される蛋白質分解
酵素(システインプロテアーゼ)である。カルパイン
は、筋蛋白質、酵素蛋白質、レセプター蛋白質あるいは
細胞骨格蛋白質等を基質とする組織崩壊、不活性酵素前
駆体の活性化、細胞内プロセッシング等の生理活性を有
することが知られている(蛋白質 核酸 酵素,第33
巻,12号,2175(1988))。2. Description of the Related Art Calpain is a proteolytic enzyme (cysteine protease) that exists widely in cells of tissue in a living body and is activated by calcium. Calpain is known to have physiological activities such as tissue breakdown using muscle proteins, enzyme proteins, receptor proteins or cytoskeletal proteins as substrates, activation of inactive zymogen, and intracellular processing (protein nucleic acid). Enzyme, No. 33
Vol. 12, No. 2, 2175 (1988)).
【0005】このカルパインの活性亢進によって引き起
こされるカルパインの活性異常は、多くの難治性疾患に
関与している。例えば虚血性疾患、炎症、筋ジストロフ
ィー、白内障、免疫疾患、本態性高血圧等への関与が報
告されている。特に虚血性疾患においては、虚血時の細
胞内カルシウムの増加によってカルパインが活性化さ
れ、細胞障害、壊死を引き起こすと考えられている。[0005] The abnormal calpain activity caused by the increased calpain activity is involved in many intractable diseases. For example, involvement in ischemic disease, inflammation, muscular dystrophy, cataract, immune disease, essential hypertension and the like has been reported. Particularly in ischemic diseases, it is thought that calpain is activated by an increase in intracellular calcium during ischemia, causing cell damage and necrosis.
【0006】従来この虚血性疾患の治療剤としては、カ
ルシウム拮抗剤、β−ブロッカー等であり、血管を拡張
する作用を有する薬剤が用いられてきた。しかしなが
ら、これらの薬剤は、虚血性疾患において見られる細胞
障害あるいは壊死を治療又は予防しうる効果を有するも
のではなかった。[0006] Conventionally, as a therapeutic agent for this ischemic disease, a calcium antagonist, a β-blocker or the like, which has a blood vessel expanding effect, has been used. However, these drugs did not have the effect of treating or preventing the cell damage or necrosis seen in ischemic diseases.
【0007】そこでカルパイン阻害剤はこれらの難治性
疾患に対する治療剤として有用になる可能性がある。カ
ルパイン阻害活性を有する化合物としては、既にエポキ
シコハク酸誘導体(J.Biochem.,87,33
9(1980)、ピペラジン誘導体(特開昭57−16
9478号、特開昭58−126879号、特開昭63
−25575号)、アミノアルデヒド誘導体(特開昭6
1−103897号、特開平1−12157号、特開平
2−268145号)、アミノアルデヒド、アミノケト
ン誘導体(特開平2−256654号)等が知られてい
る。Therefore, calpain inhibitors may be useful as therapeutic agents for these intractable diseases. Compounds having calpain inhibitory activity include epoxy succinic acid derivatives (J. Biochem., 87, 33).
9 (1980), piperazine derivatives (JP-A-57-16)
9478, JP-A-58-126879, JP-A-63
No. 25575), an aminoaldehyde derivative (Japanese Unexamined Patent Publication No.
Nos. 1-103897, JP-A-1-12157 and JP-A-2-268145), aminoaldehydes and aminoketone derivatives (JP-A-2-256654) are known.
【0008】[0008]
【発明が解決しようとする課題】これらの化合物の中で
ピペラジン誘導体は、心筋保護作用を有することが報告
され、虚血性疾患に対する治療剤としての可能性を有し
ている。しかしながらこの誘導体は、カルパインへの阻
害活性作用及び心筋保護の作用も低く充分な治療効果を
期待できるものではなかった。また、このピペラジン誘
導体以外の化合物においては、カルパインへの阻害活性
を有するものの虚血性疾患に対する治療剤として用いる
ことのできるものではなかった。Among these compounds, piperazine derivatives are reported to have a cardioprotective effect, and have potential as therapeutic agents for ischemic diseases. However, this derivative also had a low inhibitory activity on calpain and a protective effect on myocardium, and could not be expected to have a sufficient therapeutic effect. Compounds other than the piperazine derivative have calpain inhibitory activity but could not be used as a therapeutic agent for ischemic disease.
【0009】[0009]
【課題を解決するための手段】そこで本発明者らは、虚
血性疾患に有用なカルパイン阻害剤を見出すべく研究を
行った結果、虚血性疾患の治療効果を高めるために血小
板凝集抑制作用とカルパインへの特異的な阻害活性とを
有する前記一般式(I)で表されるアルデヒド誘導体を
見出し本発明を完成するに至った。The present inventors have conducted research to find a calpain inhibitor useful for ischemic disease. An aldehyde derivative represented by the above general formula (I) having specific inhibitory activity on aldehydes has been found, and the present invention has been completed.
【0010】前記一般式(I)で表わされるアルデヒド
誘導体において、R1 は芳香族炭化水素基、複素環基、
置換アルキル基又は環状アルキル基である。この芳香族
炭化水素基として、例えばフェニル基、ナフチル基、ア
ントラニル基等、複素環基として例えばフリル基、チェ
ニル基、ピロリル基、ピリジル基、キノリル基、イソキ
ノリル基、インドリル基等、置換アルキル基として前記
芳香族炭化水素基又は前記複素環基を置換基として有す
る炭素数1〜10の直鎖状及び分枝鎖状のアルキル基で
あり例えばメチル基、エチル基、プロピル基、ブチル
基、ペンチル基、ヘキシル基、2−プロピル基、sec
−ブチル基、t−ブチル基等を挙げることができ、環状
アルキル基として例えばシクロプロピル基、シクロブチ
ル基、シクロペンチル基、シクロヘキシル基等を挙げる
ことができる。In the aldehyde derivative represented by the general formula (I), R 1 represents an aromatic hydrocarbon group, a heterocyclic group,
It is a substituted alkyl group or a cyclic alkyl group. As this aromatic hydrocarbon group, for example, a phenyl group, a naphthyl group, an anthranyl group, etc. A linear or branched alkyl group having 1 to 10 carbon atoms having the aromatic hydrocarbon group or the heterocyclic group as a substituent, such as a methyl group, an ethyl group, a propyl group, a butyl group, or a pentyl group; , Hexyl group, 2-propyl group, sec
-Butyl group, t-butyl group and the like. Examples of the cyclic alkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.
【0011】さらに前記R1 の芳香族炭化水素もしくは
複素環基、及び前記置換アルキル基の置換基である芳香
族炭化水素基もしくは複素環基には、置換基を有してい
てもよく置換基として例えば、メチル基、エチル基、プ
ロピル基、ブチル基等の炭素数1〜10のアルキル基、
メトキシ基、エトキシ基、プロポキシ基、ブトキシ基、
ベンジルオキシ基等の炭素数1〜10のアルコキシ基、
フッ素、塩素、臭素、ヨウ素等のハロゲン基、アミノ
基、ジメチルアミノ基、ジエチルアミノ基等のアミノ
基、水酸基、ニトロ基等を挙げることができる。Further, the aromatic hydrocarbon or heterocyclic group represented by R 1 and the aromatic hydrocarbon or heterocyclic group which is a substituent of the substituted alkyl group may have a substituent. As an example, a methyl group, an ethyl group, a propyl group, an alkyl group having 1 to 10 carbon atoms such as a butyl group,
Methoxy, ethoxy, propoxy, butoxy,
An alkoxy group having 1 to 10 carbon atoms such as a benzyloxy group,
Examples include a halogen group such as fluorine, chlorine, bromine and iodine, an amino group such as an amino group, a dimethylamino group and a diethylamino group, a hydroxyl group and a nitro group.
【0012】R2 は、水素原子、直鎖状又は分枝鎖状の
アルキル基又は芳香族炭化水素基である。このR2 のア
ルキル基としては炭素数1〜10の直鎖状又は分枝鎖状
のアルキル基であり例えばメチル基、エチル基、プロピ
ル基、イソプロピル基、n−ブチル基、sec−ブチル
基、イソブチル基、t−ブチル基、ペンチル基、ネオペ
ンチル基、ヘキシル基等を挙げることができ、芳香族炭
化水素基としては、前記R1 で示した芳香族炭化水素基
と同様な基を挙げることができる。さらにR2のアルキ
ル基には置換基を有していてもよく、置換基として例え
ば前記R1 で示した芳香族炭化水素基、複素環基を挙げ
ることができる。R 2 is a hydrogen atom, a linear or branched alkyl group or an aromatic hydrocarbon group. The alkyl group of R 2 is a linear or branched alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, Examples thereof include an isobutyl group, a t-butyl group, a pentyl group, a neopentyl group, and a hexyl group. Examples of the aromatic hydrocarbon group include the same groups as the aromatic hydrocarbon group represented by R 1. it can. Further, the alkyl group of R 2 may have a substituent, and examples of the substituent include the aromatic hydrocarbon group and the heterocyclic group represented by R 1 .
【0013】R3 は、水素原子又はアルキル基であり、
アルキル基としては前記R2 と同様なアルキル基を挙げ
ることができる。R 3 is a hydrogen atom or an alkyl group;
Examples of the alkyl group include the same alkyl groups as those described above for R 2 .
【0014】R4 は、アルコキシカルボニル基、アシル
基、カルバモイル基又はスルホニル基である。このアル
コキシカルボニル基としては炭素数1〜10のアルコキ
シ基を有するアルコキシカルボニル基であり、例えばメ
トキシカルボニル基、エトキシカルボニル基、t−ブト
キシカルボニル基、シンナミルオキシカルボニル基、ベ
ンジルオキシカルボニル基等を挙げることができ、アシ
ル基としては、例えばアセチル基、プロピオニル基、ブ
チリル基、バレリル基、ベンゾイル基、1−ナフトイル
基、2−ナフトイル基、シクロヘキサンカルボニル基、
トルイル基、1−(ベンジルオキシカルボニル)ピペリ
ジン−4−カルボニル基等を挙げることができ、カルバ
モイル基としては、例えばN−メチルカルバモイル基、
N−エチルカルバモイル基、N−フェニルカルバモイル
基、N−(2−クロロフェニル)カルバモイル基、N−
(1−ナフチル)カルバモイル基、N−ベンジルカルバ
モイル基等を挙げることができ、さらに置換スルホニル
基としては、例えばメタンスルホニル基、トリフルオロ
メタンスルホニル基、ベンゼンスルホニル基、4−メチ
ルベンゼンスルホニル基、イソキノリン−5−スルホニ
ル基、キノリン−8−スルホニル基等を挙げることがで
きる。R 4 is an alkoxycarbonyl group, an acyl group, a carbamoyl group or a sulfonyl group. The alkoxycarbonyl group is an alkoxycarbonyl group having an alkoxy group having 1 to 10 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a cinnamyloxycarbonyl group, and a benzyloxycarbonyl group. As the acyl group, for example, acetyl, propionyl, butyryl, valeryl, benzoyl, 1-naphthoyl, 2-naphthoyl, cyclohexanecarbonyl,
Examples thereof include a toluyl group and a 1- (benzyloxycarbonyl) piperidine-4-carbonyl group. Examples of the carbamoyl group include an N-methylcarbamoyl group,
N-ethylcarbamoyl group, N-phenylcarbamoyl group, N- (2-chlorophenyl) carbamoyl group, N-
(1-Naphthyl) carbamoyl group, N-benzylcarbamoyl group, and the like. Examples of the substituted sulfonyl group include, for example, methanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, 4-methylbenzenesulfonyl group, and isoquinoline Examples thereof include a 5-sulfonyl group and a quinoline-8-sulfonyl group.
【0015】Xは酸素原子の他、−S(O)m −で表わ
される基でありここでmは0,1又は2である。nは1
〜5である。X is an oxygen atom or a group represented by -S (O) m- , wherein m is 0, 1 or 2. n is 1
~ 5.
【0016】前記一般式(I)で表わされるアルデヒド
誘導体は例えば以下式Iに示す製造法に従い製造するこ
とができる。The aldehyde derivative represented by the general formula (I) can be produced, for example, according to the production method shown in the following formula I.
【0017】式IFormula I
【0018】[0018]
【化3】 Embedded image
【0019】(式中、R1 ,R2 ,R3 ,R4 ,X,及
びnは前記と同じであり、R5 は炭素数1〜15のアル
キル基である。) 〔第1工程〕本工程は、前記一般式(II)で表わされる
カルボン酸誘導体と前記一般式(III)で表わされるアミ
ン誘導体とを縮合剤の存在下反応させることにより前記
一般式(IV)で表わされるエステル誘導体を製造するも
のである。(Wherein R 1 , R 2 , R 3 , R 4 , X, and n are the same as above, and R 5 is an alkyl group having 1 to 15 carbon atoms.) [First step] In this step, the carboxylic acid derivative represented by the general formula (II) is reacted with the amine derivative represented by the general formula (III) in the presence of a condensing agent, whereby the ester derivative represented by the general formula (IV) is reacted. Is to manufacture.
【0020】前記一般式(III )で表わされるアミン誘
導体において、R5 は炭素数1〜15のアルキル基であ
り、例えばメチル基、エチル基、プロピル基、ブチル
基、ベンジル基、ジフェニルメチル基等である。In the amine derivative represented by the general formula (III), R 5 is an alkyl group having 1 to 15 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, a diphenylmethyl group and the like. It is.
【0021】本工程は、縮合剤の存在下行うことがで
き、縮合剤として例えばジシクロヘキシルカルボジイミ
ド(DCC)、1−エチル−3−(3−ジメチルアミノ
プロピル)−カルボジイミド塩酸塩(WSC・HCl)
等のカルボジイミド試薬等を挙げることができる。This step can be carried out in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC.HCl).
And the like.
【0022】本工程に用いる縮合剤は、前記一般式(I
I)で表わされるカルボン酸誘導体又は前記一般式(III
)で表わされるアミン誘導体1モルに対して1〜3当
量、収率よく製造するためには1.5〜2当量用いるこ
とが好ましい。反応は、不活性溶媒中行なうことが望ま
しく例えば、ジクロロメタン、クロロホルム、ジクロロ
エタン等のハロゲン化炭化水素類、ベンゼル、トルエ
ン、キシレン等の芳香族炭化水素類、ジエチルエーテ
ル、ジメトキシエタン、テトラヒドロフラン(TH
F)、ジオキサン等のエーテル類、ジメチルホルムアミ
ド(DMF)等のアミド類、ジメチルスルホキシド(D
MSO)、アセトニトリル等を単独又は混合して使用す
ることができる。反応は常圧下通常−50℃〜還流温度
で進行するが、収率よく実施するためには−30℃〜3
0℃で行うことが好ましい。The condensing agent used in this step is represented by the general formula (I)
A carboxylic acid derivative represented by the formula (I) or the above-mentioned general formula (III)
) Is preferably used in an amount of 1 to 3 equivalents to 1 mol of the amine derivative represented by the formula (1), and 1.5 to 2 equivalents in order to obtain a good yield. The reaction is desirably carried out in an inert solvent. For example, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, dimethoxyethane, tetrahydrofuran (TH
F), ethers such as dioxane, amides such as dimethylformamide (DMF), dimethyl sulfoxide (D
MSO), acetonitrile and the like can be used alone or as a mixture. The reaction usually proceeds at −50 ° C. to reflux temperature under normal pressure.
It is preferably performed at 0 ° C.
【0023】なお、本工程の出発原料である前記一般式
(II) で表わされるカルボン酸誘導体は、市販のアミノ
酸誘導体又は市販のアミノ酸のアミノ基を前記R3 及び
R4で表わされる基に変換して製造したものである。
(後記参考例参照)。The carboxylic acid derivative represented by the general formula (II), which is a starting material in this step, is obtained by converting a commercially available amino acid derivative or an amino group of a commercially available amino acid into a group represented by R 3 and R 4. It was manufactured.
(See Reference Example below).
【0024】本発明で用いられる前記一般式(II)で表
わされるカルボン酸誘導体としては、例えば、L−N−
〔1−(ベンジルオキシカルボニル)ピペリジン−4−
カルボニル〕ロイシン、L−N−(N−フェニルカルバ
モイル)ロイシン、L−N−(4−メチルベンゼンスル
ホニル)ロイシン、L−N−メチル−N−(ベンジルオ
キシカルボニル)ロイシン、L−N−(シンナモイル)
ロイシン、L−N−(2−ナフトイル)ロイシン、L−
N−(ベンジルオキシカルボニル)バリン、L−N−
(ベンジルオキシカルボニル)フェニルアラニン等を挙
げることができる。The carboxylic acid derivative represented by the general formula (II) used in the present invention includes, for example, LN-
[1- (benzyloxycarbonyl) piperidine-4-
Carbonyl] leucine, LN- (N-phenylcarbamoyl) leucine, LN- (4-methylbenzenesulfonyl) leucine, LN-methyl-N- (benzyloxycarbonyl) leucine, LN- (cinnamoyl )
Leucine, LN- (2-naphthoyl) leucine, L-
N- (benzyloxycarbonyl) valine, LN-
(Benzyloxycarbonyl) phenylalanine and the like.
【0025】また、本工程の出発原料である前記一般式
(III )で表わされるアミン誘導体は、市販のアミノ酸
エステルを使用できる他、例えば下記式2に示す反応式
に従い一般式(VII )で表わされるアミノ酸より製造す
ることができる。As the amine derivative represented by the general formula (III) as a starting material in this step, a commercially available amino acid ester can be used. In addition, for example, the amine derivative represented by the general formula (VII) can be used according to the following reaction formula (2). Can be produced from the amino acid.
【0026】式2Equation 2
【0027】[0027]
【化4】 Embedded image
【0028】(式内、R1 ,R5 ,X及びnは前記と同
じ基であり、X1 はハロゲン原子である)。(Wherein R 1 , R 5 , X and n are the same groups as above, and X 1 is a halogen atom).
【0029】さらに式2に示す前記一般式(III )で表
わされるアミン誘導体は、必要に応じ前記一般式(VII
)で表わされるアミノ酸のアミノ基をペプチド合成で
用いられるアミノ基の保護基により、保護した後製造す
ることもできる。Further, the amine derivative represented by the general formula (III) shown in the formula (2) can be optionally substituted by the general formula (VII)
)) Can be produced after protecting the amino group of the amino acid with the amino group protecting group used in peptide synthesis.
【0030】本工程で用いられる前記一般式(III )で
表わされるアミン誘導体としては例えばL−O−(ベン
ジル)セリンエチルエステル、L−S−(2−フェニル
エチル)システインメチルエステル、L−S−(3−フ
ェニルプロピル)システインメチルエステル、L−O−
(3−フェニルプロピル)セリンエチルエステル、L−
O−(3−チエニルメチル)セリンエチルエステル、L
−S−(ジフェニルメチル)システインメチルエステ
ル、L−S−(シクロヘキシルメチル)システインエチ
ルエステル、L−S−(シクロペンチル)システインエ
チルエステル、L−S−(2−チエニルメチル)システ
インメチルエステル、L−S−(3−チエニルメチル)
システインエチルエステル、L−S−(1−ナフチルメ
チル)システインエチルエステル、L−S−(2−ナフ
チルメチル)システインエチルエステル、L−S−(2
−クロロベンジル)システインエチルエステル等を挙げ
ることができる。Examples of the amine derivative represented by the general formula (III) used in this step include, for example, L-O- (benzyl) serine ethyl ester, L-S- (2-phenylethyl) cysteine methyl ester, L-S -(3-phenylpropyl) cysteine methyl ester, L-O-
(3-phenylpropyl) serine ethyl ester, L-
O- (3-thienylmethyl) serine ethyl ester, L
-S- (diphenylmethyl) cysteine methyl ester, LS- (cyclohexylmethyl) cysteine ethyl ester, LS- (cyclopentyl) cysteine ethyl ester, LS- (2-thienylmethyl) cysteine methyl ester, L- S- (3-thienylmethyl)
Cysteine ethyl ester, LS- (1-naphthylmethyl) cysteine ethyl ester, LS- (2-naphthylmethyl) cysteine ethyl ester, LS- (2
-Chlorobenzyl) cysteine ethyl ester and the like.
【0031】また、本工程において、前記一般式(IV)
で表わされるエステル誘導体は、前記一般式(II)で表
わされるカルボン酸誘導体のカルボキシル基を例えば活
性エステル化合物、カルボン酸ハライド化合物、酸無水
物等に変換した後この第1工程と同様な不活性溶媒中前
記一般式(III )で表わされるアミン誘導体の存在下に
反応することにより製造することができる。In this step, the compound represented by the general formula (IV)
Is obtained by converting the carboxyl group of the carboxylic acid derivative represented by the general formula (II) into, for example, an active ester compound, a carboxylic acid halide compound, an acid anhydride, and the like. It can be produced by reacting in a solvent in the presence of the amine derivative represented by the above general formula (III).
【0032】〔第2工程〕本工程は、前記一般式(IV)
で表わされるエステル誘導体を還元し、前記一般式
(V)で表わされるアルコール誘導体を製造するもので
ある。[Second Step] This step is carried out according to the general formula (IV)
Is reduced to produce an alcohol derivative represented by the general formula (V).
【0033】本工程を実施するための還元剤としては、
例えば水素化ホウ素ナトリウム、水素化ホウ素リチウム
等のホウ素化合物を挙げることができる。As the reducing agent for carrying out this step,
Examples thereof include boron compounds such as sodium borohydride and lithium borohydride.
【0034】還元剤の使用量は、前記一般式(IV)で表
わされるエステル誘導体1モルに対し1〜4当量用いる
ことができる。反応は不活性溶媒中実施することが好ま
しく例えば、水、メタノール、エタノール等のアルコー
ル類、エーテル、THF、ジメトキシエタン、ジオキサ
ン等のエーテル類、ジクロロメタン、クロロホルム、ジ
クロロエタン等のハロゲン化炭化水素類、ベンゼン、ト
ルエン、キシレン等の芳香族炭化水素類を単独又は混合
して用いることができる。反応は−20℃〜50℃で実
施することができる。The reducing agent is used in an amount of 1 to 4 equivalents per 1 mol of the ester derivative represented by the above general formula (IV). The reaction is preferably carried out in an inert solvent, for example, water, alcohols such as methanol and ethanol, ethers such as ether, THF, dimethoxyethane and dioxane, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and benzene. And aromatic hydrocarbons such as toluene and xylene can be used alone or in combination. The reaction can be carried out at -20C to 50C.
【0035】〔第3工程〕本工程は、前記一般式(V)
で表わされるアルコール誘導体を酸化し、前記一般式
(I)で表わされるアルデヒド誘導体を製造するもので
ある。本工程を実施するための酸化方法は、活性ジメチ
ルスルホキシド(DMSO)酸化法であり、DMSO及
びDMSOの活性化剤としてジシクロヘキシルカルボジ
イミド、五酸化リン、ピリジン−三酸化イオウ錯体、塩
化オキザリル、無水酢酸、無水トリフルオロ酢酸等を用
いることができる。酸化剤の使用量は、前記一般式
(V)で表わされるアルコール誘導体1モルに対して、
1〜4当量用いることができる。[Third Step] This step is performed according to the general formula (V)
Oxidizes the alcohol derivative represented by the general formula (I) to produce the aldehyde derivative represented by the general formula (I). The oxidation method for carrying out this step is an active dimethyl sulfoxide (DMSO) oxidation method, in which dicyclohexylcarbodiimide, phosphorus pentoxide, pyridine-sulfur trioxide complex, oxalyl chloride, acetic anhydride, Trifluoroacetic anhydride or the like can be used. The amount of the oxidizing agent used is based on 1 mol of the alcohol derivative represented by the general formula (V).
1-4 equivalents can be used.
【0036】反応は、不活性溶媒中実施することが好ま
しく、例えばジクロロメンタン、ジクロロエタン、クロ
ロホルム等のハロゲン化炭化水素類、DMSO等を用い
ることができる。反応は−20℃〜30℃で実施するこ
とができる。The reaction is preferably carried out in an inert solvent. For example, halogenated hydrocarbons such as dichloromenthane, dichloroethane and chloroform, DMSO and the like can be used. The reaction can be carried out at -20C to 30C.
【0037】〔第4工程〕本工程は、前記一般式(II)
で表わされるカルボン酸誘導体と、前記一般式(VI)で
表わされるアミノアルコール誘導体とを縮合剤の存在下
反応させることにより前記一般式(V)で表わされるア
ルコール誘導体を製造するものである。[Fourth Step] This step is performed according to the general formula (II)
The alcohol derivative represented by the general formula (V) is produced by reacting the carboxylic acid derivative represented by the general formula (VI) with the amino alcohol derivative represented by the general formula (VI) in the presence of a condensing agent.
【0038】本工程は、第1工程と同様の縮合剤、反応
条件、反応溶媒を用いて実施することができる。This step can be carried out using the same condensing agent, reaction conditions and reaction solvent as in the first step.
【0039】本工程の原料である前記一般式(VI)で表
わされるアミノアルコール誘導体は、例えば前記一般式
(VII )で表わされるアミノ酸より式3に示す反応式に
従い製造することができる。The amino alcohol derivative represented by the general formula (VI), which is a raw material in this step, can be produced, for example, from the amino acid represented by the general formula (VII) according to the reaction formula shown in the formula 3.
【0040】式3Equation 3
【0041】[0041]
【化5】 Embedded image
【0042】(式中、R1 ,X,nは前記と同じであ
り、R6 は、アミノ基の保護基である。)本工程で用い
られる前記一般式(VI)で表わされるアミノアルコール
誘導体としては例えば(2R)−2−アミノ−3−(2
−フルオロベンジルチオ)プロパノール、(2R)−2
−アミノ−3−(3−クロロベンジルチオ)プロパノー
ル、(2R)−2−アミノ−3−(4−クロロベンジル
チオ)プロパノール、(2R)−2−アミノ−3−(3
−フルオロベンジルチオ)プロパノール、(2R)−2
−アミノ−3−(2−メトキシベンジルチオ)プロパノ
ール、(2R)−2−アミノ−3−(3−フルオロベン
ジルチオ)プロパノール、(2R)−2−アミノ−3−
(3−メトキシベンジルチオ)プロパノール、(2R)
−2−アミノ−3−(4−メトキシベンジルチオ)プロ
パノール、(2R)−2−アミノ−3−(3−ニトロベ
ンジルチオ)プロパノール、(2R)−2−アミノ−3
−(4−ニトロベンジルチオ)プロパノール、(2S)
−2−アミノ−4−フェノキシブタノール、(2S)−
2−アミノ−4−(フェニルチオ)ブタノール、(2
S)−2−アミノ−3−(2−クロロベンジルオキシ)
プロパノール、(2S)−2−アミノ−4−(2−フル
オロフェノキシ)ブタノール、(2S)−2−アミノ−
4−(3−フルオロフェノキシ)ブタノール、L−2−
アミノ−4−(2−クロロフェノキシ)ブタノール、
(2S)−2−アミノ−4−(3−クロロフェノキシ)
ブタノール、(2S)−2−アミノ−4−ベンジルチオ
ブタノール、(2S)−2−アミノ−4−(2−フルオ
ロベンジルチオ)ブタノール、(2S)−2−アミノ−
4−(2−クロロベンジルチオ)ブタノール、(2S)
−2−アミノ−4−(2−フルオロフェニルチオ)ブタ
ノール、(2S)−2−アミノ−4−(2−クロロフェ
ニルチオ)ブタノール、(2S)−2−アミノ−4−
(4−クロロフェニルチオ)ブタノール、(2S)−2
−アミノ−4−(2−クロロベンジルオキシ)ブタノー
ル、(2S)−2−アミノ−4−(2−フルオロベンジ
ルオキシ)ブタノール、(2S)−2−アミノ−4−
(3−ニトロベンジルオキシ)ブタノール等を挙げるこ
とができる。(Wherein R 1 , X and n are the same as described above, and R 6 is a protecting group for an amino group.) The amino alcohol derivative represented by the above general formula (VI) used in this step For example, (2R) -2-amino-3- (2
-Fluorobenzylthio) propanol, (2R) -2
-Amino-3- (3-chlorobenzylthio) propanol, (2R) -2-amino-3- (4-chlorobenzylthio) propanol, (2R) -2-amino-3- (3
-Fluorobenzylthio) propanol, (2R) -2
-Amino-3- (2-methoxybenzylthio) propanol, (2R) -2-amino-3- (3-fluorobenzylthio) propanol, (2R) -2-amino-3-
(3-methoxybenzylthio) propanol, (2R)
-2-amino-3- (4-methoxybenzylthio) propanol, (2R) -2-amino-3- (3-nitrobenzylthio) propanol, (2R) -2-amino-3
-(4-nitrobenzylthio) propanol, (2S)
-2-amino-4-phenoxybutanol, (2S)-
2-amino-4- (phenylthio) butanol, (2
S) -2-Amino-3- (2-chlorobenzyloxy)
Propanol, (2S) -2-amino-4- (2-fluorophenoxy) butanol, (2S) -2-amino-
4- (3-fluorophenoxy) butanol, L-2-
Amino-4- (2-chlorophenoxy) butanol,
(2S) -2-amino-4- (3-chlorophenoxy)
Butanol, (2S) -2-amino-4-benzylthiobutanol, (2S) -2-amino-4- (2-fluorobenzylthio) butanol, (2S) -2-amino-
4- (2-chlorobenzylthio) butanol, (2S)
-2-amino-4- (2-fluorophenylthio) butanol, (2S) -2-amino-4- (2-chlorophenylthio) butanol, (2S) -2-amino-4-
(4-chlorophenylthio) butanol, (2S) -2
-Amino-4- (2-chlorobenzyloxy) butanol, (2S) -2-amino-4- (2-fluorobenzyloxy) butanol, (2S) -2-amino-4-
(3-Nitrobenzyloxy) butanol and the like can be mentioned.
【0043】また、本工程の出発原料である前記一般式
(II)で表わされるカルボン酸誘導体は、前記第1工程
と同様に、例えば活性エステル化合物、カルボン酸ハラ
イド化合物、酸無水物等に変換した後、前記一般式
(V)で表わされるアルコール誘導体として製造するこ
ともできる。The carboxylic acid derivative represented by the general formula (II), which is a starting material in this step, is converted into, for example, an active ester compound, a carboxylic acid halide compound, an acid anhydride and the like in the first step. After that, it can also be produced as an alcohol derivative represented by the general formula (V).
【0044】本工程により製造された前記一般式(V)
で表わされるアルコール誘導体は、前記第3工程に従
い、前記一般式(I)で表わされるアルデヒド誘導体を
製造することができる。The above general formula (V) produced by this step
The aldehyde derivative represented by the general formula (I) can be produced from the alcohol derivative represented by the formula (I) according to the third step.
【0045】[0045]
【作用】本発明の前記一般式(I)で表わされるアルデ
ヒド誘導体は、試験例に示す通り、トリプシン、α−キ
モトリプシン等のプロテアーゼに対する阻害作用を持た
ずいずれも優れた特異的なカルパイン活性阻害作用、さ
らには血小板凝集抑制作用を有するため、虚血性疾患の
治療に有用である。これらの化合物は、経口投与以外
に、静脈内、皮下又は筋肉内に投与し得る。そのために
これらの化合物は、種々の投与形態、例えば錠剤、カプ
セル、液体又は坐薬等の形で使用することができる。As shown in the test examples, the aldehyde derivatives of the present invention represented by the above general formula (I) have no specific inhibitory activity against proteases such as trypsin and α-chymotrypsin, and all have excellent specific calpain activity inhibitory activity. In addition, since it has a platelet aggregation inhibitory action, it is useful for treating ischemic diseases. In addition to oral administration, these compounds can be administered intravenously, subcutaneously or intramuscularly. For this purpose, these compounds can be used in various dosage forms such as tablets, capsules, liquids or suppositories.
【0046】[0046]
【実施例】本発明を以下の参考例、実施例及び試験例に
従いさらに詳細に説明する。The present invention will be described in more detail with reference to the following Reference Examples, Examples and Test Examples.
【0047】(参考例1)L−O−(ベンジル)セリン
エチルエステル塩酸塩(化合物(1)) L−N−(t−ブトキシカルボニル)−O−(ベンジ
ル)セリン25g(8.5mmol)のエタノール溶液に濃
塩酸1ml加え室温で2時間攪拌した。反応溶液減圧下溶
媒留去し、得られた残留物のエタノール溶液に塩化チオ
ニル1.3ml(17mmol)を加え室温で一夜攪拌した。
反応溶液を減圧下溶媒留去し標記化合物(1)2.01
g(収率91.6%)を得た。Reference Example 1 L-O- (benzyl) serine ethyl ester hydrochloride (compound (1)) 25 g (8.5 mmol) of L-N- (t-butoxycarbonyl) -O- (benzyl) serine 1 ml of concentrated hydrochloric acid was added to the ethanol solution, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure of the reaction solution, and 1.3 ml (17 mmol) of thionyl chloride was added to an ethanol solution of the obtained residue, followed by stirring at room temperature overnight.
The solvent was distilled off from the reaction solution under reduced pressure to give the title compound (1) (2.01).
g (91.6% yield).
【0048】NMR(δ,CD3 OD):7.30-7.36(m,
5H),4.59(dd,J=31.74Hz,J=12.15Hz,2H),4.24-4.31(m,3
H),3.93(dd,J=10.53Hz,J=4.29Hz,1H),3.82(dd,J=10.65H
z,J=3.33Hz,1H),1.27(t,J=7.17Hz,3H) (参考例2)L−S−(2−フェニルエチル)システイ
ンメチルエステル塩酸塩(化合物(2)) システイン塩酸塩水和物4.85g(29.28mmol)
を氷冷下ナトリウムメトキシド4.74gのメタノール
溶液200mlに加え室温にて1時間攪拌した。反応溶液
に2−ブロモエチルベンゼン5.55g(30mmol)の
メタノール溶液を滴下し氷冷下1時間攪拌した。溶媒を
減圧下留去し得られた残留物を水に溶かしジエチルエー
テルで洗浄、水層を濃塩酸で中性とした。析出した結晶
を濾取し水、エタノール、ジエチルエーテルで洗浄し乾
燥後L−S−フェニルエチルシステイン5.37g(収
率85.9%)を得た。得られた上記化合物5.3g
(23.5mmol)のメタノール溶液(200ml)とし氷
冷下塩化チオニル8.6mlを滴下し滴下後反応溶液を室
温とし一夜攪拌した。減圧下溶媒留去し得られた結晶を
ジエチルエーテルで洗浄し乾燥後標記化合物(2)6.
27g(収率96.3%)を得た。NMR (δ, CD 3 OD): 7.30-7.36 (m,
5H), 4.59 (dd, J = 31.74Hz, J = 12.15Hz, 2H), 4.24-4.31 (m, 3
H), 3.93 (dd, J = 10.53Hz, J = 4.29Hz, 1H), 3.82 (dd, J = 10.65H
z, J = 3.33 Hz, 1H), 1.27 (t, J = 7.17 Hz, 3H) (Reference Example 2) L-S- (2-phenylethyl) cysteine methyl ester hydrochloride (compound (2)) Cysteine hydrochloride aqueous solution 4.85 g (29.28 mmol) of Japanese product
Was added to 200 ml of a methanol solution of 4.74 g of sodium methoxide under ice cooling, followed by stirring at room temperature for 1 hour. A methanol solution of 5.55 g (30 mmol) of 2-bromoethylbenzene was added dropwise to the reaction solution, and the mixture was stirred for 1 hour under ice cooling. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in water and washed with diethyl ether. The aqueous layer was neutralized with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, ethanol and diethyl ether, and dried to obtain 5.37 g (yield: 85.9%) of LS-phenylethylcysteine. 5.3 g of the above compound obtained
(23.5 mmol) in methanol (200 ml) was added dropwise 8.6 ml of thionyl chloride under ice-cooling, and the reaction solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with diethyl ether, dried and dried to give the title compound (2) 6.
27 g (96.3% yield) were obtained.
【0049】NMR(δ,CD3 OD):7.20-7.31(m,
5H),4.25(dd,J=7.26Hz,J=4.23Hz,1H),3.83(s,3H),3.12
(dd,J=14.49Hz,J=4.23Hz,1H),3.00(dd,J=14.54Hz,J=7.2
7Hz,1H),2.82-2.94(m,4H) (参考例3)L−S−(3−フェニルプロピル)システ
インメチルエステル塩酸塩(化合物(3)) 参考例2に準じてシステイン塩酸塩水和物4.85g
(29.28mmol)ナトリウムメトキシド4.75g
(87.84mmol)、3−ブロモプロピルベンゼン5.
97g(30mmol)、塩化チオニル6.7mlを用いて標
記化合物(3)5.196gを得た。NMR (δ, CD 3 OD): 7.20-7.31 (m,
5H), 4.25 (dd, J = 7.26Hz, J = 4.23Hz, 1H), 3.83 (s, 3H), 3.12
(dd, J = 14.49Hz, J = 4.23Hz, 1H), 3.00 (dd, J = 14.54Hz, J = 7.2
7Hz, 1H), 2.82-2.94 (m, 4H) (Reference Example 3) L-S- (3-phenylpropyl) cysteine methyl ester hydrochloride (Compound (3)) Cysteine hydrochloride hydrate according to Reference Example 2 4.85g
(29.28 mmol) sodium methoxide 4.75 g
(87.84 mmol), 3-bromopropylbenzene 5.
Using 97 g (30 mmol) and 6.7 ml of thionyl chloride, 5.196 g of the title compound (3) was obtained.
【0050】NMR(δ,CD3 OD):7.16-7.30(m,
5H),4.27(dd,J=6.57Hz,J=4.18Hz,1H),3.82(s,3H),3.15
(dd,J=14.54Hz,J=4.18Hz,1H),3.03(dd,J=14.49Hz,J=7.5
4Hz,1H),2.73(t,J=7.33Hz,2H),2.58(t,J=7.54Hz,2H),1.
86-1.97(m,2H) (参考例4)L−O−(3−フェニルプロピル)セリン
エチルエステル塩酸塩(化合物(4)) L−N−(t−ブトキシカルボニル)セリン3g(1
4.6mmol)の無水ジメチルホルムアミド溶液に氷冷攪
拌下60%油性水素化ナトリウム1.28g(32mmo
l)を加え、室温に戻し2時間攪拌後、3−ブロモプロ
ピルベンゼン3.18g(16mmol)を加え一夜攪拌し
た。反応溶液を減圧下濃縮し残留物水に溶かしジエチル
エーテルで洗浄し、水層を1N−塩酸水溶液で酸性とし
酢酸エチルで抽出し、有機層を水で洗浄し無水硫酸ナト
リウムで乾燥し減圧下溶媒留去し得られた残留物をエタ
ノールに溶かし濃塩酸を加え一夜攪拌後塩化チオニル4
ml加え一夜攪拌した。減圧下溶媒留去し得られた結晶を
ジエチルエーテルで洗浄し乾燥後標記化合物(4)1.
13gを得た。NMR (δ, CD 3 OD): 7.16-7.30 (m,
5H), 4.27 (dd, J = 6.57Hz, J = 4.18Hz, 1H), 3.82 (s, 3H), 3.15
(dd, J = 14.54Hz, J = 4.18Hz, 1H), 3.03 (dd, J = 14.49Hz, J = 7.5
4Hz, 1H), 2.73 (t, J = 7.33Hz, 2H), 2.58 (t, J = 7.54Hz, 2H), 1.
86-1.97 (m, 2H) (Reference Example 4) L-O- (3-phenylpropyl) serine ethyl ester hydrochloride (compound (4)) LN- (t-butoxycarbonyl) serine 3 g (1
1.28 g (32 mmol) of 60% oily sodium hydride was added to an anhydrous dimethylformamide solution (4.6 mmol) under ice-cooling and stirring.
l) was added, and the mixture was returned to room temperature and stirred for 2 hours. Then, 3.18 g (16 mmol) of 3-bromopropylbenzene was added, and the mixture was stirred overnight. The reaction solution is concentrated under reduced pressure, the residue is dissolved in water, washed with diethyl ether, the aqueous layer is acidified with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, the organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue obtained by evaporation was dissolved in ethanol, concentrated hydrochloric acid was added, and the mixture was stirred overnight, and then thionyl chloride was added.
ml and stirred overnight. The crystals obtained by evaporating the solvent under reduced pressure were washed with diethyl ether and dried, and then the title compound (4) 1.
13 g were obtained.
【0051】NMR(δ,CD3 OD):7.15-7.28(m,
5H),4.32(q,J=6.52Hz,2H),4.25(t,J=1.68Hz,1H),3.92(d
d,J=10.91Hz,J=4.40Hz,1H),3.82(dd,J=10.04Hz,J=2.82H
z,1H),3.44-3.59(m,2H),2.67(t,J=7.32,2H),1.85-1.95
(m,2H),1.32(t,J=7.49,3H) (参考例5)L−O−(チオフェン−3−イルメチル)
セリンエチルエステル塩酸塩(化合物(5)) 参考例4に準じL−Boc−Ser−OH40g(1
9.5mmol)60%油性水素化ナトリウム172g(4
3mmol)、3−ブロモメチルチオフェン4.44g(2
5mmol)、濃塩酸2.2g及び塩化チオニル2.3mlを
用いて標記化合物(5)1.25gを得た。NMR (δ, CD 3 OD): 7.15-7.28 (m,
5H), 4.32 (q, J = 6.52Hz, 2H), 4.25 (t, J = 1.68Hz, 1H), 3.92 (d
d, J = 10.91Hz, J = 4.40Hz, 1H), 3.82 (dd, J = 10.04Hz, J = 2.82H
z, 1H), 3.44-3.59 (m, 2H), 2.67 (t, J = 7.32,2H), 1.85-1.95
(m, 2H), 1.32 (t, J = 7.49,3H) (Reference Example 5) LO- (thiophen-3-ylmethyl)
Serine ethyl ester hydrochloride (compound (5)) 40 g of L-Boc-Ser-OH (1
9.5 mmol) 172 g of 60% oily sodium hydride (4
3 mmol), 4.44 g of 3-bromomethylthiophene (2
5 mmol), 2.2 g of concentrated hydrochloric acid and 2.3 ml of thionyl chloride to obtain 1.25 g of the title compound (5).
【0052】NMR(δ,CD3 OD):7.36-7.42(m,
2H),7.08-7.10(m,1H),4.60(q,J=12.21Hz,2H),4.27(q,J=
7.11Hz,1H),4.21(t,J=3.18Hz,1H),3.90(dd,J=4.32Hz,J=
9.87Hz,1H),3.81(dd,J=3.27Hz,J=10.47Hz,1H),1.27(t,J
=7.11Hz,3H) (参考例6)L−S−(ジフェニルメチル)システイン
メチルエステル塩酸塩(化合物(6)) L−システイン塩酸塩水和物3.0g(17.1mmol)
とジフェニルメタノール3.15g(17.1mmol)を
トリフルオロ酢酸40mlに加え室温で1時間攪拌した。
減圧下トリフルオロ酢酸を留去し残留物にジエチルエー
テルを加え結晶化し、水、エタノール、ジエチルエーテ
ルで洗浄後減圧下乾燥させL−S−ジフェニルメチルシ
ステイン5.2g(収率〜100%)を得た。得られた
上記化合物1.0g(3.5mmol)のメタノール溶液に
氷冷下塩化チオニル1.0mlを滴下し滴下後反応溶液を
室温に上げ一夜攪拌した。減圧下溶媒留去し得られた結
晶をジエチルエーテルで洗浄して標記化合物(6)1.
11g(収率〜100%)を得た。NMR (δ, CD 3 OD): 7.36-7.42 (m,
2H), 7.08-7.10 (m, 1H), 4.60 (q, J = 12.21Hz, 2H), 4.27 (q, J =
7.11Hz, 1H), 4.21 (t, J = 3.18Hz, 1H), 3.90 (dd, J = 4.32Hz, J =
9.87Hz, 1H), 3.81 (dd, J = 3.27Hz, J = 10.47Hz, 1H), 1.27 (t, J
(7.11 Hz, 3H) (Reference Example 6) L-S- (diphenylmethyl) cysteine methyl ester hydrochloride (compound (6)) L-cysteine hydrochloride hydrate 3.0 g (17.1 mmol)
And 3.15 g (17.1 mmol) of diphenylmethanol were added to 40 ml of trifluoroacetic acid, followed by stirring at room temperature for 1 hour.
The trifluoroacetic acid was distilled off under reduced pressure, and diethyl ether was added to the residue for crystallization. Obtained. Thionyl chloride (1.0 ml) was added dropwise to a methanol solution of the obtained compound (1.0 g, 3.5 mmol) under ice-cooling. After the dropwise addition, the reaction solution was raised to room temperature and stirred overnight. The crystals obtained by evaporating the solvent under reduced pressure were washed with diethyl ether to give the title compound (6) 1.
11 g (yield ~ 100%) were obtained.
【0053】NMR(δ,CDCl3 ):7.41-7.44(m,
4H),7.15-7.29(m,6H),5.42(s,1H),4.22-4.32(m,1H),3.6
1(s,3H),2.98-3.03(m,2H),2.78-2.89(m,2H) (参考例7)L−S−(シクロヘキシルメチル)システ
インエチルエステル塩酸塩(化合物(7)) 参考例2に準じた方法で2−ブロモエチルベンゼンのか
わりにシクロヘキシルメチルブロミドを用い標記化合物
(7)を得た。NMR (δ, CDCl 3 ): 7.41-7.44 (m,
4H), 7.15-7.29 (m, 6H), 5.42 (s, 1H), 4.22-4.32 (m, 1H), 3.6
1 (s, 3H), 2.98-3.03 (m, 2H), 2.78-2.89 (m, 2H) (Reference Example 7) L-S- (cyclohexylmethyl) cysteine ethyl ester hydrochloride (Compound (7)) Reference Example The title compound (7) was obtained in the same manner as in Example 2, except that cyclohexylmethyl bromide was used instead of 2-bromoethylbenzene.
【0054】NMR(δ,CDCl3 ):4.35-4.39(m,
1H),4.30(q,J=7.17Hz,2H),3.24(d,J=5.22Hz,2H),2.50(d
d,J=6.90Hz,J=3.18,2H),2.20-2.65(m,2H),1.38-1.88(m,
5H),1.33(t,J=14.28,J=7.17,3H),0.87-1.28(m,6H) (参考例8)L−S−(シクロペンチル)システインエ
チルエステル塩酸塩(化合物(8)) 参考例2に準じ2−ブロモエチルベンゼンのかわりにシ
クロペンチルブロミドを用い標記化合物(8)を得た。NMR (δ, CDCl 3 ): 4.35-4.39 (m,
1H), 4.30 (q, J = 7.17Hz, 2H), 3.24 (d, J = 5.22Hz, 2H), 2.50 (d
d, J = 6.90Hz, J = 3.18,2H), 2.20-2.65 (m, 2H), 1.38-1.88 (m,
5H), 1.33 (t, J = 14.28, J = 7.17, 3H), 0.87-1.28 (m, 6H) (Reference Example 8) L-S- (cyclopentyl) cysteine ethyl ester hydrochloride (Compound (8)) Reference The title compound (8) was obtained according to Example 2 using cyclopentyl bromide instead of 2-bromoethylbenzene.
【0055】NMR(δ,CD3 OD):4.44(t,J=5.1
9Hz,1H),4.32(t,J=6.99Hz,2H),4.27-4.29(m,1H),3.31-
3.46(m,4H),3.17(dd,J=17.19,J=4.77,1H),3.07(dd,J=1
3.91,J=6.99,1H),2.00-2.11(m,1H),1.72-1.81(m,1H),1.
46-1.68(m,2H),1.35(t,J=7.20Hz,3H) (参考例9)L−S−(チオフェン−2−イルメチル)
システインメチルエステル塩酸塩(化合物(9)) 参考例2に準じた方法で2−ブロモエチルベンゼンのか
わりに2−クロロメチルチオフェンを用い標記化合物
(9)を得た。NMR (δ, CD 3 OD): 4.44 (t, J = 5.1
9Hz, 1H), 4.32 (t, J = 6.99Hz, 2H), 4.27-4.29 (m, 1H), 3.31-
3.46 (m, 4H), 3.17 (dd, J = 17.19, J = 4.77,1H), 3.07 (dd, J = 1
3.91, J = 6.99,1H), 2.00-2.11 (m, 1H), 1.72-1.81 (m, 1H), 1.
46-1.68 (m, 2H), 1.35 (t, J = 7.20 Hz, 3H) (Reference Example 9) L-S- (thiophen-2-ylmethyl)
Cysteine methyl ester hydrochloride (compound (9)) The title compound (9) was obtained in the same manner as in Reference Example 2 except that 2-chloromethylthiophene was used instead of 2-bromoethylbenzene.
【0056】NMR(δ,CD3 OD):7.34(dd,J=5.
26Hz,J=1.36Hz,1H),7.04(d,J=4.56Hz,1H),6.95(dd,J=5.
04Hz,J=1.62Hz,1H),4.22(dd,J=7.92Hz,J=4.5Hz,1H),4.0
6(d,J=3.31Hz,2H),3.84(s,3H),3.10(dd,J=14.81Hz,J=4.
56Hz,1H),2.96(dd,J=14.92Hz,J=8.03Hz,1H) (参考例10)L−S−(チオフェン−3−イルメチ
ル)システインエチルエステル塩酸塩(化合物(1
0)) 参考例2に準じた方法で2−ブロモエチルベンゼンのか
わりに3−ブロモメチルチオフェンを用いて標記化合物
(10)を得た。NMR (δ, CD 3 OD): 7.34 (dd, J = 5.
26Hz, J = 1.36Hz, 1H), 7.04 (d, J = 4.56Hz, 1H), 6.95 (dd, J = 5.
04Hz, J = 1.62Hz, 1H), 4.22 (dd, J = 7.92Hz, J = 4.5Hz, 1H), 4.0
6 (d, J = 3.31Hz, 2H), 3.84 (s, 3H), 3.10 (dd, J = 14.81Hz, J = 4.
56Hz, 1H), 2.96 (dd, J = 14.92Hz, J = 8.03Hz, 1H) (Reference Example 10) LS- (thiophen-3-ylmethyl) cysteine ethyl ester hydrochloride (compound (1
0)) The title compound (10) was obtained in the same manner as in Reference Example 2 except that 3-bromomethylthiophene was used instead of 2-bromoethylbenzene.
【0057】NMR(δ,CD3 OD):7.41(dd,J=4.
95Hz,J=2.01Hz,1H),7.32(br,s,1H),7.12(d,J=4.89Hz,1
H),4.29(q,J=7.26Hz,2H),4.14(dd,J=8.04Hz,J=3.57Hz,1
H),3.87(s,2H),3.03(dd,J=14.76Hz,J=4.5Hz,1H),2.90(d
d,J=14.82Hz,J=8.13Hz,1H),1.31(t,J=7.23Hz,3H) (参考例11)L−S−(1−ナフチルメチル)システ
インエチルエステル塩酸塩(化合物(11)) 参考例2に準じた方法で2−ブロモエチルベンゼンのか
わりに1−ナフチルメチルブロミドを用いて標記化合物
(11)を得た。NMR (δ, CD 3 OD): 7.41 (dd, J = 4.
95Hz, J = 2.01Hz, 1H), 7.32 (br, s, 1H), 7.12 (d, J = 4.89Hz, 1
H), 4.29 (q, J = 7.26Hz, 2H), 4.14 (dd, J = 8.04Hz, J = 3.57Hz, 1
H), 3.87 (s, 2H), 3.03 (dd, J = 14.76Hz, J = 4.5Hz, 1H), 2.90 (d
d, J = 14.82 Hz, J = 8.13 Hz, 1H), 1.31 (t, J = 7.23 Hz, 3H) (Reference Example 11) L-S- (1-naphthylmethyl) cysteine ethyl ester hydrochloride (compound (11 )) The title compound (11) was obtained in the same manner as in Reference Example 2, except that 1-naphthylmethyl bromide was used instead of 2-bromoethylbenzene.
【0058】NMR(δ,CD3 OD):8.18(d,J=8.3
7Hz,1H),7.80-7.90(m,2H),7.35-7.58(m,4H),4.33(s,2
H),4.17-4.29(m,3H),3.04(dd,J=4.44Hz,J=9.72,1H),2.9
5(dd,J=7.80Hz,J=14.64Hz,1H),1.25(t,J=7.02Hz,3H) (参考例12)L−S−(2−ナフチルメチル)システ
インエチルエステル塩酸塩(化合物(12)) 参考例2に準じた方法で2−ブロモエチルベンゼンのか
わりに2−ナフチルメチルブロミドを用いて標記化合物
(12)を得た。NMR (δ, CD 3 OD): 8.18 (d, J = 8.3
7Hz, 1H), 7.80-7.90 (m, 2H), 7.35-7.58 (m, 4H), 4.33 (s, 2
H), 4.17-4.29 (m, 3H), 3.04 (dd, J = 4.44Hz, J = 9.72,1H), 2.9
5 (dd, J = 7.80Hz, J = 14.64Hz, 1H), 1.25 (t, J = 7.02Hz, 3H) (Reference Example 12) L-S- (2-naphthylmethyl) cysteine ethyl ester hydrochloride (compound (12)) The title compound (12) was obtained in the same manner as in Reference Example 2 except that 2-naphthylmethyl bromide was used instead of 2-bromoethylbenzene.
【0059】NMR(δ,CD3 OD):7.81-7.88(m,
4H),7.47-7.55(m,3H),4.21-4.25(m,2H),4.13-4.20(m,1
H),4.00(s,2H),3.01(dd,J=9.78Hz,J=4.38Hz,1H),2.89(d
d,J=8.19Hz,J=6.39Hz,1H),1.22(t,J=7.05Hz,3H) (参考例13)L−S−(2−クロロベンジル)システ
インエチルエステル塩酸塩(化合物(13)) 参考例2に準じた方法で2−ブロモエチルベンゼンのか
わりに2−クロロベンジルクロリドを用い標記化合物
(13)を得た。NMR (δ, CD 3 OD): 7.81 to 7.88 (m,
4H), 7.47-7.55 (m, 3H), 4.21-4.25 (m, 2H), 4.13-4.20 (m, 1
H), 4.00 (s, 2H), 3.01 (dd, J = 9.78Hz, J = 4.38Hz, 1H), 2.89 (d
d, J = 8.19 Hz, J = 6.39 Hz, 1 H), 1.22 (t, J = 7.05 Hz, 3 H) (Reference Example 13) LS- (2-chlorobenzyl) cysteine ethyl ester hydrochloride (compound (13 )) The title compound (13) was obtained in the same manner as in Reference Example 2 except that 2-chlorobenzyl chloride was used instead of 2-bromoethylbenzene.
【0060】NMR(δ,CD3 OD):7.41-7.48(m,
2H),7.28-7.31(m,2H),4.30(q,J=7.33Hz,2H),4.25-4.29
(m,1H),3.12(dd,J=14.71Hz,J=4.45Hz,1H),2.97(dd,J=1
4.65Hz,J=7.86Hz,1H),1.31(t,J=7.16Hz,3H) (参考例14)(2R)−2−アミノ−3(2−フルオ
ロベンジルチオ)プロパノール(化合物(14)) 金属ナトリウム12.0g(519mmol)とメタノール
700mlより調製したナトリウムメトキシドのメタノー
ル溶液にL−システイン塩酸塩・水和物30.4g(1
73mmol)を加えた。次いで2−フルオロベンジルクロ
リド25.0g(173mmol)を滴下し、さらに室温で
一夜攪拌した。減圧下メタノールを留去して得られた残
留物を水に溶かしエーテルで2回洗浄後濃塩酸を加え
(pH=7)、析出した結晶を濾取し水、エタノール次い
でジエチルエーテルで洗浄し減圧下乾燥させ(2R)−
2−アミノ−3(2−フルオロベンジルチオ)プロピオ
ニックアシド29.7g(収率74.8%)を得た。水
素化ホウ素リチウム0.58g(26.4mmol)の無水
テトラヒドロフラン溶液にクロロトリメチルシラン6.
7ml(52.8mmol)を加え室温で30分攪拌した。そ
の混合溶液に(2R)−2−アミノ−3(2−フルオロ
ベンジルチオプロピオニックアシド2.02g(8.8
mmol)を加え室温で一夜攪拌した。反応溶液にメタノー
ルを加え減圧下溶媒留去した。得られた残留物を1N−
水酸化ナトリウム水溶液に溶かしクロロホルムにて抽出
した。無水硫酸ナトリウムで乾燥後、減圧下溶媒留去し
標記化合物(14)1.69g(収率89.4%)を得
た。NMR (δ, CD 3 OD): 7.41-7.48 (m,
2H), 7.28-7.31 (m, 2H), 4.30 (q, J = 7.33Hz, 2H), 4.25-4.29
(m, 1H), 3.12 (dd, J = 14.71Hz, J = 4.45Hz, 1H), 2.97 (dd, J = 1
4.65 Hz, J = 7.86 Hz, 1 H), 1.31 (t, J = 7.16 Hz, 3 H) (Reference Example 14) (2R) -2-amino-3 (2-fluorobenzylthio) propanol (compound (14)) To a methanol solution of sodium methoxide prepared from 12.0 g (519 mmol) of metallic sodium and 700 ml of methanol, 30.4 g of L-cysteine hydrochloride hydrate (1
73 mmol) was added. Then, 25.0 g (173 mmol) of 2-fluorobenzyl chloride was added dropwise, and the mixture was further stirred at room temperature overnight. The residue obtained by distilling off methanol under reduced pressure was dissolved in water, washed twice with ether, concentrated hydrochloric acid was added (pH = 7), and the precipitated crystals were collected by filtration, washed with water, ethanol and diethyl ether, and then reduced in pressure. Dry under (2R)-
29.7 g (yield 74.8%) of 2-amino-3 (2-fluorobenzylthio) propionic acid was obtained. 5. To a solution of 0.58 g (26.4 mmol) of lithium borohydride in anhydrous tetrahydrofuran was added chlorotrimethylsilane.
7 ml (52.8 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 2.02 g (8.8 g) of (2R) -2-amino-3 (2-fluorobenzylthiopropionic acidide was added to the mixed solution.
mmol) and stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue obtained is 1N-
It was dissolved in aqueous sodium hydroxide solution and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.69 g (yield: 89.4%) of the title compound (14).
【0061】NMR(δ,CDCl3 ):7.19-7.36(m,
2H),7.00-7.12(m,2H),3.75(s,2H),3.65(dd,J=10.86Hz,J
=3.78Hz,1H),3.42(dd,J=10.74Hz,J=6.45Hz,1H),3.00-3.
10(m,1H),2.80(br,s,3H),2.62(dd,J=13.56Hz,J=4.92Hz,
1H),2.45(dd,J=13.35Hz,J=8.22Hz,1H) (参考例15)(2R)−2−アミノ−3(3−クロロ
ベンジルチオ)プロパノール(化合物(15)) 参考例14に準じた方法で2−フルオロベンジルクロリ
ドのかわりに3−クロロベンジルブロミドを用い標記化
合物(15)を得た。NMR (δ, CDCl 3 ): 7.19-7.36 (m,
2H), 7.00-7.12 (m, 2H), 3.75 (s, 2H), 3.65 (dd, J = 10.86Hz, J
= 3.78Hz, 1H), 3.42 (dd, J = 10.74Hz, J = 6.45Hz, 1H), 3.00-3.
10 (m, 1H), 2.80 (br, s, 3H), 2.62 (dd, J = 13.56Hz, J = 4.92Hz,
1H), 2.45 (dd, J = 13.35 Hz, J = 8.22 Hz, 1H) (Reference Example 15) (2R) -2-amino-3 (3-chlorobenzylthio) propanol (Compound (15)) Reference Example 14 The title compound (15) was obtained using 3-chlorobenzyl bromide instead of 2-fluorobenzyl chloride according to a method similar to that described above.
【0062】NMR(δ,CDCl3 ):7.15-7.35(m,
4H),3.68(s,2H),3.64(d,J=3.52Hz,1H),3.44(dd,J=6.45H
z,J=10.85Hz,1H),2.98(br s,4H),2.60(dd,J=5.21Hz,J=1
3.4Hz,1H),2.45(dd,J=8.08Hz,J=13.45Hz,1H) (参考例16)(2R)−2−アミノ−3(4−クロロ
ベンジルチオ)プロパノール(化合物(16)) 参考例14に準じた方法で2−フルオロベンジルクロリ
ドのかわりに4−クロロベンジルクロリドを用い標記化
合物(16)を得た。NMR (δ, CDCl 3 ): 7.15-7.35 (m,
4H), 3.68 (s, 2H), 3.64 (d, J = 3.52Hz, 1H), 3.44 (dd, J = 6.45H
z, J = 10.85Hz, 1H), 2.98 (br s, 4H), 2.60 (dd, J = 5.21Hz, J = 1
(3.4 Hz, 1H), 2.45 (dd, J = 8.08 Hz, J = 13.45 Hz, 1H) (Reference Example 16) (2R) -2-amino-3 (4-chlorobenzylthio) propanol (compound (16)) The title compound (16) was obtained in the same manner as in Reference Example 14 except that 4-chlorobenzyl chloride was used instead of 2-fluorobenzyl chloride.
【0063】NMR(δ,CDCl3 ):7.26(q,J=8.5
2,4H),3.68(s,2H),3.60(dd,J=4.02Hz,J=10.75Hz,1H),3.
38(dd,J=6.46Hz,J=10.8Hz,1H),2.96(br s,1H),2.54(dd,
J=4.77Hz,J=13.18Hz,1H),2.36(dd,J=8.25Hz,J=13.35Hz,
1H),2.24(br s,3H) (参考例17)L−2−アミノ−3(3−フルオロベン
ジルチオ)プロパノール(化合物(17)) 参考例14に準じた方法で2−フルオロベンジルクロリ
ドのかわりに3−フルオロベンジルクロリドを用い標記
化合物(17)を得た。NMR (δ, CDCl 3 ): 7.26 (q, J = 8.5
2,4H), 3.68 (s, 2H), 3.60 (dd, J = 4.02Hz, J = 10.75Hz, 1H), 3.
38 (dd, J = 6.46Hz, J = 10.8Hz, 1H), 2.96 (br s, 1H), 2.54 (dd,
J = 4.77Hz, J = 13.18Hz, 1H), 2.36 (dd, J = 8.25Hz, J = 13.35Hz,
1H), 2.24 (br s, 3H) (Reference Example 17) L-2-amino-3 (3-fluorobenzylthio) propanol (compound (17)) Instead, 3-fluorobenzyl chloride was used to obtain the title compound (17).
【0064】NMR(δ,CDCl3 ):7.21〜7.28
(m,1H),6.89 〜7.10(m,3H),4.76(s,3H),3.76(dd,J=3.42
Hz,J=11.5Hz,1H),3.72(s,2H),3.57(dd,J=7.82Hz,J=12.5
9Hz,1H),3.25(br s,1H),2.62(d,J=7.05Hz,2H) (参考例18)(2R)−2−アミノ−3(4−フルオ
ロベンジルチオ)プロパノール(化合物(18)) 参考例14に準じた方法で2−フルオロベンジルクロリ
ドのかわりに4−フルオロベンジルクロリドを用い標記
化合物(18)を得た。NMR (δ, CDCl 3 ): 7.21 to 7.28
(m, 1H), 6.89-7.10 (m, 3H), 4.76 (s, 3H), 3.76 (dd, J = 3.42
Hz, J = 11.5Hz, 1H), 3.72 (s, 2H), 3.57 (dd, J = 7.82Hz, J = 12.5
9 Hz, 1H), 3.25 (brs, 1H), 2.62 (d, J = 7.05 Hz, 2H) (Reference Example 18) (2R) -2-amino-3 (4-fluorobenzylthio) propanol (compound (18 )) The title compound (18) was obtained in the same manner as in Reference Example 14 except that 4-fluorobenzyl chloride was used instead of 2-fluorobenzyl chloride.
【0065】NMR(δ,CDCl3 ):7.25〜7.30
(m,2H),6.97 〜7.03(m,2H),3.69(s,2H),3.60(dd,J=4.23
Hz,J=10.74Hz,1H),3.37(dd,J=6.57Hz,J=10.74Hz,1H),2.
95(brs,1H),2.55(dd,J=4.93Hz,J=13.29Hz,1H),2.01(br
d,J=10.25Hz,3H),2.36(dd,J=8.31Hz,13.30Hz,1H) (参考例19)(2R)−2−アミノ−3(2−メトキ
シベンジルチオ)プロパノール(化合物(19)) 参考例14に準じた方法で2−フルオロベンジルクロリ
ドのかわりに2−メトキシベンジルクロリドを用い標記
化合物(19)を得た。NMR (δ, CDCl 3 ): 7.25 to 7.30
(m, 2H), 6.97 〜7.03 (m, 2H), 3.69 (s, 2H), 3.60 (dd, J = 4.23
Hz, J = 10.74Hz, 1H), 3.37 (dd, J = 6.57Hz, J = 10.74Hz, 1H), 2.
95 (brs, 1H), 2.55 (dd, J = 4.93Hz, J = 13.29Hz, 1H), 2.01 (br
d, J = 10.25 Hz, 3H), 2.36 (dd, J = 8.31 Hz, 13.30 Hz, 1H) (Reference Example 19) (2R) -2-amino-3 (2-methoxybenzylthio) propanol (compound (19 )) The title compound (19) was obtained in the same manner as in Reference Example 14 except that 2-methoxybenzyl chloride was used instead of 2-fluorobenzyl chloride.
【0066】NMR(δ,CDCl3 ):7.21〜7.26
(m,2H),6.86 〜6.94(m,2H),3.85(s,3H),3.74(s,2H),3.6
2(dd,J=10.74Hz,J=4.13Hz,1H),3.37(dd,J=10.74Hz,J=6.
73,1H),2.97-3.05(m,1H),2.62(dd,J=13.51Hz,J=4.83Hz,
1H),2.40(dd,J=13.57Hz,J=8.31Hz,1H),2.08(br s,3H) (参考例20)(2R)−2−アミノ−3(3−メトキ
シベンジルチオ)プロパノール(化合物(20)) 参考例14に準じた方法で2−フルオロベンジルクロリ
ドのかわりに3−メトキシベンジルクロリドを用い標記
化合物(20)を得た。NMR (δ, CDCl 3 ): 7.21 to 7.26
(m, 2H), 6.86 to 6.94 (m, 2H), 3.85 (s, 3H), 3.74 (s, 2H), 3.6
2 (dd, J = 10.74Hz, J = 4.13Hz, 1H), 3.37 (dd, J = 10.74Hz, J = 6.
73,1H), 2.97-3.05 (m, 1H), 2.62 (dd, J = 13.51Hz, J = 4.83Hz,
1H), 2.40 (dd, J = 13.57 Hz, J = 8.31 Hz, 1H), 2.08 (brs, 3H) (Reference Example 20) (2R) -2-amino-3 (3-methoxybenzylthio) propanol ( Compound (20)) The title compound (20) was obtained in the same manner as in Reference Example 14 except that 3-methoxybenzyl chloride was used instead of 2-fluorobenzyl chloride.
【0067】NMR(δ,CDCl3 ):7.22(t,J=8.2
5,1H),6.88(d,J=6.68Hz,1H),6.86(s,1H),6.79(dd,J=2.0
6Hz,J=7.48Hz,1H),3.80(s,3H),3.68(s,2H),3.58(dd,J=
4.18Hz,J=10.8Hz,1H),3.36(dd,J=6.62Hz,J=10.75Hz,1
H),2.90〜3.00(m,1H),2.56(dd,J=4.88Hz,J=13.29Hz,1
H),2.36(dd,J=8.19Hz,J=13.35Hz,1H),2.11(br s,3H) (参考例21)(2R)−2−アミノ−3(4−メトキ
シベンジルチオ)プロパノール(化合物(21)) 参考例14に準じた方法で2−フルオロベンジルクロリ
ドのかわりに4−メトキシベンジルクロリドを用い標記
化合物(21)を得た。NMR (δ, CDCl 3 ): 7.22 (t, J = 8.2
5,1H), 6.88 (d, J = 6.68Hz, 1H), 6.86 (s, 1H), 6.79 (dd, J = 2.0
6Hz, J = 7.48Hz, 1H), 3.80 (s, 3H), 3.68 (s, 2H), 3.58 (dd, J =
4.18Hz, J = 10.8Hz, 1H), 3.36 (dd, J = 6.62Hz, J = 10.75Hz, 1
H), 2.90 to 3.00 (m, 1H), 2.56 (dd, J = 4.88 Hz, J = 13.29 Hz, 1
H), 2.36 (dd, J = 8.19 Hz, J = 13.35 Hz, 1H), 2.11 (brs, 3H) (Reference Example 21) (2R) -2-amino-3 (4-methoxybenzylthio) propanol ( Compound (21)) The title compound (21) was obtained in the same manner as in Reference Example 14 except that 4-methoxybenzyl chloride was used instead of 2-fluorobenzyl chloride.
【0068】NMR(δ,CDCl3 ):7.22(d,J=8.6
3Hz,2H),6.85(d,J=8.63Hz,2H),3.80(s,3H),3.67(s,2H),
3.59(dd,J=4.13Hz,J=10.74Hz,1H),3.36(dd,J=6.62Hz,J=
10.75Hz,1H),2.90〜2.98(m,1H),2.55(dd,J=4.88Hz,J=1
3.29Hz,1H),2.36(dd,J=8.24Hz,J=13.29Hz,1H),1.99(s,3
H) (参考例22)(2R)−2−アミノ−3(3−ニトロ
ベンジルチオ)プロパノール(化合物(22)) 参考例14に準じた方法で2−フルオロベンジルクロリ
ドのかわりに3−ニトロベンジルクロリドを用い標記化
合物(22)を得た。NMR (δ, CDCl 3 ): 7.22 (d, J = 8.6
3Hz, 2H), 6.85 (d, J = 8.63Hz, 2H), 3.80 (s, 3H), 3.67 (s, 2H),
3.59 (dd, J = 4.13Hz, J = 10.74Hz, 1H), 3.36 (dd, J = 6.62Hz, J =
10.75Hz, 1H), 2.90-2.98 (m, 1H), 2.55 (dd, J = 4.88Hz, J = 1
3.29Hz, 1H), 2.36 (dd, J = 8.24Hz, J = 13.29Hz, 1H), 1.99 (s, 3
H) (Reference Example 22) (2R) -2-Amino-3 (3-nitrobenzylthio) propanol (compound (22)) In the same manner as in Reference Example 14, 3-nitrobenzyl was used instead of 2-fluorobenzyl chloride. The title compound (22) was obtained using chloride.
【0069】NMR(δ,CDCl3 ):8.20(s,1H),
8.13(d,J=8.24Hz,1H),7.67(d,J=7.75Hz,1H),7.51(t,J=
7.87Hz,1H),3.81(s,2H),3.62(dd,J=10.75Hz,J=4.24Hz,1
H),3.42(dd,J=10.75Hz,J=6.35Hz,1H),3.00-3.08(m,1H),
2.58(dd,J=13.18Hz,J=4.94Hz,1H),2.41(dd,J=13.23Hz,J
=8.13Hz,1H),2.05(br s,3H) (参考例23)(2R)−2−アミノ−3(4−ニトロ
ベンジルチオ)プロパノール(化合物(23)) L−システイン塩酸塩水和物5.27g(30mmol)を
1N−水酸化ナトリウム水溶液に加え、次いで4−ニト
ロベンジルクロリド5.15g(30mmol)のジオキサ
ン溶液を滴下して室温で1時間攪拌した。反応溶液をジ
エチルエーテル洗浄し、濃塩酸で弱酸性とし冷却したと
ころ結晶が析出した結晶を濾過しエタノール次いでジエ
チルエーテル洗浄し減圧下乾燥しL−2−アミノ−3
(4−ニトロベンジルチオ)プロピオニックアシド3.
55g(収率45.9%)を得た。アルコール体への変
換反応は参考例14に準じた方法を用いて標記化合物
(23)を得た。NMR (δ, CDCl 3 ): 8.20 (s, 1H),
8.13 (d, J = 8.24Hz, 1H), 7.67 (d, J = 7.75Hz, 1H), 7.51 (t, J =
7.87Hz, 1H), 3.81 (s, 2H), 3.62 (dd, J = 10.75Hz, J = 4.24Hz, 1
H), 3.42 (dd, J = 10.75Hz, J = 6.35Hz, 1H), 3.00-3.08 (m, 1H),
2.58 (dd, J = 13.18Hz, J = 4.94Hz, 1H), 2.41 (dd, J = 13.23Hz, J
= 8.13Hz, 1H), 2.05 (brs, 3H) (Reference Example 23) (2R) -2-amino-3 (4-nitrobenzylthio) propanol (compound (23)) L-cysteine hydrochloride hydrate 5 .27 g (30 mmol) were added to a 1N aqueous solution of sodium hydroxide, and then a solution of 5.15 g (30 mmol) of 4-nitrobenzyl chloride in dioxane was added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made weakly acidic with concentrated hydrochloric acid, and cooled. Crystals precipitated were filtered, washed with ethanol and then with diethyl ether, dried under reduced pressure, and dried under reduced pressure.
(4-nitrobenzylthio) propionic acid3.
55 g (45.9% yield) were obtained. The title compound (23) was obtained by a method similar to that in Reference Example 14 for the conversion reaction to the alcohol compound.
【0070】NMR(δ,CDCl3 ):8.19(d,J=8.6
3Hz,2H),7.50(d,J=8.69Hz,2H),3.80(s,2H),3.60(dd,J=
4.18Hz,J=10.74Hz,1H),3.40(dd,J=6.35Hz,J=10.74Hz,1
H),2.92-3.02(m,1H),2.57(dd,J=4.94Hz,J=13.19Hz,1H),
2.39(dd,J=8.13Hz,J=13.18Hz,1H),2.01(s,3H) (参考例24)(2S)−2−アミノ−4−フェニルオ
キシブタノール塩酸塩(化合物(24)) (Tetrahedron Letters 20巻,
2243,1978年の方法に従って合成した)L−N
−(t−ブトキシカルボニル)−ホモセリンカリウム塩
142g(0.59 mol)の無水ジメチルホルムアミド
溶液にエチルブロミド320g(2.94 mol)を滴下
して加え室温にて一夜攪拌した。減圧下溶媒留去して、
得られた残留物を水にとかし酢酸エチルで抽出し飽和食
塩水で洗浄後、無水硫酸ナトリウムで乾燥して、減圧下
溶媒留去した。得られた残留物をシリカゲルカラムクロ
マトグラフィーにて精製しL−N−(t−ブトキシカル
ボニル)−ホモセリンエチルエステルを44.5g(収
率31%)を得た。上記で得た化合物6.18g(25
mmol)とトリエチルアミン3.04g(30mmol)の酢
酸エチル溶液に氷冷攪拌下メタンスルホニルクロリド
3.44g(30mmol)を加え1時間攪拌した。反応溶
液を水洗し無水硫酸ナトリウムで乾燥後減圧下濃縮する
ことによりメタンスルホナート体を8.12g(収率〜
100%)を得た。フェノール0.88gの無水ジメチ
ルホルムアミド溶液に60%油性水素化ナトリウム0.
35gを加え1時間攪拌した後先の反応で得たメタンス
ルホナート体2.55g(7.83mmol)のジメチルホ
ルムアミド溶液を滴下し室温で一夜攪拌した。反応溶液
に飽和NH4 Cl水を加え酢酸エチルで抽出し飽和炭酸
水素ナトリウム水溶液、次いで水で洗浄した。無水硫酸
ナトリウムで乾燥後溶媒留去し得られる残留物をシリカ
ゲルカラムクロマトグラフィーで精製しL−N−(t−
ブトキシカルボニル)−O−フェニルホモセリンエチル
エステル2.13g(収率84%)を得た。NMR (δ, CDCl 3 ): 8.19 (d, J = 8.6
3Hz, 2H), 7.50 (d, J = 8.69Hz, 2H), 3.80 (s, 2H), 3.60 (dd, J =
4.18Hz, J = 10.74Hz, 1H), 3.40 (dd, J = 6.35Hz, J = 10.74Hz, 1
H), 2.92-3.02 (m, 1H), 2.57 (dd, J = 4.94Hz, J = 13.19Hz, 1H),
2.39 (dd, J = 8.13 Hz, J = 13.18 Hz, 1H), 2.01 (s, 3H) (Reference Example 24) (2S) -2-amino-4-phenyloxybutanol hydrochloride (compound (24)) ( Tetrahedron Letters, Volume 20,
2243, synthesized according to the method of 1978) LN
To a solution of potassium salt of-(t-butoxycarbonyl) -homoserine 142 g (0.59 mol) in anhydrous dimethylformamide, 320 g (2.94 mol) of ethyl bromide was added dropwise, and the mixture was stirred at room temperature overnight. The solvent is distilled off under reduced pressure,
The obtained residue was dissolved in water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 44.5 g (yield: 31%) of LN- (t-butoxycarbonyl) -homoserine ethyl ester. 6.18 g of the compound obtained above (25
3.44 g (30 mmol) of triethylamine and 3.04 g (30 mmol) of triethylamine were added with 3.44 g (30 mmol) of methanesulfonyl chloride under ice-cooling with stirring. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8.12 g of a methanesulfonate compound (yield to
100%). To a solution of 0.88 g of phenol in anhydrous dimethylformamide was added 60% oily sodium hydride.
After adding 35 g and stirring for 1 hour, a dimethylformamide solution of 2.55 g (7.83 mmol) of the methanesulfonate obtained in the previous reaction was added dropwise, and the mixture was stirred at room temperature overnight. Saturated aqueous NH 4 Cl was added to the reaction solution, and the mixture was extracted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution and then with water. After drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue obtained is purified by silica gel column chromatography to obtain LN- (t-
2.13 g (yield 84%) of (butoxycarbonyl) -O-phenylhomoserine ethyl ester was obtained.
【0071】NMR(δ,CDCl3 ):7.20-7.30(m,
2H),6.83-6.97(m,3H),5.34-5.42(m,1H),4.45-4.52(m,1
H),4.18(q,J=7.22Hz,2H),4.04(t,J=6.08Hz,2H),2.20-2.
37(m,2H),1.44(s,9H),1.25(t,J=7.06Hz,3H) 上記化合物2.10g(6.5mmol)のテトラヒドロフ
ラン溶液に水素化ホウ素リチウム0.28g加え次いで
冷却攪拌下メタノールを滴下し1時間攪拌した。反応溶
液に水を加え減圧下溶媒留去し得られた残留物に1N−
塩酸水溶液を加え酢酸エチルで抽出した。有機層を飽和
炭酸水素ナトリウム水溶液次いで水で洗浄し無水硫酸ナ
トリウムで乾燥後減圧下溶媒留去した。得られた残留物
を4N−塩酸酢酸エチルに溶解し1時間攪拌した。減圧
下溶媒留去し標記化合物(24)0.64g(収率46
%)を得た。NMR (δ, CDCl 3 ): 7.20-7.30 (m,
2H), 6.83-6.97 (m, 3H), 5.34-5.42 (m, 1H), 4.45-4.52 (m, 1
H), 4.18 (q, J = 7.22Hz, 2H), 4.04 (t, J = 6.08Hz, 2H), 2.20-2.
37 (m, 2H), 1.44 (s, 9H), 1.25 (t, J = 7.06 Hz, 3H) To a solution of 2.10 g (6.5 mmol) of the above compound in tetrahydrofuran was added 0.28 g of lithium borohydride, followed by cooling and stirring. Under methanol was added dropwise and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the solvent was distilled off under reduced pressure.
An aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 4N-ethyl acetate hydrochloride and stirred for 1 hour. The solvent was distilled off under reduced pressure, and 0.64 g of the title compound (24) was obtained (yield: 46).
%).
【0072】(参考例25)(2S)−2−アミノ−4
−(フェニルチオ)ブタノール塩酸塩(化合物(2
5)) 参考例24に準じた方法でエチルブロミドのかわりにベ
ンジルブロミドを用い、フェノールのかわりにチオフェ
ノールを用いてL−N−(t−ブトキシカルボニル)−
S−フェニルホモシステインベンジルエステルを得た。Reference Example 25 (2S) -2-Amino-4
-(Phenylthio) butanol hydrochloride (compound (2
5)) LN- (t-butoxycarbonyl)-using benzyl bromide instead of ethyl bromide and thiophenol instead of phenol according to the method of Reference Example 24.
S-phenylhomocysteine benzyl ester was obtained.
【0073】NMR(δ,CDCl3 ):7.16-7.37(m,
10H),5.15(d,J=3.31Hz,2H),5.09-5.20(m,1H),4.47-4.53
(m,1H),2.90(dt,J=6.3Hz,J=2.11,2H),2.10-2.20(m,1H),
1.89-2.00(m,1H),1.43(s,9H) 更に参考例24に準じた方法で標記化合物(25)を得
た。NMR (δ, CDCl 3 ): 7.16-7.37 (m,
10H), 5.15 (d, J = 3.31Hz, 2H), 5.09-5.20 (m, 1H), 4.47-4.53
(m, 1H), 2.90 (dt, J = 6.3Hz, J = 2.11,2H), 2.10-2.20 (m, 1H),
1.89-2.00 (m, 1H), 1.43 (s, 9H) Further, the title compound (25) was obtained in the same manner as in Reference Example 24.
【0074】(参考例26)(2R)−2−アミノ−3
−(2−クロロベンジルオキシ)−プロパノール塩酸塩
(化合物(26)) L−N−(t−ブトキシカルボニル)セリン7.0g
(34mmol)の無水ジメチルホルムアミド溶液に60%
油性水素化ナトリウム3.0gを加え室温で3時間攪拌
した。次いで2−クロロベンジルクロリド6.0g(3
7mmol)を滴下し、室温で一夜攪拌した。溶媒を減圧下
留去後得られる残留物を酢酸エチル−1N−塩酸混合溶
媒に溶解し酢酸エチル層を水洗し、無水硫酸ナトリウム
で乾燥後溶媒を留去することによりL−N−(t−ブト
キシカルボニル)−O−(2−クロロベンジル)−セリ
ン4.3g(収率38%)を得た。得られた上記化合物
2.15g(6.5mmol)とトリエチルアミンのテトラ
ヒドロフラン溶液に塩−氷で冷却しながらクロロ炭酸エ
チル0.93gを滴下し、2時間攪拌した。析出した結
晶を濾過して除き濾液に氷冷攪拌下水素化ホウ素ナトリ
ウム次いでメタノールを滴下し2時間攪拌した。溶媒を
減圧下留去し得られた残留物の水溶液に1N−塩酸水溶
液を加え酢酸エチルで抽出した。有機層を10%水酸化
ナトリウム水溶液次いで水洗浄し無水硫酸ナトリウムで
乾燥後溶媒留去しシリカゲルカラムクロマトグラフィー
で精製しアルコール体0.81gを得た。得られたアル
コール体0.8gを4N−塩酸酢酸エチルに溶解し室温
で30分間攪拌、溶媒を留去後標記化合物(26)0.
55g(収率19%)を得た。Reference Example 26 (2R) -2-amino-3
-(2-chlorobenzyloxy) -propanol hydrochloride (compound (26)) 7.0 g of LN- (t-butoxycarbonyl) serine
(34 mmol) in 60% anhydrous dimethylformamide solution
3.0 g of oily sodium hydride was added, and the mixture was stirred at room temperature for 3 hours. Then, 6.0 g of 2-chlorobenzyl chloride (3
7 mmol), and the mixture was stirred at room temperature overnight. The residue obtained after evaporating the solvent under reduced pressure was dissolved in a mixed solvent of ethyl acetate-1N-hydrochloric acid, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to remove L-N- (t- 4.3 g of butoxycarbonyl) -O- (2-chlorobenzyl) -serine were obtained (yield 38%). 0.93 g of ethyl chlorocarbonate was added dropwise to a solution of 2.15 g (6.5 mmol) of the above compound and triethylamine in tetrahydrofuran while cooling with salt-ice, and the mixture was stirred for 2 hours. Precipitated crystals were removed by filtration, and sodium borohydride and then methanol were added dropwise to the filtrate under ice-cooling and stirring, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, a 1N aqueous hydrochloric acid solution was added to an aqueous solution of the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous sodium hydroxide solution and then with water, dried over anhydrous sodium sulfate, evaporated, and purified by silica gel column chromatography to obtain 0.81 g of an alcohol. 0.8 g of the obtained alcohol compound was dissolved in 4N-ethyl acetate hydrochloride, stirred at room temperature for 30 minutes, and the solvent was distilled off.
55 g (19% yield) were obtained.
【0075】NMR(δ,CD3 OD):7.53-7.56(m,
1H),7.39-7.42(m,1H),7.30-7.35(m,2H),4.70(s,2H),3.6
7-3.82(m,4H),3.42-3.49(m,1H) (参考例27)(2S)−2−アミノ−4−(2−フル
オロフェニルオキシ)ブタノール塩酸塩(化合物(2
7)) 参考例24に準じた方法でフェノールのかわりに2−フ
ルオロフェノールを用いてL−N−(t−ブトキシカル
ボニル)−O−(2−フルオロフェニル)−ホモセリン
エチルエステルを得た。NMR (δ, CD 3 OD): 7.53-7.56 (m,
1H), 7.39-7.42 (m, 1H), 7.30-7.35 (m, 2H), 4.70 (s, 2H), 3.6
7-3.82 (m, 4H), 3.42-3.49 (m, 1H) (Reference Example 27) (2S) -2-amino-4- (2-fluorophenyloxy) butanol hydrochloride (compound (2
7)) LN- (t-butoxycarbonyl) -O- (2-fluorophenyl) -homoserine ethyl ester was obtained in the same manner as in Reference Example 24 except that 2-fluorophenol was used instead of phenol.
【0076】NMR(δ,CDCl3 ):6.85-7.10(m,
4H),5.40-5.46(m,1H),4.42-4.51(m,1H),4.22(q,J=7.0H
z,2H),4.12(q,J=5.48Hz,2H),2.23-2.41(m,2H),1.44(s,9
H),1.26(t,J=7.16Hz,3H) 更に参考例24に準じた方法で標記化合物(27)を得
た。NMR (δ, CDCl 3 ): 6.85-7.10 (m,
4H), 5.40-5.46 (m, 1H), 4.42-4.51 (m, 1H), 4.22 (q, J = 7.0H
z, 2H), 4.12 (q, J = 5.48Hz, 2H), 2.23-2.41 (m, 2H), 1.44 (s, 9
H), 1.26 (t, J = 7.16 Hz, 3H) Further, the title compound (27) was obtained in the same manner as in Reference Example 24.
【0077】(参考例28)(2S)−2−アミノ−4
(3−フルオロフェニルオキシ)ブタノール塩酸塩(化
合物(28)) 参考例24に準じた方法でフェノールのかわりに3−フ
ルオロフェノールを用いてL−N−(t−ブトキシカル
ボニル)−O−(3−フルオロフェニル)−ホモセリン
エチルエステルを得た。Reference Example 28 (2S) -2-Amino-4
(3-Fluorophenyloxy) butanol hydrochloride (compound (28)) L-N- (t-butoxycarbonyl) -O- (3 -Fluorophenyl) -homoserine ethyl ester was obtained.
【0078】NMR(δ,CDCl3 ):7.11-7.24(m,
1H),6.55-6.69(m,3H),5.31-5.38(m,1H),4.45-4.51(m,1
H),4.20(q,J=7.16Hz,2H),4.03(t,J=6.02Hz,2H),2.20-2.
38(m,2H),1.44(s,9H),1.26(t,J=7.11Hz,3H) 参考例24に準じた方法で標記化合物(28)を得た。NMR (δ, CDCl 3 ): 7.11-7.24 (m,
1H), 6.55-6.69 (m, 3H), 5.31-5.38 (m, 1H), 4.45-4.51 (m, 1
H), 4.20 (q, J = 7.16Hz, 2H), 4.03 (t, J = 6.02Hz, 2H), 2.20-2.
38 (m, 2H), 1.44 (s, 9H), 1.26 (t, J = 7.11 Hz, 3H) The title compound (28) was obtained in the same manner as in Reference Example 24.
【0079】(参考例29)(2S)−2−アミノ−4
(2−クロロフェニルオキシ)ブタノール塩酸塩(化合
物(29)) 参考例24に準じた方法でエチルブロミドのかわりにベ
ンジルブロミドを用い、フェノールのかわりに2−クロ
ロフェノールを用いてL−N−(t−ブトキシカルボニ
ル)−O−(2−クロロフェニル)−ホモセリンベンジ
ルエステルを得た。Reference Example 29 (2S) -2-Amino-4
(2-Chlorophenyloxy) butanol hydrochloride (compound (29)) LN- (t) using benzyl bromide instead of ethyl bromide and 2-chlorophenol instead of phenol according to the method of Reference Example 24. -Butoxycarbonyl) -O- (2-chlorophenyl) -homoserine benzyl ester was obtained.
【0080】NMR(δ,CDCl3 ):7.30-7.36(m,
6H),7.18(dt,J=6.67Hz,J=1.6,1H),6.90(dt,J=6.3Hz,J=
1.35Hz,1H),6.80(d,J=8.24Hz,1H),5.80-5.83(m,1H),5.1
8(d,J=2.17Hz,2H),4.55-4.62(m,1H),4.07-4.14(m,1H),
3.95-4.00(m,1H),2.40-2.50(m,2H),1.43(s,9H) 更に参考例24に準じた方法で標記化合物(29)を得
た。NMR (δ, CDCl 3 ): 7.30-7.36 (m,
6H), 7.18 (dt, J = 6.67Hz, J = 1.6,1H), 6.90 (dt, J = 6.3Hz, J =
1.35Hz, 1H), 6.80 (d, J = 8.24Hz, 1H), 5.80-5.83 (m, 1H), 5.1
8 (d, J = 2.17Hz, 2H), 4.55-4.62 (m, 1H), 4.07-4.14 (m, 1H),
3.95-4.00 (m, 1H), 2.40-2.50 (m, 2H), 1.43 (s, 9H) Further, the title compound (29) was obtained in the same manner as in Reference Example 24.
【0081】(参考例30)(2S)−2−アミノ−4
(3−クロロフェニルオキシ)ブタノール塩酸塩(化合
物(30)) 参考例24に準じた方法でエチルブロミドのかわりにベ
ンジルブロミドを用い、フェノールのかわりに3−クロ
ロフェノールを用いてL−N−(t−ブトキシカルボニ
ル)−O−(3−クロロフェニル)−ホモセリンベンジ
ルエステルを得た。Reference Example 30 (2S) -2-amino-4
(3-Chlorophenyloxy) butanol hydrochloride (compound (30)) LN- (t) using benzyl bromide instead of ethyl bromide and 3-chlorophenol instead of phenol according to the method of Reference Example 24. -Butoxycarbonyl) -O- (3-chlorophenyl) -homoserine benzyl ester was obtained.
【0082】NMR(δ,CDCl3 ):7.34(s,5H),
7.16(t,J=8.14Hz,1H),6.92(dd,J=5.53Hz,J=1.96Hz,1H),
6.80(s,1H),6.69(dd,J=6.35Hz,J=2.01,1H),5.25-5.30
(m,1H),5.18(d,J=2.23Hz,2H),4.50-4.57(m,1H),3.98(t,
J=5.96Hz,2H),2.25-2.37(m,2H),1.43(s,9H) 更に参考例24に準じた方法で標記化合物(30)を得
た。NMR (δ, CDCl 3 ): 7.34 (s, 5H),
7.16 (t, J = 8.14Hz, 1H), 6.92 (dd, J = 5.53Hz, J = 1.96Hz, 1H),
6.80 (s, 1H), 6.69 (dd, J = 6.35Hz, J = 2.01,1H), 5.25-5.30
(m, 1H), 5.18 (d, J = 2.23Hz, 2H), 4.50-4.57 (m, 1H), 3.98 (t,
J = 5.96 Hz, 2H), 2.25-2.37 (m, 2H), 1.43 (s, 9H) Further, the title compound (30) was obtained in the same manner as in Reference Example 24.
【0083】(参考例31)L−2−アミノ−4−ベン
ジルチオブタノール(化合物(31)) −78℃に冷却した液体アンモニアに金属ナトリウム1
gを加え30分間攪拌後反応溶液にホモシステイン2.
0g(7.45mmol)を加えて30分間攪拌した。反応
溶液に反応液の青色が無くなるまで塩化アンモニウムを
加え次いでベンジルブロミド0.69g(30mmol)を
加え室温で液体アンモニアを蒸発させる。得られた残留
物を水に溶かしジエチルエーテルで洗浄し濃塩酸を加え
弱酸性とし冷所で結晶を析出させた。得られた結晶を
水、エタノール、エーテルで順次洗浄し減圧下乾燥させ
(2S)−2−アミノ−4−ベンジルチオブタノイック
アシド2.8g(収率86%)を得た。Reference Example 31 L-2-Amino-4-benzylthiobutanol (compound (31)) Metallic sodium was added to liquid ammonia cooled to -78 ° C.
g, and after stirring for 30 minutes, homocysteine was added to the reaction solution.
0 g (7.45 mmol) was added and stirred for 30 minutes. Ammonium chloride is added to the reaction solution until blue color of the reaction solution disappears, then 0.69 g (30 mmol) of benzyl bromide is added, and liquid ammonia is evaporated at room temperature. The obtained residue was dissolved in water, washed with diethyl ether, made weakly acidic by adding concentrated hydrochloric acid, and precipitated in a cold place. The obtained crystals were washed successively with water, ethanol and ether, and dried under reduced pressure to obtain 2.8 g (86% yield) of (2S) -2-amino-4-benzylthiobutanoic acid acid.
【0084】水素化ホウ素リチウム0.49g(22mm
ol)の無水テトラヒドロフラン溶液にトリメチルシリロ
キシクロリド5.6ml(44mmol)を加え室温で30分
攪拌した。その混合溶液に(2S)−2−アミノ−4−
ベンジルチオブタノイックアシド2.5g(11mmol)
を加え室温で一夜攪拌した。反応溶液にメタノールを加
え減圧下溶媒留去した得られた残留物を1N−水酸化ナ
トリウム水溶液に溶かしクロロホルムにて抽出した。無
水硫酸ナトリウムで乾燥後減圧下溶媒留去し標記化合物
(31)2.0g(収率85.5%)を得た。0.49 g of lithium borohydride (22 mm
ol) in anhydrous tetrahydrofuran, 5.6 ml (44 mmol) of trimethylsilyloxycyclolide was added, and the mixture was stirred at room temperature for 30 minutes. (2S) -2-amino-4- was added to the mixed solution.
2.5 g (11 mmol) of benzylthiobutanoic acid
Was added and stirred at room temperature overnight. Methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in a 1N aqueous solution of sodium hydroxide and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.0 g (yield: 85.5%) of the title compound (31).
【0085】NMR(δ,CDCl3 ):7.22-7.32(m,
5H),3.72(s,2H),3.51-3.56(m,1H),3.26-3.30(m,1H),2.9
0-3.00(m,1H),2.42-2.58(m,2H),2.00-2.12(m,1H),1.62-
1.73(m,1H),1.48-1.58(m,1H) (参考例32)(2S)−2−アミノ−4(2−フルオ
ロベンジルチオ)ブタノール(化合物(32)) 参考例31に準じた方法でベンジルブロミドのかわりに
2−フルオロベンジルブロミドを用い標記化合物(3
2)を得た。NMR (δ, CDCl 3 ): 7.22-7.32 (m,
5H), 3.72 (s, 2H), 3.51-3.56 (m, 1H), 3.26-3.30 (m, 1H), 2.9
0-3.00 (m, 1H), 2.42-2.58 (m, 2H), 2.00-2.12 (m, 1H), 1.62-
1.73 (m, 1H), 1.48-1.58 (m, 1H) (Reference Example 32) (2S) -2-amino-4 (2-fluorobenzylthio) butanol (Compound (32)) Method according to Reference Example 31 Using 2-fluorobenzyl bromide instead of benzyl bromide in the title compound (3
2) was obtained.
【0086】NMR(δ,CDCl3 ):7.31-7.36(m,
1H),7.19-7.27(m,1H),7.00-7.12(m,2H),3.75(s,2H),3.5
5(dd,J=10.68Hz,J=3.96Hz,1H),3.28(dd,J=13.59Hz,J=7.
49Hz,1H),2.89-2.97(m,1H),2.47-2.62(m,2H),1.98(br
s,3H),1.65-1.76(m,1H),1.49-1.59(m,1H) (参考例33)(2S)−2−アミノ−4(2−クロロ
ベンジルチオ)ブタノール(化合物(33)) 参考例31に準じた方法でベンジルブロミドのかわりに
2−クロロベンジルクロリドを用い標記化合物(33)
を得た。NMR (δ, CDCl 3 ): 7.31 to 7.36 (m,
1H), 7.19-7.27 (m, 1H), 7.00-7.12 (m, 2H), 3.75 (s, 2H), 3.5
5 (dd, J = 10.68Hz, J = 3.96Hz, 1H), 3.28 (dd, J = 13.59Hz, J = 7.
49Hz, 1H), 2.89-2.97 (m, 1H), 2.47-2.62 (m, 2H), 1.98 (br
(s, 3H), 1.65-1.76 (m, 1H), 1.49-1.59 (m, 1H) (Reference Example 33) (2S) -2-amino-4 (2-chlorobenzylthio) butanol (Compound (33)) The title compound (33) using 2-chlorobenzyl chloride instead of benzyl bromide according to the method of Reference Example 31
I got
【0087】NMR(δ,CDCl3 ):7.33-7.39(m,
2H),7.19-7.26(m,2H),3.84(s,2H),3.57(dd,J=10.69Hz,J
=4.01Hz,1H),3.29(dd,J=10.69Hz,J=7.49Hz,1H),2.93-3.
01(m,1H),2.50-2.66(m,2H),2.04(br s,3H),1.66-1.78
(m,1H),1.50-1.62(m,1H) (参考例34)(2S)−2−アミノ−4(2−フルオ
ロフェニルチオ)ブタノール塩酸塩(化合物(34)) 参考例24に準じた方法でエチルブロミドのかわりにベ
ンジルブロミドを用い、フェノールのかわりに2−フル
オロチオフェノールを用いてL−N−(t−ブトキシカ
ルボニル)−S−(2−フルオロフェニル)ホモシステ
インベンジルエステルを得た。NMR (δ, CDCl 3 ): 7.33 to 7.39 (m,
2H), 7.19-7.26 (m, 2H), 3.84 (s, 2H), 3.57 (dd, J = 10.69Hz, J
= 4.01Hz, 1H), 3.29 (dd, J = 10.69Hz, J = 7.49Hz, 1H), 2.93-3.
01 (m, 1H), 2.50-2.66 (m, 2H), 2.04 (br s, 3H), 1.66-1.78
(m, 1H), 1.50-1.62 (m, 1H) (Reference Example 34) (2S) -2-amino-4 (2-fluorophenylthio) butanol hydrochloride (Compound (34)) Using the method, benzyl bromide was used instead of ethyl bromide, and 2-fluorothiophenol was used instead of phenol to obtain LN- (t-butoxycarbonyl) -S- (2-fluorophenyl) homocysteine benzyl ester. .
【0088】NMR(δ,CDCl3 ):7.18-7.42(m,
6H),7.01-7.07(m,2H),5.16(d,J=2.66Hz,2H),5.09-5.14
(m,1H),4.45-4.53(m,1H),2.90(t,J=7.49Hz,2H),2.06-2.
18(m,1H),1.86-1.98(m,1H),1.43(s,9H) 更に参考例24に準じた方法で標記化合物(34)を得
た。NMR (δ, CDCl 3 ): 7.18-7.42 (m,
6H), 7.01-7.07 (m, 2H), 5.16 (d, J = 2.66Hz, 2H), 5.09-5.14
(m, 1H), 4.45-4.53 (m, 1H), 2.90 (t, J = 7.49Hz, 2H), 2.06-2.
18 (m, 1H), 1.86-1.98 (m, 1H), 1.43 (s, 9H) Further, the title compound (34) was obtained in the same manner as in Reference Example 24.
【0089】(参考例35)(2S)−2−アミノ−4
(2−クロロフェニルチオ)ブタノール塩酸塩(化合物
(35)) 参考例24に準じた方法でエチルブロミドのかわりにベ
ンジルブロミドを用いフェノールのかわりに2−クロロ
チオフェノールを用いてL−N−(t−ブトキシカルボ
ニル)−S−(2−クロロフェニル)ホモシステインベ
ンジルエステルを得た。Reference Example 35 (2S) -2-amino-4
(2-Chlorophenylthio) butanol hydrochloride (compound (35)) LN- (t) using benzyl bromide instead of ethyl bromide and 2-chlorothiophenol instead of phenol according to the method of Reference Example 24 -Butoxycarbonyl) -S- (2-chlorophenyl) homocysteine benzyl ester was obtained.
【0090】NMR(δ,CDCl3 ):7.34(s,6H),
7.08-7.23(m,3H),5.17(d,J=3.31Hz,3H),4.40-4.51(m,1
H),2.90-2.96(m,2H),2.17-2.25(m,1H),1.95-2.05(m,1
H),1.44(s,9H) 更に参考例24に準じた方法で標記化合物(35)を得
た。NMR (δ, CDCl 3 ): 7.34 (s, 6H),
7.08-7.23 (m, 3H), 5.17 (d, J = 3.31Hz, 3H), 4.40-4.51 (m, 1
H), 2.90-2.96 (m, 2H), 2.17-2.25 (m, 1H), 1.95-2.05 (m, 1
H), 1.44 (s, 9H) Further, the title compound (35) was obtained by a method similar to that of Reference Example 24.
【0091】(参考例36)(2S)−2−アミノ−4
(4−クロロフェニルチオ)ブタノール塩酸塩(化合物
(36)) 参考例24に準じた方法でエチルブロミドのかわりにベ
ンジルブロミドを用い、フェノールのかわりに4−クロ
ロチオフェノールを用いてL−N−(t−ブトキシカル
ボニル)−S−(4−クロロフェニル)ホモシステイン
ベンジルエステルを得た。Reference Example 36 (2S) -2-Amino-4
(4-Chlorophenylthio) butanol hydrochloride (compound (36)) LN- (4-chlorothiophenol) was used in place of ethyl bromide, and 4-chlorothiophenol was used instead of phenol, according to the method of Reference Example 24. (t-butoxycarbonyl) -S- (4-chlorophenyl) homocysteine benzyl ester was obtained.
【0092】NMR(δ,CDCl3 ):7.29-7.37(m,
4H),7.21(s,5H),5.15(d,J=7.16Hz,2H),5.10-5.15(m,1
H),4.12-4.19(m,1H),2.84-2.90(m,2H),2.05-2.18(m,1
H),1.86-1.97(m,1H),1.43(s,9H) 更に参考例24に準じた方法で標記化合物(36)を得
た。NMR (δ, CDCl 3 ): 7.29-7.37 (m,
4H), 7.21 (s, 5H), 5.15 (d, J = 7.16Hz, 2H), 5.10-5.15 (m, 1
H), 4.12-4.19 (m, 1H), 2.84-2.90 (m, 2H), 2.05-2.18 (m, 1
H), 1.86-1.97 (m, 1H), 1.43 (s, 9H) Further, the title compound (36) was obtained in the same manner as in Reference Example 24.
【0093】(参考例37)(L)−N−〔1−(ベン
ジルオキシカルボニル)−ピペリジン−4−カルボニ
ル〕ロイシン(化合物(37)) L−ロイシンエチルエステル・塩酸塩5g(25.5mm
ol)のクロロホルム溶液(100ml)に氷冷攪拌下トリ
エチルアミン2.58g(25.5mmol)、N−(ベン
ジルオキシカルボニル)−ピペリジン−4−カルボン酸
6.7g(25.5mmol)、1−エチル−3(3−ジメ
チルアミノプロピル)カルボジイミド・塩酸塩4.88
g(25.5mmol)を順次加え、室温に戻し一夜攪拌し
た。反応溶液を1N−塩酸、飽和炭酸水素ナトリウム溶
液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾
燥後減圧下濃縮し、L−N−〔1−(ベンジルオキシカ
ルボニル)−ピペリジン−4−カルボニル〕ロイシンエ
チルエステル10.1g(収率98%)を得た。Reference Example 37 (L) -N- [1- (benzyloxycarbonyl) -piperidine-4-carbonyl] leucine (compound (37)) L-leucine ethyl ester hydrochloride 5 g (25.5 mm)
ol) in a chloroform solution (100 ml) under ice-cooling and stirring, 2.58 g (25.5 mmol) of triethylamine, 6.7 g (25.5 mmol) of N- (benzyloxycarbonyl) -piperidine-4-carboxylic acid, 1-ethyl- 3 (3-dimethylaminopropyl) carbodiimide hydrochloride 4.88
g (25.5 mmol) were sequentially added, and the mixture was returned to room temperature and stirred overnight. The reaction solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and treated with LN- [1- (benzyloxycarbonyl) -piperidine-4-carbonyl. 10.1 g (yield 98%) of leucine ethyl ester was obtained.
【0094】得られた上記エステル体10.1gのメタ
ノール溶液に氷冷攪拌下水酸化ナトリウム1.02g
(25.5mmol)の水溶液(10ml)を加えそのまま3
時間攪拌した。反応溶液を減圧下濃縮し、得られた残留
物を水に溶解し、エーテルで2回洗浄した。水層に濃塩
酸を加え酸性(pH=1)とした後酢酸エチルで2回抽出
し、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥
後減圧下濃縮することにより標記化合物(37)9.3
g(収率96%)を油状物質として得た。To a methanol solution of 10.1 g of the ester obtained above was added 1.02 g of sodium hydroxide while stirring with ice cooling.
(25.5 mmol) in water (10 ml) and 3
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in water and washed twice with ether. The aqueous layer was made acidic (pH = 1) by adding concentrated hydrochloric acid, extracted twice with ethyl acetate, and washed with saturated saline. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the title compound (37) 9.3 was obtained.
g (96% yield) was obtained as an oil.
【0095】NMR(δ,CDCl3 ):8.80-9.00(m,
1H),7.32-7.38(m,5H),6.05-6.15(m,1H),5.14(s,2H),4.5
8-4.68(m,1H),4.16-4.26(m,2H),2.82-2.95(m,2H),2.37-
2.48(m,1H),1.82-1.92(m,2H),1.56-1.75(m,5H),0.95-0.
97(m,6H) (参考例38)(L)−N−(N−フェニルカルバモイ
ル)ロイシン(化合物(38)) (L)−ロイシンエチルエステル塩酸塩5g(25.5
mmol)のクロロホルム溶液(200ml)に氷冷攪拌下ト
リエチルアミン5.16g(51mmol)を加え、次いで
イソシアン酸フェニルエステル2.76ml(25.5mm
ol)のクロロホルム溶液を滴下した。一夜攪拌後、反応
溶液を1N−塩酸、飽和炭酸水素ナトリウム溶液、飽和
食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後減圧
下濃縮することにより、(L)−N−(N−フェニルカ
ルバモイル)ロイシンエチルエステル5.85g(収率
82%)を得た。NMR (δ, CDCl 3 ): 8.80-9.00 (m,
1H), 7.32-7.38 (m, 5H), 6.05-6.15 (m, 1H), 5.14 (s, 2H), 4.5
8-4.68 (m, 1H), 4.16-4.26 (m, 2H), 2.82-2.95 (m, 2H), 2.37-
2.48 (m, 1H), 1.82-1.92 (m, 2H), 1.56-1.75 (m, 5H), 0.95-0.
97 (m, 6H) (Reference Example 38) (L) -N- (N-phenylcarbamoyl) leucine (compound (38)) (L) -leucine ethyl ester hydrochloride 5 g (25.5)
5.16 g (51 mmol) of triethylamine was added to a chloroform solution (200 ml) of ice-cold solution with stirring under ice-cooling, and then 2.76 ml (25.5 mm) of phenyl isocyanate.
ol) in chloroform. After stirring overnight, the reaction solution is washed with 1N-hydrochloric acid, saturated sodium hydrogen carbonate solution and saturated saline solution in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (L) -N- (N-phenylcarbamoyl). 5.85 g (82% yield) of leucine ethyl ester was obtained.
【0096】得られた上記化合物5.85gのメタノー
ル溶液(200ml)に氷冷攪拌下水酸化ナトリウム1.
848g(46mmol)の水溶液(10ml)を加えそのま
ま3時間攪拌した。反応溶液を減圧下濃縮し、得られた
残留物を水に溶解し、エーテルで2回洗浄した。水層に
濃塩酸を加え酸性(pH=1)とし、析出した結晶を濾取
し水、冷エタノール、エーテルで順次洗浄し、乾燥する
ことに標記化合物(38)3.55g(収率6.7%)
を得た。A solution of 5.85 g of the above compound in methanol (200 ml) was stirred under ice-cooling with sodium hydroxide 1.
An aqueous solution (10 ml) of 848 g (46 mmol) was added and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in water and washed twice with ether. Concentrated hydrochloric acid was added to the aqueous layer to make it acidic (pH = 1), and the precipitated crystals were collected by filtration, washed successively with water, cold ethanol and ether, and dried, yielding 3.55 g of the title compound (38) (yield 6.5). 7%)
I got
【0097】融点(℃):143.8〜145.8 NMR(δ,CD3 OD):7.33(dd,J=8.5Hz,0.96Hz,2
H),7.25(t,J=5.1Hz,2H),6.96(td,J=8.5Hz,1.2Hz,1H),4.
37(dd,J=9.3Hz,5.1Hz,1H),1.51〜1.89(m,3H),0.99(d,J=
3.2Hz,3H),0.97(d,J=3.0Hz,3H) (参考例39)(L)−N−(4−メチルベンゼンスル
ホニル)ロイシン(化合物(39)) 参考例39に準ずる方法でイソシアン酸フェニルエステ
ルの代りに4−メチルベンゼンスルホニルクロリド4.
86gを用いて標記化合物(39)6.2gを得た。Melting point (° C.): 143.8-145.8 NMR (δ, CD 3 OD): 7.33 (dd, J = 8.5 Hz, 0.96 Hz, 2
H), 7.25 (t, J = 5.1Hz, 2H), 6.96 (td, J = 8.5Hz, 1.2Hz, 1H), 4.
37 (dd, J = 9.3Hz, 5.1Hz, 1H), 1.51 ~ 1.89 (m, 3H), 0.99 (d, J =
(3.2 Hz, 3H), 0.97 (d, J = 3.0 Hz, 3H) (Reference Example 39) (L) -N- (4-methylbenzenesulfonyl) leucine (compound (39)) 3. 4-methylbenzenesulfonyl chloride instead of acid phenyl ester
Using 86 g, 6.2 g of the title compound (39) was obtained.
【0098】融点(℃):117.2〜120 NMR(δ,CDCl3 ):7.73(d,J=8.3Hz,2H),7.28
(d,J=8.3Hz,2H),5.07(d,J=9.7Hz,1H),3.86 〜3.99(m,1
H),2.41(s,3H),1.70〜1.85(m,1H),1.45 〜1.60(m,2H)、
0.89(d,J=6.6Hz,3H),0.82(d,J=6.5Hz,3H) (参考例40)(L)−N−メチル−N−(ベンジルオ
キシカルボニル)ロイシン(化合物(40)) 市販のL−N−メチルロイシン1g(6.88mmol) の
1N−水酸化ナトリウム水溶液(10ml) に氷冷攪拌下
ベンジルオキシカルボニルクロリド0.982ml(6.
88mmol) のベンゼン溶液(10ml) と1N−水酸化ナ
トリウム水溶液(10ml) を同時に滴下した。室温に戻
し一夜攪拌後反応溶液をエーテルで2回洗浄した。水層
に濃塩酸を加え酸性(pH=1)とした後酢酸エチルで2
回抽出した。無水硫酸ナトリウムで乾燥後減圧下濃縮す
ることにより標記化合物(40)0.46gを得た。Melting point (° C.): 117.2 to 120 NMR (δ, CDCl 3 ): 7.73 (d, J = 8.3 Hz, 2H), 7.28
(d, J = 8.3Hz, 2H), 5.07 (d, J = 9.7Hz, 1H), 3.86 to 3.99 (m, 1
H), 2.41 (s, 3H), 1.70 ~ 1.85 (m, 1H), 1.45 ~ 1.60 (m, 2H),
0.89 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H) (Reference Example 40) (L) -N-methyl-N- (benzyloxycarbonyl) leucine (compound (40)) 0.92 ml of benzyloxycarbonyl chloride was added to 1 g (6.88 mmol) of a commercially available LN-methylleucine aqueous solution (10 ml) of 1N sodium hydroxide under ice-cooling and stirring.
A benzene solution (88 ml) and a 1N aqueous solution of sodium hydroxide (10 ml) were simultaneously added dropwise. After returning to room temperature and stirring overnight, the reaction solution was washed twice with ether. The aqueous layer was made acidic (pH = 1) by adding concentrated hydrochloric acid and then extracted with ethyl acetate.
Extracted times. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, 0.46 g of the title compound (40) was obtained.
【0099】NMR(δ,CDCl3 ):7.30-7.40(m,
5H),5.10-5.23(m,2H),4.92(t,J=8.3Hz,2/3H),4.77(dd,J
=10.5Hz,4.5Hz,1/3H),2.88(s,3H),1.45 〜1.82(m,3H),
0.86〜1.05(m,6H) (実施例1)L−N−ベンジルオキシカルボニルロイシ
ン−(2S)−(1−ホルミル−2−ベンジルオキシ)
エチルアミド(化合物(41)) 参考例1で合成した化合物(1)2.01g(7.8mm
ol)のクロロホルム懸濁液(200ml)に氷冷攪拌下ト
リエチルアミン784mg(7.8mmol),L−Cbz−
Len−OH・トルエン溶液23ml(8.5mmol)およ
び1−ヒドロキシベンズトリアゾール1.18g(7.
8mmol)を順次加えた後ジシクロヘキシルカルボジイミ
ド1.76g(8.525mmol)のクロロホルム溶液
(50ml)を滴下した。室温にて一夜攪拌した後不溶物
を濾去し、濾液を1N−塩酸,飽和炭酸水素ナトリウム
水溶液,飽和食塩水の順に洗浄した有機層を無水硫酸ナ
トリウムで乾燥後、濃縮して得られた残留物をシリカゲ
ルカラムクロマトグラフィーで精製することによりL−
N−(ベンジルオキシカルボニル)−ロイシル−L−
(O−ベンジル)−セリンエチルエステルを得た(2.
74,75%)。得られたエステル体1.58g(3.
4mmol)の無水テトラヒドロフラン溶液(50ml)に氷
冷攪拌下、水素化ホウ素リチウム182mg(8.4mmo
l)を加え、次いでメタノール3mlを滴下した。さらに
1時間攪拌後反応溶液に水10mlを滴下し、減圧下濃縮
した。得られた残留物に1N−塩酸を加え酸性(pH=
1)にした後塩化メチレンで2回抽出した。有機層を飽
和炭酸水素ナトリウム溶液,飽和食塩水で洗浄し、無水
硫酸ナトリウムで乾燥後濃縮して得られた残留物をベン
ゼン−酢酸エチルから再結晶し対応するアルコール0.
965g(収率67%)を得た。得られたアルコール体
900mg(2.1mmol)およびトリエチルアミン850
mg(8.4mmol)の無水ジメチルスルホキシド溶液(1
0ml)に室温攪拌下三酸化イオウピリジンコレプレック
ス1.33g(8.4mmol)の無水ジメチルスルホキシ
ド溶液(10ml)を滴下した。30分間攪拌後反応溶液
を氷水に注ぎ酢酸エチルで3回抽出した。合わせた有機
層を10%−クエン酸水溶液、水、飽和炭酸水素ナトリ
ウム水溶液、飽和食塩水で順次洗浄し無水硫酸ナトリウ
ムで乾燥後減圧下濃縮した。得られた残留物をシリカゲ
ルカラムクロマトグラフィーで精製することにより標記
化合物(41)0.425g(収率47%)を油状物質
として得た。NMR (δ, CDCl 3 ): 7.30-7.40 (m,
5H), 5.10-5.23 (m, 2H), 4.92 (t, J = 8.3Hz, 2 / 3H), 4.77 (dd, J
= 10.5Hz, 4.5Hz, 1 / 3H), 2.88 (s, 3H), 1.45-1.82 (m, 3H),
0.86 to 1.05 (m, 6H) (Example 1) LN-benzyloxycarbonylleucine- (2S)-(1-formyl-2-benzyloxy)
Ethylamide (compound (41)) 2.01 g (7.8 mm) of compound (1) synthesized in Reference Example 1
ol) in chloroform suspension (200 ml) under ice cooling and stirring, with 784 mg (7.8 mmol) of triethylamine, L-Cbz-
23 ml (8.5 mmol) of a Len-OH-toluene solution and 1.18 g of 1-hydroxybenztriazole (7.
Then, a solution of 1.76 g (8.525 mmol) of dicyclohexylcarbodiimide in chloroform (50 ml) was added dropwise. After stirring overnight at room temperature, the insolubles were removed by filtration, and the filtrate was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in that order. The product is purified by silica gel column chromatography to give L-
N- (benzyloxycarbonyl) -leucyl-L-
(O-benzyl) -serine ethyl ester was obtained (2.
74, 75%). 1.58 g of the obtained ester compound (3.
4 mmol) in anhydrous tetrahydrofuran (50 ml) was stirred under ice-cooling with lithium borohydride (182 mg, 8.4 mmol).
l) was added and then 3 ml of methanol were added dropwise. After further stirring for 1 hour, 10 ml of water was added dropwise to the reaction solution, and the mixture was concentrated under reduced pressure. 1N-hydrochloric acid was added to the obtained residue to make it acidic (pH =
After 1), the mixture was extracted twice with methylene chloride. The organic layer was washed with a saturated sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate and concentrated, and the residue obtained was recrystallized from benzene-ethyl acetate to give the corresponding alcohol.
965 g (67% yield) were obtained. The obtained alcohol compound 900 mg (2.1 mmol) and triethylamine 850
mg (8.4 mmol) of anhydrous dimethyl sulfoxide solution (1
(0 ml) was added dropwise a solution of 1.33 g (8.4 mmol) of sulfur trioxide pyridine complex (10 ml) in anhydrous dimethyl sulfoxide with stirring at room temperature. After stirring for 30 minutes, the reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic layer was washed successively with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.425 g (yield 47%) of the title compound (41) as an oil.
【0100】NMR(δ,CDCl3 ):9.56(s,1H),
7.25-7.36(m,10H),6.75-6.95(m,1H),5.20-5.22(m,1H),
5.11(s,2H),4.55-4.59(m,1H),4.43-4.50(m,2H),4.25-4.
35(m,1H),3.99-4.03(m,1H),3.66-3.70(m,1H),1.49-1.73
(m,3H),0.92-0.95(m,6H) Rf値:0.19(展開溶媒A,ヘキサン:酢酸エチル
=1:1) :0.14(展開溶媒B,塩化メチレン:アセトン=1
0:1) (実施例2)L−N−ベンジルオキシカルボニルロイシ
ン−(2R)−(1−ホルミル−2−ベンジルチオ)エ
チルアミド(化合物(42)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに市販のL−S−ベンジル−システインエ
チルエステル塩酸塩2.2gを用いて標記化合物(4
2)0.14gを得た。NMR (δ, CDCl 3 ): 9.56 (s, 1H),
7.25-7.36 (m, 10H), 6.75-6.95 (m, 1H), 5.20-5.22 (m, 1H),
5.11 (s, 2H), 4.55-4.59 (m, 1H), 4.43-4.50 (m, 2H), 4.25-4.
35 (m, 1H), 3.99-4.03 (m, 1H), 3.66-3.70 (m, 1H), 1.49-1.73
(m, 3H), 0.92-0.95 (m, 6H) Rf value: 0.19 (developing solvent A, hexane: ethyl acetate = 1: 1): 0.14 (developing solvent B, methylene chloride: acetone = 1)
0: 1) (Example 2) LN-benzyloxycarbonylleucine- (2R)-(1-formyl-2-benzylthio) ethylamide (compound (42)) Synthesized in Reference Example 1 by a method similar to that in Example 1. The title compound (4) was obtained using 2.2 g of commercially available L-S-benzyl-cysteine ethyl ester hydrochloride instead of the compound (1).
2) 0.14 g was obtained.
【0101】融点(℃):116.8〜122.1 NMR(δ,CDCl3 ):9.49(s,1H),7.28-7.34(m,1
0H),6.72-6.79(m,1H),5.11(s,2H),5.17-5.20(m,2H),4.4
8-4.57(m,1H),4.20-4.28(m,1H),3.71(s,2H),2.88(d,J=
5.86Hz,2H),1.48-1.75(m,3H),0.95(d,J=5.97Hz,6H) Rf値:0.35(展開溶媒A) :0.25(展開溶媒B) (実施例3)L−N−ベンジルオキシカルボニルロイシ
ン−(2R)−〔1−ホルミル−2−(2−フェニルエ
チルチオ)〕エチルアミド(化合物(43)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに参考例2で合成した化合物(2)3.3
gを用いて標記化合物(43)0.57gを油状物質と
して得た。Melting point (° C.): 116.8-122.1 NMR (δ, CDCl 3 ): 9.49 (s, 1H), 7.28-7.34 (m, 1
0H), 6.72-6.79 (m, 1H), 5.11 (s, 2H), 5.17-5.20 (m, 2H), 4.4
8-4.57 (m, 1H), 4.20-4.28 (m, 1H), 3.71 (s, 2H), 2.88 (d, J =
5.86 Hz, 2H), 1.48-1.75 (m, 3H), 0.95 (d, J = 5.97 Hz, 6H) Rf value: 0.35 (developing solvent A): 0.25 (developing solvent B) (Example 3) ) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (2-phenylethylthio)] ethylamide (compound (43)) Compound synthesized in Reference Example 1 by a method similar to that in Example 1. Compound (2) 3.3 synthesized in Reference Example 2 instead of (1)
Using 0.5 g of the title compound (43), 0.57 g of the title compound (43) was obtained as an oil.
【0102】NMR(δ,CDCl3 ):9.57(s,1H),
7.18-7.36(m,10H),6.90-7.00(m,1H),5.15-5.20(m,1H),
5.10(s,2H),4.48-4.55(m,1H),4.24-4.27(m,1H),2.77-2.
96(m,6H),1.49-1.71(m,3H),0.92-0.95(m,6H) Rf値:0.30(展開溶媒A) :0.23(展開溶媒B) (実施例4)L−N−ベンジルオキシカルボニルロイシ
ン−(2R)−〔1−ホルミル−2−(3−フェニルプ
ロピルチオ)〕エチルアミド(化合物(44)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに参考例3で合成した化合物(3)3.4
7gを用いて標記化合物(44)0.79gを油状物質
として得た。NMR (δ, CDCl 3 ): 9.57 (s, 1H),
7.18-7.36 (m, 10H), 6.90-7.00 (m, 1H), 5.15-5.20 (m, 1H),
5.10 (s, 2H), 4.48-4.55 (m, 1H), 4.24-4.27 (m, 1H), 2.77-2.
96 (m, 6H), 1.49-1.71 (m, 3H), 0.92-0.95 (m, 6H) Rf value: 0.30 (developing solvent A): 0.23 (developing solvent B) (Example 4) L -N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3-phenylpropylthio)] ethylamide (compound (44)) Compound (1) synthesized in Reference Example 1 by a method similar to that in Example 1. Instead of compound (3) 3.4 synthesized in Reference Example 3
0.79 g of the title compound (44) was obtained as an oil using 7 g.
【0103】NMR(δ,CDCl3 ):9.59(br s,1
H),7.28-7.36(m,8H),7.15-7.21(m,2H),6.90-7.00(m,1
H),5.11(s,2H),5.10-5.20(m,1H),4.50-4.58(m,1H),4.22
-4.30(m,1H),2.95(br s,2H),2.69(t,J=7.33Hz,2H),2.53
(t,J=7.32Hz,2H),1.84-1.94(m,2H),1.48-1.70(m,3H),0.
94(d,J=6.73Hz,6H) Rf値:0.31(展開溶媒A) :0.26(展開溶媒B) (実施例5)L−N−ベンジルオキシカルボニルロイシ
ン−(2R)−〔1−ホルミル−2−(3−フェニルプ
ロピルオキシ)〕エチルアミド(化合物(45)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに参考例4で合成した化合物(4)1.1
3gを用いて標記化合物(45)0.315gを油状物
質として得た。NMR (δ, CDCl 3 ): 9.59 (br s, 1
H), 7.28-7.36 (m, 8H), 7.15-7.21 (m, 2H), 6.90-7.00 (m, 1
H), 5.11 (s, 2H), 5.10-5.20 (m, 1H), 4.50-4.58 (m, 1H), 4.22
-4.30 (m, 1H), 2.95 (br s, 2H), 2.69 (t, J = 7.33Hz, 2H), 2.53
(t, J = 7.32Hz, 2H), 1.84-1.94 (m, 2H), 1.48-1.70 (m, 3H), 0.
94 (d, J = 6.73 Hz, 6H) Rf value: 0.31 (developing solvent A): 0.26 (developing solvent B) (Example 5) LN-benzyloxycarbonylleucine- (2R)-[ 1-formyl-2- (3-phenylpropyloxy)] ethylamide (compound (45)) The compound (4) synthesized in Reference Example 4 in place of the compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1. ) 1.1
Using 3 g, 0.315 g of the title compound (45) was obtained as an oil.
【0104】NMR(δ,CDCl3 ):9.57(s,1H),
7.25-7.36(m,8H),7.14-7.21(m,2H),6.77-6.93(m,1H),5.
20-5.26(m,1H),5.05-5.14(m,2H),4.54-4.59(m,1H),4.27
-4.32(m,1H),3.94-3.98(m,1H),3.61-3.65(m,1H),3.41
(t,J=6.35Hz,2H),2.62(t,J=7.92Hz,2H),1.79-1.90(m,2
H),1.51-1.79(m,3H),0.93-0.96(m,6H) Rf値:0.18(展開溶媒A) :0.16(展開溶媒B) (実施例6)L−N−ベンジルオキシカルボニルロイシ
ン−(2S)−〔1−ホルミル−2−(チオフェン−3
−イルメチル)オキシ〕エチルアミド(化合物(4
6)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに参考例5で合成した化合物(5)1.2
0gを用いて標記化合物(46)0.33gを油状物質
として得た。NMR (δ, CDCl 3 ): 9.57 (s, 1H),
7.25-7.36 (m, 8H), 7.14-7.21 (m, 2H), 6.77-6.93 (m, 1H), 5.
20-5.26 (m, 1H), 5.05-5.14 (m, 2H), 4.54-4.59 (m, 1H), 4.27
-4.32 (m, 1H), 3.94-3.98 (m, 1H), 3.61-3.65 (m, 1H), 3.41
(t, J = 6.35Hz, 2H), 2.62 (t, J = 7.92Hz, 2H), 1.79-1.90 (m, 2
H), 1.51-1.79 (m, 3H), 0.93-0.96 (m, 6H) Rf value: 0.18 (developing solvent A): 0.16 (developing solvent B) (Example 6) LN-benzyl Oxycarbonylleucine- (2S)-[1-formyl-2- (thiophene-3
-Ylmethyl) oxy] ethylamide (compound (4
6)) Compound (5) 1.2 synthesized in Reference Example 5 instead of compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1.
Using 0 g, 0.33 g of the title compound (46) was obtained as an oil.
【0105】NMR(δ,CDCl3 ):9.55(s,1H),
7.26-7.34(m,6H),7.18(s,1H),6.97-7.05(m,1H),6.70-6.
93(m,1H),5.12(s,2H),5.10-5.20(m,1H),4.53-4.60(m,1
H),4.49(s,2H),4.22-4.31(m,1H),3.97-4.05(m,1H),3.65
-3.72(m,1H),1.50-1.75(m,3H),0.95(t,J=4.45Hz,6H) Rf値:0.21(展開溶媒A) :0.24(展開溶媒B) (実施例7)L−N−ベンジルオキシカルボニルロイシ
ン−(2R)−(1−ホルミル−2−ジフェニルメチル
チオ)エチルアミド(化合物(47)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに参考例6で合成した化合物(6)1.1
3gを用いて標記化合物(47)0.17gを油状物質
として得た。NMR (δ, CDCl 3 ): 9.55 (s, 1H),
7.26-7.34 (m, 6H), 7.18 (s, 1H), 6.97-7.05 (m, 1H), 6.70-6.
93 (m, 1H), 5.12 (s, 2H), 5.10-5.20 (m, 1H), 4.53-4.60 (m, 1
H), 4.49 (s, 2H), 4.22-4.31 (m, 1H), 3.97-4.05 (m, 1H), 3.65
-3.72 (m, 1H), 1.50-1.75 (m, 3H), 0.95 (t, J = 4.45 Hz, 6H) Rf value: 0.21 (developing solvent A): 0.24 (developing solvent B) (implementation Example 7) LN-benzyloxycarbonylleucine- (2R)-(1-formyl-2-diphenylmethylthio) ethylamide (compound (47)) Compound (1) synthesized in Reference Example 1 by a method similar to that in Example 1. Compound (6) 1.1 synthesized in Reference Example 6 instead of
Using 3 g, 0.17 g of the title compound (47) was obtained as an oil.
【0106】NMR(δ,CDCl3 ):9.44(s,1H),
7.21-7.41(m,15H),6.72-6.85(m,1H),5.08-5.18(m,4H),
4.46-4.51(m,1H),4.20-4.30(m,1H),2.75-2.92(m,2H),1.
47-1.71(m,3H),0.93-0.95(m,6H) Rf値:0.32(展開溶媒A) :0.25(展開溶媒B) (実施例8)L−N−ベンジルオキシカルボニルロイシ
ン−(2R)−(1−ホルミル−2−シクロヘキシルメ
チルチオ)エチルアミド(化合物(48)) 実施例1に準ずる方法で合成した化合物(1)の代りに
参考例7で合成した化合物(7)2.53gを用いて標
記化合物(48)0.74gを油状物質として得た。NMR (δ, CDCl 3 ): 9.44 (s, 1H),
7.21-7.41 (m, 15H), 6.72-6.85 (m, 1H), 5.08-5.18 (m, 4H),
4.46-4.51 (m, 1H), 4.20-4.30 (m, 1H), 2.75-2.92 (m, 2H), 1.
47-1.71 (m, 3H), 0.93-0.95 (m, 6H) Rf value: 0.32 (developing solvent A): 0.25 (developing solvent B) (Example 8) LN-benzyloxycarbonylleucine -(2R)-(1-Formyl-2-cyclohexylmethylthio) ethylamide (Compound (48)) The compound (7) synthesized in Reference Example 7 instead of the compound (1) synthesized in the same manner as in Example 1. 0.74 g of the title compound (48) was obtained as an oil using 53 g.
【0107】NMR(δ,CDCl3 ):9.61(s,1H),
7.35(s,5H),6.89-6.93(m,1H),5.12(s,2H),5.10-5.20(s,
1H),4.51-4.57(m,1H),4.22-4.30(m,1H),2.92-2.96(m,2
H),2.42(d,J=6.84Hz,2H),1.28-1.82(m,10H),1.11-1.26
(m,4H),0.95(d,J=6.02Hz,6H) Rf値:0.38(展開溶媒A) :0.28(展開溶媒B) (実施例9)L−N−ベンジルオキシカルボニルロイシ
ン−(2R)−(1−ホルミル−2−シクロペンチルチ
オ)エチルアミド(化合物(49)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに参考例8で合成した化合物(8)2.0
gを用いて標記化合物(49)0.29gを油状物質と
して得た。NMR (δ, CDCl 3 ): 9.61 (s, 1H),
7.35 (s, 5H), 6.89-6.93 (m, 1H), 5.12 (s, 2H), 5.10-5.20 (s,
1H), 4.51-4.57 (m, 1H), 4.22-4.30 (m, 1H), 2.92-2.96 (m, 2
H), 2.42 (d, J = 6.84Hz, 2H), 1.28-1.82 (m, 10H), 1.11-1.26
(m, 4H), 0.95 (d, J = 6.02 Hz, 6H) Rf value: 0.38 (developing solvent A): 0.28 (developing solvent B) (Example 9) LN-benzyloxycarbonyl leucine -(2R)-(1-Formyl-2-cyclopentylthio) ethylamide (Compound (49)) The compound synthesized in Reference Example 8 in place of the compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1 ( 8) 2.0
Using g, 0.29 g of the title compound (49) was obtained as an oil.
【0108】NMR(δ,CDCl3 ):9.62(s,1H),
7.35(s,5H),6.89-6.92(m,1H),5.12(s,2H),5.10-5.20(m,
1H),4.55-4.60(m,1H),4.32-4.41(m,1H),2.90-3.12(m,3
H),1.95-2.05(m,3H),1.46-1.72(m,8H),0.95(d,J=5.26H
z,6H) Rf値:0.37(展開溶媒A) :0.32(展開溶媒B) (実施例10)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(チオフェン−
2−イルメチル)チオ〕エチルアミド(化合物(5
0)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに参考例9で合成した化合物(9)0.9
6gを用いて標記化合物(50)0.22gを油状物質
として得た。NMR (δ, CDCl 3 ): 9.62 (s, 1H),
7.35 (s, 5H), 6.89-6.92 (m, 1H), 5.12 (s, 2H), 5.10-5.20 (m,
1H), 4.55-4.60 (m, 1H), 4.32-4.41 (m, 1H), 2.90-3.12 (m, 3
H), 1.95-2.05 (m, 3H), 1.46-1.72 (m, 8H), 0.95 (d, J = 5.26H
(z, 6H) Rf value: 0.37 (developing solvent A): 0.32 (developing solvent B) (Example 10) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- ( Thiophene-
2-ylmethyl) thio] ethylamide (compound (5
0)) Compound (9) 0.9 synthesized in Reference Example 9 instead of Compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1.
Using 6 g, 0.22 g of the title compound (50) was obtained as an oil.
【0109】NMR(δ,CDCl3 ):9.50(s,1H),
7.34(s,5H),7.21-7.23(m,1H),6.89-6.96(m,2H),6.79-6.
83(m,1H),5.12(s,2H),5.11-5.17(m,1H),4.48-4.53(m,1
H),4.21-4.30(m,1H),3.92(s,2H),2.94(d,J=5.76,2H),1.
49-1.72(m,3H),0.95(d,J=6.08Hz,6H) Rf値:0.28(展開溶媒A) :0.18(展開溶媒B) (実施例11)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(チオフェン−
3−イルメチル)チオ〕エチルアミド(化合物(5
1)) 実施例1に準ずる方法で参考例1で合成した化合物
(1)の代りに参考例10で合成した化合物(10)
2.5gを用いて標記化合物(51)1.49gを油状
物質として得た。NMR (δ, CDCl 3 ): 9.50 (s, 1H),
7.34 (s, 5H), 7.21-7.23 (m, 1H), 6.89-6.96 (m, 2H), 6.79-6.
83 (m, 1H), 5.12 (s, 2H), 5.11-5.17 (m, 1H), 4.48-4.53 (m, 1
H), 4.21-4.30 (m, 1H), 3.92 (s, 2H), 2.94 (d, J = 5.76,2H), 1.
49-1.72 (m, 3H), 0.95 (d, J = 6.08 Hz, 6H) Rf value: 0.28 (developing solvent A): 0.18 (developing solvent B) (Example 11) L-N-benzyl Oxycarbonylleucine- (2R)-[1-formyl-2- (thiophene-
3-ylmethyl) thio] ethylamide (compound (5
1)) Compound (10) synthesized in Reference Example 10 in place of compound (1) synthesized in Reference Example 1 by a method similar to that of Example 1.
Using 2.5 g, 1.49 g of the title compound (51) was obtained as an oil.
【0110】NMR(δ,CDCl3 ):9.49(s,1H),
7.26-7.34(m,6H),7.16(s,1H),7.05(d,J=4.93,1H),6.79-
6.91(m,1H),5.14-5.18(m,1H),5.12(s,2H),4.48-4.52(m,
1H),4.20-4.30(m,1H),3.73(s,2H),2.86(br s,2H),1.49-
1.71(m,3H),0.95(d,J=5.96Hz,6H) Rf値:0.33(展開溶媒A) :0.22(展開溶媒B) (実施例12)L−N−〔1−(ベンジルオキシカルボ
ニル)−ピペリジン−4−カルボニル〕ロイシン−(2
R)−〔1−ホルミル−2−ベンジルチオ)エチルアミ
ド(化合物(52)) 実施例1に準ずる方法でN−(ベンジルオキシカルボニ
ル)ロイシンの代りに参考例37で合成した化合物(3
8)と参考例1で合成した化合物(1)の代りに市販の
L−S−ベンジル−システインエチルエステル塩酸塩
0.98gを用いて標記化合物(52)0.39gを油
状物質として得た。NMR (δ, CDCl 3 ): 9.49 (s, 1H),
7.26-7.34 (m, 6H), 7.16 (s, 1H), 7.05 (d, J = 4.93,1H), 6.79-
6.91 (m, 1H), 5.14-5.18 (m, 1H), 5.12 (s, 2H), 4.48-4.52 (m,
1H), 4.20-4.30 (m, 1H), 3.73 (s, 2H), 2.86 (br s, 2H), 1.49-
1.71 (m, 3H), 0.95 (d, J = 5.96 Hz, 6H) Rf value: 0.33 (developing solvent A): 0.22 (developing solvent B) (Example 12) LN- [1- (Benzyloxycarbonyl) -piperidine-4-carbonyl] leucine- (2
R)-[1-Formyl-2-benzylthio) ethylamide (Compound (52)) Compound (3) synthesized in Reference Example 37 in place of N- (benzyloxycarbonyl) leucine according to the method of Example 1.
0.39 g of the title compound (52) was obtained as an oil using 0.98 g of commercially available LS-benzyl-cysteine ethyl ester hydrochloride instead of the compound (1) synthesized in 8) and Reference Example 1.
【0111】NMR(δ,CDCl3 ):9.46(s,1H),
7.24-7.36(m,10H),6.25-6.40(m,1H),5.11(s,2H),4.56-
4.59(m,1H),4.42-4.47(m,1H),4.10-4.25(m,2H),3.70(d,
J=3.27Hz,2H),2.74-2.91(m,4H),2.25-2.33(m,1H),1.52-
1.82(m,8H),0.93(t,J=5.58Hz,6H) Rf値:0.04(展開溶媒A) :0.05(展開溶媒B) (実施例13)L−N−(ベンジルオキシカルボニル)
ロイシン−(2R)−〔1−ホルミル−2−(ナフタレ
ン−1−イルメチルチオ)〕エチルアミド(化合物(5
3)) 参考例11で合成した化合物(11)1.25g(3.
98mmol)とL−N−(ベンジルオキシカルボニル)ロ
イシン N−ヒドロキシスクシンイミドエステル1.4
5g(3.98mmol)のクロロホルム溶液に氷冷攪拌下
トリエチルアミン0.81g(3.98mmol)を滴下し
さらに一夜攪拌した。反応溶液を1N−塩酸水溶液,飽
和炭酸水素ナトリウム水溶液さらに水で洗浄し、無水硫
酸ナトリウムで乾燥し減圧下溶媒留去し得られた残留物
をシリカゲルカラムクロマトグラフィーにて精製しエス
テル体であるL−N−(ベンジルオキシカルボニル)−
ロイシル−(L)−S−(ナフタレン−1−イル−メチ
ル)システインエチルエステル0.9g(42%)を得
た。得られたエステル体0.9g(1.68mmol)の無
水テトラヒドロフラン溶液に水素化ホウ素リチウム0.
073g(3.35mmol)を加え、氷冷下メタノールを
滴下し3時間攪拌した反応溶液に水を滴下し減圧下溶媒
留去した。得られた残留物の水溶液を1N−塩酸水溶液
で酸性とし酢酸エチルで抽出し水洗後無水硫酸ナトリウ
ムで乾燥し減圧下溶媒留去し得られた残留物をシリカゲ
ルカラムクロマトグラフィーで精製してアルコール体
0.577gを得た(収率69%)。NMR (δ, CDCl 3 ): 9.46 (s, 1H),
7.24-7.36 (m, 10H), 6.25-6.40 (m, 1H), 5.11 (s, 2H), 4.56-
4.59 (m, 1H), 4.42-4.47 (m, 1H), 4.10-4.25 (m, 2H), 3.70 (d,
J = 3.27Hz, 2H), 2.74-2.91 (m, 4H), 2.25-2.33 (m, 1H), 1.52-
1.82 (m, 8H), 0.93 (t, J = 5.58 Hz, 6H) Rf value: 0.04 (developing solvent A): 0.05 (developing solvent B) (Example 13) LN- (benzyloxy) Carbonyl)
Leucine- (2R)-[1-formyl-2- (naphthalen-1-ylmethylthio)] ethylamide (compound (5
3)) 1.25 g of compound (11) synthesized in Reference Example 11 (3.
98 mmol) and LN- (benzyloxycarbonyl) leucine N-hydroxysuccinimide ester 1.4
To a chloroform solution of 5 g (3.98 mmol), 0.81 g (3.98 mmol) of triethylamine was added dropwise with stirring under ice-cooling, and the mixture was further stirred overnight. The reaction solution was washed with a 1N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the ester L. -N- (benzyloxycarbonyl)-
0.9 g (42%) of leucyl- (L) -S- (naphthalen-1-yl-methyl) cysteine ethyl ester was obtained. To a solution of 0.9 g (1.68 mmol) of the obtained ester in anhydrous tetrahydrofuran was added lithium borohydride (0.5%).
073 g (3.35 mmol) was added, methanol was added dropwise under ice cooling, water was added dropwise to the reaction solution stirred for 3 hours, and the solvent was distilled off under reduced pressure. The aqueous solution of the obtained residue was acidified with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 0.577 g was obtained (69% yield).
【0112】アルコール体0.55g(1.11mmol)
とトリエチルアミン0.45g(4.44mmol)の無水
ジメチルスルホキシド溶液に室温攪拌下に三酸化イオウ
−ピリジンコンプレックス0.708g(4.44mmo
l)ジメチルスルホキシド溶液を滴下し室温で1時間攪
拌した。反応溶液を氷水に注ぎ、酢酸エチルで3回抽出
し、10%クエン酸水溶液,飽和食塩水,飽和炭酸水素
ナトリウム水溶液及び飽和食塩水の順で洗浄し無水硫酸
ナトリウムで乾燥し減圧下溶媒留去し得られた残留物を
シリカゲルカラムクロマトグラフィーで精製し標記化合
物(53)0.26g(収率47%)を得た。Alcohol 0.55 g (1.11 mmol)
To a solution of 0.45 g (4.44 mmol) of triethylamine and anhydrous dimethyl sulfoxide, 0.708 g (4.44 mmol) of a sulfur trioxide-pyridine complex was stirred at room temperature.
l) A dimethyl sulfoxide solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted three times with ethyl acetate, washed sequentially with a 10% aqueous citric acid solution, a saturated saline solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography to obtain 0.26 g (yield 47%) of the title compound (53).
【0113】融点(℃):115.0〜126.1(分
解) NMR(δ,CDCl3 ):9.46(s,1H),8.06(d,J=7.92
Hz,1H),7.86(d,J=9.23,1H),7.76-7.80(m,2H),7.31-7.58
(m,8H),6.75-6.90(m,1H),5.08(d,J=3.78Hz,2H),4.98-5.
05(m,1H),4.48-4.58(m,1H),4.17-4.27(m,1H),4.17(s,2
H),2.90-2.93(m,2H),1.35-1.72(m,3H),0.91-0.93(m,6H) Rf値:0.28(展開溶媒A) :0.22(展開溶媒B) (実施例14)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2(ナフタレン−2
−イルメチル)チオ〕エチルアミド(化合物(54)) 実施例13に準ずる方法で、参考例11で合成した化合
物(11)の代りに参考例12で合成した化合物(1
2)1.26gを用いて標記化合物(54)0.1gを
油状物質として得た。Melting point (° C.): 115.0-126.1 (decomposition) NMR (δ, CDCl 3 ): 9.46 (s, 1H), 8.06 (d, J = 7.92)
Hz, 1H), 7.86 (d, J = 9.23,1H), 7.76-7.80 (m, 2H), 7.31-7.58
(m, 8H), 6.75-6.90 (m, 1H), 5.08 (d, J = 3.78Hz, 2H), 4.98-5.
05 (m, 1H), 4.48-4.58 (m, 1H), 4.17-4.27 (m, 1H), 4.17 (s, 2
H), 2.90-2.93 (m, 2H), 1.35-1.72 (m, 3H), 0.91-0.93 (m, 6H) Rf value: 0.28 (developing solvent A): 0.22 (developing solvent B) ( Example 14) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2 (naphthalene-2
-Ylmethyl) thio] ethylamide (compound (54)) The compound (1) synthesized in Reference Example 12 in place of the compound (11) synthesized in Reference Example 11 by a method similar to that of Example 13.
2) Using 1.26 g, 0.1 g of the title compound (54) was obtained as an oil.
【0114】NMR(δ,CDCl3 ):9.48(d,J=5.1
0Hz,1H),7.71-7.83(m,3H),7.32-7.49(m,9H),6.80-6.82
(m,1H),5.11(d,J=3.36Hz,2H),5.07-5.18(m,1H),5.50-5.
57(m,1H),4.22-4.30(m,1H),3.87(s,2H),2.87(d,J=5.01H
z,2H),1.45-1.80(m,3H),0.93(d,J=6.36Hz,6H) Rf値:0.29(展開溶媒A) :0.22(展開溶媒B) (実施例15)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(2−クロロベ
ンジル)チオ〕エチルアミド(化合物(55)) 実施例13に準ずる方法で参考例11で合成した化合物
(11)の代りに参考例13で合成した化合物(13)
1.24gを用いて標記化合物(55)0.57gを得
た。NMR (δ, CDCl 3 ): 9.48 (d, J = 5.1
0Hz, 1H), 7.71-7.83 (m, 3H), 7.32-7.49 (m, 9H), 6.80-6.82
(m, 1H), 5.11 (d, J = 3.36Hz, 2H), 5.07-5.18 (m, 1H), 5.50-5.
57 (m, 1H), 4.22-4.30 (m, 1H), 3.87 (s, 2H), 2.87 (d, J = 5.01H
(z, 2H), 1.45-1.80 (m, 3H), 0.93 (d, J = 6.36 Hz, 6H) Rf value: 0.29 (developing solvent A): 0.22 (developing solvent B) (Example 15) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (2-chlorobenzyl) thio] ethylamide (compound (55)) The compound synthesized in Reference Example 11 by a method similar to that in Example 13 ( Compound (13) synthesized in Reference Example 13 instead of 11)
Using 1.24 g, 0.57 g of the title compound (55) was obtained.
【0115】融点(℃):128.6〜131.9 NMR(δ,CDCl3 ):9.55(s,1H),7.20-7.40(m,9
H),6.83-6.91(m,1H),5.10-5.20(br s,3H),4.52-4.60(m,
1H),4.20-4.30(m,1H),3.84(s,2H),2.93(br s,2H),1.49-
1.73(m,4H),0.95(d,J=4.29Hz,6H) Rf値:0.31(展開溶媒A) :0.24(展開溶媒B) (実施例16)L−N−メチル−N−(ベンジルオキシ
カルボニル)ロイシン−(2R)−〔1−ホルミル−2
−(4−クロロベンジルチオ)〕エチルアミド(化合物
(56)) 参考例40で合成した化合物(40)0.9g(3.2
2mmol),トリエチルアミン0.326g(3.22mm
ol)1−ヒドロキシベンズトリアゾール0.443g
(3.22mmol)および参考例16で合成した化合物
(17)0.748g(3.22mmol)のクロロホルム
溶液(100ml)に塩−氷浴で冷却攪拌下ジシクロヘキ
シルカルボジイミド0.664g(3.22mmol)のク
ロロホルム溶液を滴下した。さらに一夜攪拌した。不溶
物を濾去し、濾液を1N−塩酸,飽和NaHCO3 溶
液,飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾
燥後減圧下濃縮した。得られた残留物をシリカゲルカラ
ムクロマトグラフィーで精製することによりL−N−メ
チル−N−(ベンジルオキシカルボニル)ロイシン−
(2R)−〔1−ヒドロキシメチル−2−(4−クロロ
フェニル)〕エチルアミド1.2g(収率75%)を得
た。Melting point (° C.): 128.6-131.9 NMR (δ, CDCl 3 ): 9.55 (s, 1H), 7.20-7.40 (m, 9
H), 6.83-6.91 (m, 1H), 5.10-5.20 (br s, 3H), 4.52-4.60 (m,
1H), 4.20-4.30 (m, 1H), 3.84 (s, 2H), 2.93 (br s, 2H), 1.49-
1.73 (m, 4H), 0.95 (d, J = 4.29 Hz, 6H) Rf value: 0.31 (developing solvent A): 0.24 (developing solvent B) (Example 16) L-N-methyl-N -(Benzyloxycarbonyl) leucine- (2R)-[1-formyl-2
-(4-chlorobenzylthio)] ethylamide (compound (56)) 0.9 g of compound (40) synthesized in Reference Example 40 (3.2)
2 mmol), 0.326 g of triethylamine (3.22 mm
ol) 1-hydroxybenztriazole 0.443 g
To a chloroform solution (100 ml) of (3.22 mmol) and 0.748 g (3.22 mmol) of the compound (17) synthesized in Reference Example 16, 0.664 g (3.22 mmol) of dicyclohexylcarbodiimide was stirred while cooling with a salt-ice bath. A chloroform solution was added dropwise. The mixture was further stirred overnight. The insoluble material was removed by filtration, and the filtrate was washed successively with 1N hydrochloric acid, a saturated NaHCO 3 solution, and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give L-N-methyl-N- (benzyloxycarbonyl) leucine-
1.2 g (yield 75%) of (2R)-[1-hydroxymethyl-2- (4-chlorophenyl)] ethylamide was obtained.
【0116】得られた上記化合物0.89g(1.8mm
ol)およびトリエチルアミン0.13g(7.22mmo
l)の無水ジメチルスルホキシド溶液(10ml)に室温
攪拌下三酸化イオウ−ピリジンコンプレックス1.14
g(7.22mmol)の無水ジメチルスルホキシド溶液
(10ml)を滴下、さらに30分間攪拌した。反応溶液
を氷水に注ぎ酢酸エチルで3回抽出した。合わせた有機
層を10%−クエン酸水溶液,水,飽和炭酸水素ナトリ
ウム水溶液,飽和食塩水で順次洗浄し、無水硫酸ナトリ
ウムで乾燥後減圧下濃縮した。得られた残留物をシリカ
ゲルカラムクロマトグラフィーで精製することにより標
記化合物(56)0.52gを油状物質として得た。The above compound (0.89 g, 1.8 mm) was obtained.
ol) and 0.13 g (7.22 mmol) of triethylamine.
l) An anhydrous dimethyl sulfoxide solution (10 ml) was added to a sulfur trioxide-pyridine complex 1.14 while stirring at room temperature.
g (7.22 mmol) in anhydrous dimethyl sulfoxide (10 ml) was added dropwise, and the mixture was further stirred for 30 minutes. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic layer was washed successively with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.52 g of the title compound (56) as an oil.
【0117】NMR(δ,CDCl3 ):9.50(s,1H),
7.15-7.40(m,9H),6.80-6.95(m,1H),5.10-5.30(m,2H),4.
60-4.90(m,1H),4.40-4.55(m,1H),3.60-3.71(m,2H),2.85
(s,3H),2.60-2.85(m,2H),1.60-1.80(m,2H),1.42-1.60
(m,1H),0.80-1.05(m,6H) Rf値:0.42(展開溶媒A) :0.30(展開溶媒B) (実施例17)L−N−(N−フェニルカルバモイル)
ロイシン−(2R)−〔1−ホルミル−2−(4−クロ
ロベンジルチオ)〕エチルアミド(化合物(57)) 実施例16に準ずる方法で参考例40で合成した化合物
(40)の代りに参考例38で合成した化合物(38)
1gを用いて標記化合物(57)0.34gを非結晶質
として得た。NMR (δ, CDCl 3 ): 9.50 (s, 1H),
7.15-7.40 (m, 9H), 6.80-6.95 (m, 1H), 5.10-5.30 (m, 2H), 4.
60-4.90 (m, 1H), 4.40-4.55 (m, 1H), 3.60-3.71 (m, 2H), 2.85
(s, 3H), 2.60-2.85 (m, 2H), 1.60-1.80 (m, 2H), 1.42-1.60
(m, 1H), 0.80-1.05 (m, 6H) Rf value: 0.42 (developing solvent A): 0.30 (developing solvent B) (Example 17) LN- (N-phenylcarbamoyl)
Leucine- (2R)-[1-formyl-2- (4-chlorobenzylthio)] ethylamide (Compound (57)) Reference example instead of compound (40) synthesized in Reference example 40 by the method according to Example 16. Compound (38) synthesized in 38
Using 1 g, 0.34 g of the title compound (57) was obtained as amorphous.
【0118】NMR(δ,CDCl3 ):9.40(s,1H),
7.97(bs,1H),7.05 〜7.45(m,9H),6.63(bs,1H),4.50 〜
4.60(m,1H),4.30 〜4.40(m,1H),3.60 〜3.75(m,2H),3.1
0 〜3.30(m,2H),1.45 〜1.85(m,3H),0.85 〜1.10(m,6H) Rf値:0.20(展開溶媒A) :0.10(展開溶媒B) (実施例18)L−N−(4−メチルベンゼンスルホニ
ル)ロイシン−(2R)−〔1−ホルミル−2−(4−
クロロベンジルチオ)〕エチルアミド(化合物(5
8)) 実施例16に準ずる方法で参考例40で合成した化合物
(40)の代りに参考例39で合成した化合物(39)
1gを用いて標記化合物(58)0.54gを非結晶質
として得た。NMR (δ, CDCl 3 ): 9.40 (s, 1H),
7.97 (bs, 1H), 7.05-7.45 (m, 9H), 6.63 (bs, 1H), 4.50-
4.60 (m, 1H), 4.30 to 4.40 (m, 1H), 3.60 to 3.75 (m, 2H), 3.1
0 to 3.30 (m, 2H), 1.45 to 1.85 (m, 3H), 0.85 to 1.10 (m, 6H) Rf value: 0.20 (developing solvent A): 0.10 (developing solvent B) (Example 18) ) LN- (4-methylbenzenesulfonyl) leucine- (2R)-[1-formyl-2- (4-
Chlorobenzylthio)] ethylamide (compound (5
8)) Compound (39) synthesized in Reference Example 39 instead of compound (40) synthesized in Reference Example 40 by a method similar to that in Example 16.
Using 1 g, 0.54 g of the title compound (58) was obtained as amorphous.
【0119】NMR(δ,CDCl3 ):9.37(s,1H),
7.73(d,J=8.2Hz,2H),7.20-7.35(m,6H),6.61(d,J=8.4Hz,
1H),4.99(d,J=5.8Hz,1H),4.29-4.45(m,2H),3.63(s,2H),
2.70〜2.90(m,2H),2.40(s,3H),1.40〜1.70(m,3H),0.90
〜1.10(m,6H) Rf値:0.33(展開溶媒A) :0.25(展開溶媒B) (実施例19)L−N−(ベンジルオキシカルボニル)
フェニルアラニン−(2R)−〔1−ホルミル−2−
(4−クロロベンジルチオ)〕エチルアミド(化合物
(59)) 実施例16に準ずる方法で参考例40で合成した化合物
(40)の代りに市販の(L)−N−(ベンジルオキシ
カルボニル)フェニルアラニン1gを用いて標記化合物
(59)0.4gを得た。NMR (δ, CDCl 3 ): 9.37 (s, 1H),
7.73 (d, J = 8.2Hz, 2H), 7.20-7.35 (m, 6H), 6.61 (d, J = 8.4Hz,
1H), 4.99 (d, J = 5.8Hz, 1H), 4.29-4.45 (m, 2H), 3.63 (s, 2H),
2.70-2.90 (m, 2H), 2.40 (s, 3H), 1.40-1.70 (m, 3H), 0.90
-1.10 (m, 6H) Rf value: 0.33 (developing solvent A): 0.25 (developing solvent B) (Example 19) LN- (benzyloxycarbonyl)
Phenylalanine- (2R)-[1-formyl-2-
(4-chlorobenzylthio)] ethylamide (Compound (59)) 1 g of commercially available (L) -N- (benzyloxycarbonyl) phenylalanine instead of compound (40) synthesized in Reference Example 40 by a method similar to that in Example 16. Was used to obtain 0.4 g of the title compound (59).
【0120】融点(℃):129.4〜133.4 NMR(δ,CDCl3 ):9.38(s,1H),7.10 〜7.41
(m,14H),6.30〜6.40(m,1H),5.20 〜5.30(m,1H),5.09(s,
2H),4.35〜4.51(m,2H),3.35 〜3.45(m,2H),3.00〜3.20
(m,2H),2.70 〜2.80(m,2H) Rf値:0.36(展開溶媒A) :0.24(展開溶媒B) (実施例20)(L)−N−(ベンジルオキシカルボニ
ル)−バリン−(2R)−〔1−ホルミル−2−(4−
クロロベンジルチオ)〕エチルアミド(化合物(6
0)) 実施例16に準ずる方法で参考例40で合成した化合物
(40)の代りに市販のL−N−(ベンジルオキシカル
ボニル)バリン1gを用いて標記化合物(60)0.1
4gを得た。Melting point (° C.): 129.4 to 133.4 NMR (δ, CDCl 3 ): 9.38 (s, 1H), 7.10 to 7.41
(m, 14H), 6.30-6.40 (m, 1H), 5.20-5.30 (m, 1H), 5.09 (s,
2H), 4.35 to 4.51 (m, 2H), 3.35 to 3.45 (m, 2H), 3.00 to 3.20
(m, 2H), 2.70 to 2.80 (m, 2H) Rf value: 0.36 (developing solvent A): 0.24 (developing solvent B) (Example 20) (L) -N- (benzyloxycarbonyl) -Valine- (2R)-[1-formyl-2- (4-
Chlorobenzylthio)] ethylamide (compound (6
0)) The title compound (60) 0.1 was obtained using 1 g of commercially available LN- (benzyloxycarbonyl) valine in place of the compound (40) synthesized in Reference Example 40 by a method similar to that in Example 16.
4 g were obtained.
【0121】融点(℃):126.2〜128.7 NMR(δ,CDCl3 ):9.52(s,1H),7.20 〜7.45
(m,9H),6.60 〜6.75(m,1H),5.25 〜5.35(m,1H),5.11(s,
2H),4.50〜4.61(m,1H),4.00 〜4.15(m,1H),3.68(s,2H),
2.75〜2.90(m,2H),2.10 〜2.25(m,1H),0.90 〜1.05(m,6
H) Rf値:0.36(展開溶媒A) :0.21(展開溶媒B) (実施例21)L−N−(ベンジルオキシカルボニル)
ロイシン−(2R)−〔1−ホルミル−2−(4−クロ
ロベンジル)チオ〕エチルアミド(化合物(61)) 参考例16で合成した化合物(17)4g(17.26
mmol)およびトリエチルアミン1.74g(17.26
mmol)のクロロホルム溶液(200ml)に氷冷攪拌下L
−N−(ベンジルオキシカルボニル)ロイシン N−ヒ
ドロキシスクシンイミドエステル6.25g(17.2
6mmol)を少量ずつ加え、室温に戻した後一夜攪拌し
た。反応溶液を1N−塩酸,飽和炭酸水素ナトリウム溶
液(3回),飽和食塩水で順次洗浄し、無水硫酸ナトリ
ウムで乾燥後減圧下濃縮し、アルコール体である(L)
−N−(ベンジルオキシカルボニル)ロイシン−(2
R)−〔1−ヒドロキシメチル−2−(4−クロロベン
ジルチオ)〕エチルアミド7.8g(94%)を得た。
得られた上記アルコール体7.8g(16.28mmol)
およびトリエチルアミン6.57g(65mmol)の無水
ジメチルスルホキシド溶液(100ml)に室温攪拌下三
酸化イオウピリジンコンプレックス10.34g(65
mmol)の無水ジメチルスルホキシド溶液(30ml)を滴
下した。30分間攪拌後、反応溶液を氷水に注ぎ酢酸エ
チルで3回抽出した。合わせた有機層を10%−クエン
酸水溶液水,飽和炭酸水素ナトリウム溶液,飽和食塩水
で順次洗浄し、無水硫酸ナトリウムで乾燥後減圧下濃縮
した。得られた残留物をシリカゲルカラムクロマトグラ
フィーで精製し標記化合物(61)2.4gを得た。Melting point (° C.): 126.2-128.7 NMR (δ, CDCl 3 ): 9.52 (s, 1H), 7.20 to 7.45
(m, 9H), 6.60-6.75 (m, 1H), 5.25-5.35 (m, 1H), 5.11 (s,
2H), 4.50-4.61 (m, 1H), 4.00-4.15 (m, 1H), 3.68 (s, 2H),
2.75 to 2.90 (m, 2H), 2.10 to 2.25 (m, 1H), 0.90 to 1.05 (m, 6
H) Rf value: 0.36 (developing solvent A): 0.21 (developing solvent B) (Example 21) LN- (benzyloxycarbonyl)
Leucine- (2R)-[1-formyl-2- (4-chlorobenzyl) thio] ethylamide (compound (61)) 4 g of compound (17) synthesized in Reference Example 16 (17.26
mmol) and 1.74 g of triethylamine (17.26
mmol) in chloroform solution (200 ml) under ice-cooling and stirring.
6.25 g of -N- (benzyloxycarbonyl) leucine N-hydroxysuccinimide ester (17.2
6 mmol) was added little by little, and after returning to room temperature, the mixture was stirred overnight. The reaction solution was washed successively with 1N hydrochloric acid, saturated sodium hydrogen carbonate solution (three times) and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an alcohol (L)
-N- (benzyloxycarbonyl) leucine- (2
7.8 g (94%) of R)-[1-hydroxymethyl-2- (4-chlorobenzylthio)] ethylamide were obtained.
7.8 g (16.28 mmol) of the alcohol obtained above
To a solution of 6.57 g (65 mmol) of triethylamine and anhydrous dimethyl sulfoxide (100 ml) were added 10.34 g (65 ml) of sulfur trioxide pyridine complex under stirring at room temperature.
mmol) in anhydrous dimethylsulfoxide (30 ml) was added dropwise. After stirring for 30 minutes, the reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic layers were washed successively with 10% aqueous citric acid, aqueous saturated sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.4 g of the title compound (61).
【0122】融点(℃):116.0〜130.7(分
解) NMR(δ,CDCl3 ):9.52(d,J=4.88Hz,1H),7.22
-7.33(m,10H),6.83-6.91(m,1H),5.11(d,J=2.33Hz,3H),
4.50-4.59(m,1H),4.23-4.30(m,1H),3.67(s,2H),2.85(d,
J=4.99Hz,2H),1.49-1.72(m,3H),0.94-0.96(m,6H) Rf値:0.25(展開溶媒A) :0.19(展開溶媒B) (実施例22)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(3−クロロベ
ンジル)チオ〕エチルアミド(化合物(62)) 実施例21に準ずる方法で参考例16で合成された化合
物(16)の代りに参考例15で合成した化合物(1
5)3.0gを用いて標記化合物(62)0.68gを
得た。Melting point (° C.): 116.0 to 130.7 (decomposition) NMR (δ, CDCl 3 ): 9.52 (d, J = 4.88 Hz, 1H), 7.22
-7.33 (m, 10H), 6.83-6.91 (m, 1H), 5.11 (d, J = 2.33Hz, 3H),
4.50-4.59 (m, 1H), 4.23-4.30 (m, 1H), 3.67 (s, 2H), 2.85 (d,
J = 4.99Hz, 2H), 1.49-1.72 (m, 3H), 0.94-0.96 (m, 6H) Rf value: 0.25 (developing solvent A): 0.19 (developing solvent B) (Example 22) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3-chlorobenzyl) thio] ethylamide (compound (62)) The compound synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (1) synthesized in Reference Example 15 instead of (16)
5) Using 3.0 g, 0.68 g of the title compound (62) was obtained.
【0123】融点(℃):97.6〜103.3 NMR(δ,CDCl3 ):9.53(s,1H),7.16-7.34(m,9
H),6.84-6.90(m,1H),5.11(s,2H),5.10-5.17(m,1H),4.50
-4.60(m,1H),4.20-4.30(m,1H),3.68(s,2H),2.80-2.93
(m,2H),1.48-1.76(m,3H),0.94-0.97(m,6H) Rf値:0.25(展開溶媒A) :0.18(展開溶媒B) (実施例23)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(2−フルオロ
ベンジル)チオ〕エチルアミド(化合物(63)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例14で合成した化合物(14)
8.7gを用いて標記化合物(63)2.75gを得
た。Melting point (° C.): 97.6 to 103.3 NMR (δ, CDCl 3 ): 9.53 (s, 1H), 7.16-7.34 (m, 9
H), 6.84-6.90 (m, 1H), 5.11 (s, 2H), 5.10-5.17 (m, 1H), 4.50
-4.60 (m, 1H), 4.20-4.30 (m, 1H), 3.68 (s, 2H), 2.80-2.93
(m, 2H), 1.48-1.76 (m, 3H), 0.94-0.97 (m, 6H) Rf value: 0.25 (developing solvent A): 0.18 (developing solvent B) (Example 23) L- N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (2-fluorobenzyl) thio] ethylamide (compound (63)) Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (14) synthesized in Reference Example 14 instead of
Using 8.7 g, 2.75 g of the title compound (63) was obtained.
【0124】融点(℃):110.1〜118.3 NMR(δ,CDCl3 ):9.54(s,1H),7.08-7.34(m,7
H),7.02-7.12(m,2H),6.83(br s,1H),5.11(s,3H),4.50-
4.60(m,1H),4.20-4.30(m,1H),3.75(d,J=2.93Hz,2H),2.9
3(d,J=5.48Hz,2H),1.50-1.75(m,3H),0.95(d,J=6.18Hz,6
H) Rf値:0.30(展開溶媒A) :0.22(展開溶媒B) (実施例24)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(3−フルオロ
ベンジル)チオ〕エチルアミド(化合物(64)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例17で合成した化合物(17)
6.5gを用いて標記化合物(64)0.37gを得
た。Melting point (° C.): 110.1 to 118.3 NMR (δ, CDCl 3 ): 9.54 (s, 1H), 7.08-7.34 (m, 7
H), 7.02-7.12 (m, 2H), 6.83 (br s, 1H), 5.11 (s, 3H), 4.50-
4.60 (m, 1H), 4.20-4.30 (m, 1H), 3.75 (d, J = 2.93Hz, 2H), 2.9
3 (d, J = 5.48Hz, 2H), 1.50-1.75 (m, 3H), 0.95 (d, J = 6.18Hz, 6
H) Rf value: 0.30 (developing solvent A): 0.22 (developing solvent B) (Example 24) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3- (Fluorobenzyl) thio] ethylamide (Compound (64)) Compound (17) synthesized in Reference Example 17 instead of Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 6.5 g, 0.37 g of the title compound (64) was obtained.
【0125】融点(℃):111.8〜116.6 NMR(δ,CDCl3 ):9.53(s,1H),7.24-7.34(m,6
H),7.06(t,J=8.19Hz,1H),6.95(t,J=8.96Hz,1H),6.81-6.
87(m,1H),5.11(s,3H),4.50-4.59(m,1H),4.21-4.30(m,1
H),3.70(s,7H),2.87(d,J=5.37Hz,2H),1.45-1.73(m,3H),
0.94-0.97(m,6H) Rf値:0.23(展開溶媒A) :0.19(展開溶媒B) (実施例25)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(4−フルオロ
ベンジル)チオ〕エチルアミド(化合物(65)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例18で合成した化合物(18)
6.46gを用いて標記化合物(65)0.8gを得
た。Melting point (° C.): 111.8 to 116.6 NMR (δ, CDCl 3 ): 9.53 (s, 1H), 7.24 to 7.34 (m, 6
H), 7.06 (t, J = 8.19Hz, 1H), 6.95 (t, J = 8.96Hz, 1H), 6.81-6.
87 (m, 1H), 5.11 (s, 3H), 4.50-4.59 (m, 1H), 4.21-4.30 (m, 1
H), 3.70 (s, 7H), 2.87 (d, J = 5.37 Hz, 2H), 1.45-1.73 (m, 3H),
0.94-0.97 (m, 6H) Rf value: 0.23 (developing solvent A): 0.19 (developing solvent B) (Example 25) LN-benzyloxycarbonylleucine- (2R)-[1-formyl -2- (4-Fluorobenzyl) thio] ethylamide (compound (65)) Compound (18) synthesized in Reference Example 18 instead of compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 6.46 g, 0.8 g of the title compound (65) was obtained.
【0126】融点(℃):71.2〜76.3 NMR(δ,CDCl3 ):9.52(d,J=5.37Hz,1H),7.25
-7.34(m,7H),6.95-7.07(m,2H),6.82-6.90(m,1H),5.11-
5.20(m,3H),4.50-4.60(m,1H),4.20-4.30(m,1H),3.69(s,
2H),2.80-2.90(m,2H),1.49-1.73(m,3H),0.95(d,J=4.12H
z,6H) Rf値:0.25(展開溶媒A) :0.20(展開溶媒B) (実施例26)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(2−メトキシ
ベンジル)チオ〕エチルアミド(化合物(66)) 実施例21に準ずる方法で参考例17で合成した化合物
(17)の代りに参考例19で合成した化合物(19)
5.0gを用いて標記化合物(66)0.88gを得
た。Melting point (° C.): 71.2-76.3 NMR (δ, CDCl 3 ): 9.52 (d, J = 5.37 Hz, 1H), 7.25
-7.34 (m, 7H), 6.95-7.07 (m, 2H), 6.82-6.90 (m, 1H), 5.11-
5.20 (m, 3H), 4.50-4.60 (m, 1H), 4.20-4.30 (m, 1H), 3.69 (s,
2H), 2.80-2.90 (m, 2H), 1.49-1.73 (m, 3H), 0.95 (d, J = 4.12H
(z, 6H) Rf value: 0.25 (developing solvent A): 0.20 (developing solvent B) (Example 26) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- ( 2-methoxybenzyl) thio] ethylamide (compound (66)) Compound (19) synthesized in Reference Example 19 instead of compound (17) synthesized in Reference Example 17 by a method similar to that in Example 21.
Using 5.0 g, 0.88 g of the title compound (66) was obtained.
【0127】融点(℃):110.8〜120.2 NMR(δ,CDCl3 ):9.51(s,1H),7.22-7.34(m,7
H),6.86-6.97(m,2H),6.80-6.85(m,1H),5.15-5.25(m,1
H),5.11(s,2H),4.51-4.59(m,1H),4.22-4.28(m,1H),3.83
(s,3H),3.85(d,J=5.42Hz,1H),3.74(d,J=5.7Hz,1H),2.91
(d,J=5.86Hz,2H),1.42-1.74(m,3H),0.93-0.96(m,6H) Rf値:0.27(展開溶媒A) :0.20(展開溶媒B) (実施例27)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(3−メトキシ
ベンジル)チオ〕エチルアミド(化合物(67)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例20で合成した化合物(20)
3.41gを用いて標記化合物(67)0.71gを得
た。Melting point (° C.): 110.8-120.2 NMR (δ, CDCl 3 ): 9.51 (s, 1H), 7.22-7.34 (m, 7
H), 6.86-6.97 (m, 2H), 6.80-6.85 (m, 1H), 5.15-5.25 (m, 1
H), 5.11 (s, 2H), 4.51-4.59 (m, 1H), 4.22-4.28 (m, 1H), 3.83
(s, 3H), 3.85 (d, J = 5.42Hz, 1H), 3.74 (d, J = 5.7Hz, 1H), 2.91
(d, J = 5.86 Hz, 2H), 1.42-1.74 (m, 3H), 0.93-0.96 (m, 6H) Rf value: 0.27 (developing solvent A): 0.20 (developing solvent B) (implementation Example 27) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (3-methoxybenzyl) thio] ethylamide (compound (67)) Synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (20) synthesized in Reference Example 20 instead of compound (16)
Using 3.41 g, 0.71 g of the title compound (67) was obtained.
【0128】融点(℃):113.8〜117.8 NMR(δ,CDCl3 ):9.50(s,1H),7.20-7.34(m,6
H),6.76-6.90(m,4H),4.49-4.53(m,1H),4.23-4.30(m,1
H),3.80(s,3H),3.68(s,2H),2.88(d,J=5.75Hz,2H),1.50-
1.75(m,3H),0.95(d,J=5.97Hz,6H) Rf値:0.25(展開溶媒A) :0.19(展開溶媒B) (実施例28)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(4−メトキシ
ベンジル)チオ〕エチルアミド(化合物(68)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例21で合成した化合物(21)
4.54gを用いて標記化合物(68)0.13gを油
状物質として得た。Melting point (° C.): 113.8-117.8 NMR (δ, CDCl 3 ): 9.50 (s, 1H), 7.20-7.34 (m, 6
H), 6.76-6.90 (m, 4H), 4.49-4.53 (m, 1H), 4.23-4.30 (m, 1
H), 3.80 (s, 3H), 3.68 (s, 2H), 2.88 (d, J = 5.75Hz, 2H), 1.50-
1.75 (m, 3H), 0.95 (d, J = 5.97 Hz, 6H) Rf value: 0.25 (developing solvent A): 0.19 (developing solvent B) (Example 28) L-N-benzyloxycarbonyl Leucine- (2R)-[1-formyl-2- (4-methoxybenzyl) thio] ethylamide (Compound (68)) Reference example instead of compound (16) synthesized in Reference example 16 by a method similar to Example 21. Compound (21) synthesized in 21
Using 4.54 g, 0.13 g of the title compound (68) was obtained as an oil.
【0129】NMR(δ,CDCl3 ):9.45(br s,1
H),7.30-7.35(m,5H),7.22(d,J=8.57Hz,2H),6.85(d,J=7.
54Hz,2H),6.76-6.89(m,1H),5.11(s,2H),5.08-5.18(m,1
H),4.45-4.52(m,1H),4.20-4.30(m,1H),3.79(s,3H),2.78
-2.89(m,2H),1.46-1.85(m,3H),0.94(d,J=5.86Hz,6H) Rf値:0.19(展開溶媒A) :0.26(展開溶媒B) (実施例29)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−3−ニトロベン
ジル)チオ〕エチルアミド(化合物(69)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例22で合成した化合物(22)
4.18gを用いて標記化合物(69)0.37gを得
た。NMR (δ, CDCl 3 ): 9.45 (br s, 1
H), 7.30-7.35 (m, 5H), 7.22 (d, J = 8.57Hz, 2H), 6.85 (d, J = 7.
54Hz, 2H), 6.76-6.89 (m, 1H), 5.11 (s, 2H), 5.08-5.18 (m, 1
H), 4.45-4.52 (m, 1H), 4.20-4.30 (m, 1H), 3.79 (s, 3H), 2.78
-2.89 (m, 2H), 1.46-1.85 (m, 3H), 0.94 (d, J = 5.86 Hz, 6H) Rf value: 0.19 (developing solvent A): 0.26 (developing solvent B) (implementation Example 29) LN-benzyloxycarbonylleucine- (2R)-[1-formyl-2-nitrobenzyl) thio] ethylamide (Compound (69)) The compound was synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (22) synthesized in Reference Example 22 instead of compound (16)
Using 4.18 g, 0.37 g of the title compound (69) was obtained.
【0130】融点(℃):72.9〜104.9(分
解) NMR(δ,CDCl3 ):9.56(d,J=6.95Hz,1H),8.21
(s,1H),8.13(dd,J=2.44Hz,7.22Hz,1H),7.65(d,J=7.43H
z),7.45-7.52(m,1H),7.33(d,J=4.1Hz,5H),6.91-7.07(m,
1H),5.20(d,J=7.70Hz,1H),5.11(d,J=5.48Hz,2H),4.53-
4.59(m,1H),4.20-4.35(m,1H),3.80(s,2H),2.80-2.95(m,
2H),1.51-1.80(m,3H),0.95(d,J=5.68Hz,6H) Rf値:0.17(展開溶媒A) :0.17(展開溶媒B) (実施例30)L−N−ベンジルオキシカルボニルロイ
シン−(2R)−〔1−ホルミル−2−(4−ニトロベ
ンジル)チオ〕エチルアミド(化合物(70)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例23で合成した化合物(23)
2.17gを用いて標記化合物(70)0.1gを油状
物質として得た。Melting point (° C.): 72.9 to 104.9 (decomposition) NMR (δ, CDCl 3 ): 9.56 (d, J = 6.95 Hz, 1H), 8.21
(s, 1H), 8.13 (dd, J = 2.44Hz, 7.22Hz, 1H), 7.65 (d, J = 7.43H
z), 7.45-7.52 (m, 1H), 7.33 (d, J = 4.1Hz, 5H), 6.91-7.07 (m,
1H), 5.20 (d, J = 7.70Hz, 1H), 5.11 (d, J = 5.48Hz, 2H), 4.53-
4.59 (m, 1H), 4.20-4.35 (m, 1H), 3.80 (s, 2H), 2.80-2.95 (m,
2H), 1.51-1.80 (m, 3H), 0.95 (d, J = 5.68 Hz, 6H) Rf value: 0.17 (developing solvent A): 0.17 (developing solvent B) (Example 30) L- N-benzyloxycarbonylleucine- (2R)-[1-formyl-2- (4-nitrobenzyl) thio] ethylamide (compound (70)) Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (23) synthesized in Reference Example 23 instead of
Using 2.17 g, 0.1 g of the title compound (70) was obtained as an oil.
【0131】NMR(δ,CDCl3 ):9.56(s,1H),
8.15-8.20(m,2H),7.47-7.51(m,2H),7.30-7.34(m,5H),6.
84-7.00(m,1H),5.05-5.15(m,3H),4.53-4.60(m,1H),4.20
-4.30(m,1H),3.79(s,2H),2.87(d,J=5.26Hz,2H),1.49-1.
75(m,3H),0.94-0.97(m,6H) Rf値:0.15(展開溶媒A) :0.15(展開溶媒B) (実施例31)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3−フェニルオキ
シ)プロピルアミド(化合物(71)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例25で合成した化合物(24)
0.52gを用いて標記化合物(71)0.52gを油
状物質として得た。NMR (δ, CDCl 3 ): 9.56 (s, 1H),
8.15-8.20 (m, 2H), 7.47-7.51 (m, 2H), 7.30-7.34 (m, 5H), 6.
84-7.00 (m, 1H), 5.05-5.15 (m, 3H), 4.53-4.60 (m, 1H), 4.20
-4.30 (m, 1H), 3.79 (s, 2H), 2.87 (d, J = 5.26Hz, 2H), 1.49-1.
75 (m, 3H), 0.94-0.97 (m, 6H) Rf value: 0.15 (developing solvent A): 0.15 (developing solvent B) (Example 31) LN-benzyloxycarbonylleucine- ( 2S)-[1-Formyl-3-phenyloxy) propylamide (Compound (71)) Compound (24) synthesized in Reference Example 25 instead of Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. )
0.52 g of the title compound (71) was obtained as an oil using 0.52 g.
【0132】NMR(δ,CDCl3 ):9.64(s,1H),
7.24-7.33(m,8H),6.82-6.98(m,3H),4.95-5.15(m,3H),4.
55-4.59(m,1H),4.20-4.30(m,1H),3.95-4.10(m,2H),2.27
-2.53(m,2H),1.45-1.72(m,3H),0.92(t,J=6.24Hz,6H) Rf値:0.26(展開溶媒A) :0.19(展開溶媒B) (実施例32)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3−フェニルチオ)
プロピルアミド(化合物(72)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例25で合成した化合物(25)
0.87gを用いて標記化合物(72)0.42gを油
状物質として得た。NMR (δ, CDCl 3 ): 9.64 (s, 1H),
7.24-7.33 (m, 8H), 6.82-6.98 (m, 3H), 4.95-5.15 (m, 3H), 4.
55-4.59 (m, 1H), 4.20-4.30 (m, 1H), 3.95-4.10 (m, 2H), 2.27
-2.53 (m, 2H), 1.45-1.72 (m, 3H), 0.92 (t, J = 6.24 Hz, 6H) Rf value: 0.26 (developing solvent A): 0.19 (developing solvent B) (implementation Example 32) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3-phenylthio)
Propylamide (Compound (72)) Compound (25) synthesized in Reference Example 25 instead of Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 0.87 g, 0.42 g of the title compound (72) was obtained as an oil.
【0133】NMR(δ,CDCl3 ):9.52(d,J=6.2
4Hz,1H),7.12-7.38(m,10H),6.71-6.86(m,1H),5.14-5.16
(d,J=6.95Hz,1H),5.10(s,2H),4.51-4.59(m,1H),4.20-4.
25(m,1H),2.91-2.96(m,2H),2.25-2.35(m,1H),1.85-2.00
(m,1H),1.48-1.72(m,3H),0.92-0.96(m,6H) Rf値:0.31(展開溶媒A) :0.24(展開溶媒B) (実施例33)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−2−(2−クロロベ
ンジル)オキシ〕エチルアミド(化合物(73)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例26で合成した化合物(26)
0.55gを用いて標記化合物(73)0.50gを油
状物質として得た。NMR (δ, CDCl 3 ): 9.52 (d, J = 6.2
4Hz, 1H), 7.12-7.38 (m, 10H), 6.71-6.86 (m, 1H), 5.14-5.16
(d, J = 6.95Hz, 1H), 5.10 (s, 2H), 4.51-4.59 (m, 1H), 4.20-4.
25 (m, 1H), 2.91-2.96 (m, 2H), 2.25-2.35 (m, 1H), 1.85-2.00
(m, 1H), 1.48-1.72 (m, 3H), 0.92-0.96 (m, 6H) Rf value: 0.31 (developing solvent A): 0.24 (developing solvent B) (Example 33) L- N-benzyloxycarbonylleucine- (2S)-[1-formyl-2- (2-chlorobenzyl) oxy] ethylamide (compound (73)) Compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (26) synthesized in Reference Example 26 instead of
0.50 g of the title compound (73) was obtained as an oil using 0.55 g.
【0134】NMR(δ,CDCl3 ):9.61(s,1H),
7.23-7.36(m,9H),6.80-6.93(m,1H),5.09-5.17(m,3H),4.
55-4.63(m,3H),4.25-4.35(m,1H),4.08-4.16(m,1H),3.75
-3.79(m,1H),1.49-1.71(m,3H),0.92-0.96(m,6H) Rf値:0.31(展開溶媒A) :0.24(展開溶媒B) (実施例34)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3−(2−フルオロ
フェニル)オキシ〕プロピルアミド(化合物(74)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例27で合成した化合物(27)
0.69gを用いて標記化合物(74)0.66gを油
状物質として得た。NMR (δ, CDCl 3 ): 9.61 (s, 1H),
7.23-7.36 (m, 9H), 6.80-6.93 (m, 1H), 5.09-5.17 (m, 3H), 4.
55-4.63 (m, 3H), 4.25-4.35 (m, 1H), 4.08-4.16 (m, 1H), 3.75
-3.79 (m, 1H), 1.49-1.71 (m, 3H), 0.92-0.96 (m, 6H) Rf value: 0.31 (developing solvent A): 0.24 (developing solvent B) (Example 34) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3- (2-fluorophenyl) oxy] propylamide (compound (74)) Compound synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (27) synthesized in Reference Example 27 instead of (16)
0.66 g of the title compound (74) was obtained as an oil using 0.69 g.
【0135】NMR(δ,CDCl3 ):9.65(s,1H),
7.28-7.37(m,5H),7.02-7.10(m,3H),6.88-6.95(m,2H),5.
10-5.22(m,1H),5.06(s,2H),4.57-4.61(m,1H),4.22-4.30
(m,1H),4.05-4.13(m,2H),2.32-2.50(m,2H),1.50-1.72
(m,3H),0.91-0.95(m,6H) Rf値:0.26(展開溶媒A) :0.19(展開溶媒B) (実施例35)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3−(3−フルオロ
フェニル)オキシ〕プロピルアミド(化合物(75)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例28で合成した化合物(28)
0.27gを用いて標記化合物(75)0.06gを油
状物質として得た。NMR (δ, CDCl 3 ): 9.65 (s, 1H),
7.28-7.37 (m, 5H), 7.02-7.10 (m, 3H), 6.88-6.95 (m, 2H), 5.
10-5.22 (m, 1H), 5.06 (s, 2H), 4.57-4.61 (m, 1H), 4.22-4.30
(m, 1H), 4.05-4.13 (m, 2H), 2.32-2.50 (m, 2H), 1.50-1.72
(m, 3H), 0.91-0.95 (m, 6H) Rf value: 0.26 (developing solvent A): 0.19 (developing solvent B) (Example 35) LN-benzyloxycarbonylleucine- (2S )-[1-Formyl-3- (3-fluorophenyl) oxy] propylamide (Compound (75)) In the same manner as in Example 21, synthesized in Reference Example 28 instead of compound (16) synthesized in Reference Example 16. Compound (28)
Using 0.27 g, 0.06 g of the title compound (75) was obtained as an oil.
【0136】NMR(δ,CDCl3 ):9.64(s,1H),
7.30-7.35(m,5H),7.20(q,J=8.25Hz,1H),6.81-6.88(m,1
H),6.54-6.70(m,3H),5.05-5.12(m,3H),4.56-4.63(m,1
H),4.17-4.27(m,1H),3.96-4.04(m,2H),2.27-2.54(m,2
H),1.45-1.75(m,3H),0.88-0.95(m,6H) Rf値:0.25(展開溶媒A) :0.19(展開溶媒B) (実施例36)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3−(2−クロロフ
ェニル)オキシ〕プロピルアミド(化合物(76)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例29で合成した化合物(29)
1.05gを用いて標記化合物(76)0.41gを得
た。NMR (δ, CDCl 3 ): 9.64 (s, 1H),
7.30-7.35 (m, 5H), 7.20 (q, J = 8.25Hz, 1H), 6.81-6.88 (m, 1
H), 6.54-6.70 (m, 3H), 5.05-5.12 (m, 3H), 4.56-4.63 (m, 1
H), 4.17-4.27 (m, 1H), 3.96-4.04 (m, 2H), 2.27-2.54 (m, 2
H), 1.45-1.75 (m, 3H), 0.88-0.95 (m, 6H) Rf value: 0.25 (developing solvent A): 0.19 (developing solvent B) (Example 36) LN-benzyl Oxycarbonylleucine- (2S)-[1-formyl-3- (2-chlorophenyl) oxy] propylamide (Compound (76)) Instead of the compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (29) synthesized in Reference Example 29
Using 1.05 g, 0.41 g of the title compound (76) was obtained.
【0137】融点(℃):107.1〜111.3 NMR(δ,CDCl3 ):9.70(s,1H),7.33-7.39(m,5
H),7.18-7.23(m,2H),7.06-7.09(m,1H),6.85-6.94(m,2
H),5.17-5.19(m,1H),5.07(s,2H),4.60-4.64(m,1H),4.26
-4.29(m,1H),4.06-4.10(m,2H),2.42-2.46(m,2H),1.45-
1.75(m,3H),0.90-0.98(m,6H) Rf値:0.27(展開溶媒A) :0.20(展開溶媒B) (実施例37)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3−(3−クロロフ
ェニル)オキシ〕プロピルアミド(化合物(77)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例30で合成した化合物(30)
1.07gを用いて標記化合物(77)0.42gを油
状物質として得た。Melting point (° C.): 107.1 to 111.3 NMR (δ, CDCl 3 ): 9.70 (s, 1H), 7.33 to 7.39 (m, 5
H), 7.18-7.23 (m, 2H), 7.06-7.09 (m, 1H), 6.85-6.94 (m, 2
H), 5.17-5.19 (m, 1H), 5.07 (s, 2H), 4.60-4.64 (m, 1H), 4.26
-4.29 (m, 1H), 4.06-4.10 (m, 2H), 2.42-2.46 (m, 2H), 1.45-
1.75 (m, 3H), 0.90-0.98 (m, 6H) Rf value: 0.27 (developing solvent A): 0.20 (developing solvent B) (Example 37) LN-benzyloxycarbonylleucine- ( 2S)-[1-Formyl-3- (3-chlorophenyl) oxy] propylamide (compound (77)) In the same manner as in Example 21, synthesized in Reference Example 30 instead of compound (16) synthesized in Reference Example 16. Compound (30)
Using 1.07 g, 0.42 g of the title compound (77) was obtained as an oil.
【0138】NMR(δ,CDCl3 ):9.63(s,1H),
7.28-7.35(m,6H),7.17(t,J=8.19Hz,1H),6.92-6.95(m,1
H),6.85(s,1H),6.72(d,J=8.31Hz,1H),5.03-5.18(m,3H),
4.56-4.59(m,1H),4.16-4.22(m,1H),3.93-4.03(m,2H),2.
25-2.53(m,2H),1.47-1.70(m,3H),0.91-0.95(m,6H) Rf値:0.28(展開溶媒A) :0.27(展開溶媒B) (実施例38)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3−ベンジルチオ)
プロピルアミド(化合物(78)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例31で合成した化合物(31)
1.9gを用いて標記化合物(78)0.8gを得た。NMR (δ, CDCl 3 ): 9.63 (s, 1H),
7.28-7.35 (m, 6H), 7.17 (t, J = 8.19Hz, 1H), 6.92-6.95 (m, 1
H), 6.85 (s, 1H), 6.72 (d, J = 8.31Hz, 1H), 5.03-5.18 (m, 3H),
4.56-4.59 (m, 1H), 4.16-4.22 (m, 1H), 3.93-4.03 (m, 2H), 2.
25-2.53 (m, 2H), 1.47-1.70 (m, 3H), 0.91-0.95 (m, 6H) Rf value: 0.28 (developing solvent A): 0.27 (developing solvent B) (Example 38) ) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3-benzylthio)
Propylamide (compound (78)) Compound (31) synthesized in Reference Example 31 instead of compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 1.9 g, 0.8 g of the title compound (78) was obtained.
【0139】融点(℃):72.8〜81.8 NMR(δ,CDCl3 ):9.49(d,J=5.76Hz,1H),7.24
-7.33(m,10H),6.67-6.69(m,1H),5.14-5.18(m,1H),5.10
(s,2H),4.55-4.64(m,1H),4.15-4.21(m,1H),3.66(s,2H),
2.39-2.43(m,2H),2.11-2.20(m,1H),1.82-1.90(m,1H),1.
47-1.69(m,3H),0.92-0.95(m,6H) Rf値:0.52(展開溶媒A) :0.25(展開溶媒B) (実施例39)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3−(2−フルオロ
ベンジル)チオ〕プロピルアミド(化合物(79)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例32で合成した化合物(32)
1.6gを用いて標記化合物(79)1.3gを得た。Melting point (° C.): 72.8-81.8 NMR (δ, CDCl 3 ): 9.49 (d, J = 5.76 Hz, 1H), 7.24
-7.33 (m, 10H), 6.67-6.69 (m, 1H), 5.14-5.18 (m, 1H), 5.10
(s, 2H), 4.55-4.64 (m, 1H), 4.15-4.21 (m, 1H), 3.66 (s, 2H),
2.39-2.43 (m, 2H), 2.11-2.20 (m, 1H), 1.82-1.90 (m, 1H), 1.
47-1.69 (m, 3H), 0.92-0.95 (m, 6H) Rf value: 0.52 (developing solvent A): 0.25 (developing solvent B) (Example 39) LN-benzyloxycarbonylleucine -(2S)-[1-Formyl-3- (2-fluorobenzyl) thio] propylamide (Compound (79)) A reference example instead of the compound (16) synthesized in Reference example 16 by a method according to Example 21. Compound (32) synthesized in 32
Using 1.6 g, 1.3 g of the title compound (79) was obtained.
【0140】融点(℃):99.6〜101.0 NMR(δ,CDCl3 ):9.54(s,1H),7.19-7.37(m,7
H),6.67-6.69(m,1H),5.11(s,2H),5.10-5.15(m,1H),4.50
-4.54(m,1H),4.18-4.23(m,1H),3.70(s,2H),2.45-2.48
(m,2H),2.18-2.30(m,2H),1.86-1.97(m,2H),1.48-1.72
(m,3H),0.95(d,J=6.24Hz,6H) Rf値:0.51(展開溶媒A) :0.24(展開溶媒B) (実施例40)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3(2−クロロベン
ジル)チオ〕プロピルアミド(化合物(80)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例33で合成した化合物(33)
1.2gを用いて標記化合物(80)0.72gを油状
物質として得た。Melting point (° C.): 99.6 to 101.0 NMR (δ, CDCl 3 ): 9.54 (s, 1H), 7.19 to 7.37 (m, 7
H), 6.67-6.69 (m, 1H), 5.11 (s, 2H), 5.10-5.15 (m, 1H), 4.50
-4.54 (m, 1H), 4.18-4.23 (m, 1H), 3.70 (s, 2H), 2.45-2.48
(m, 2H), 2.18-2.30 (m, 2H), 1.86-1.97 (m, 2H), 1.48-1.72
(m, 3H), 0.95 (d, J = 6.24 Hz, 6H) Rf value: 0.51 (developing solvent A): 0.24 (developing solvent B) (Example 40) L-N-benzyloxycarbonylleucine -(2S)-[1-Formyl-3 (2-chlorobenzyl) thio] propylamide (Compound (80)) Reference Example 33 was used in place of compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (33) synthesized by
0.72 g of the title compound (80) was obtained as an oil using 1.2 g.
【0141】NMR(δ,CDCl3 ):9.53(d,J=6.4
6Hz,1H),7.30-7.38(m,7H),7.16-7.25(m,2H),6.73-6.75
(m,1H),5.20(d,J=7.81Hz,1H),5.10(s,2H),4.47-4.53(m,
1H),4.18-4.24(m,1H),3.80(s,2H),2.47-2.52(m,2H),2.1
6-2.24(m,1H),1.88-1.94(m,1H),1.48-1.68(m,3H),0.92-
0.94(m,6H) Rf値:0.29(展開溶媒A) :0.26(展開溶媒B) (実施例41)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3(2−フルオロフ
ェニル)チオ〕プロピルアミド(化合物(81)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例34で合成した化合物(34)
1.35gを用いて標記化合物(81)0.96gを油
状物質として得た。NMR (δ, CDCl 3 ): 9.53 (d, J = 6.4)
6Hz, 1H), 7.30-7.38 (m, 7H), 7.16-7.25 (m, 2H), 6.73-6.75
(m, 1H), 5.20 (d, J = 7.81Hz, 1H), 5.10 (s, 2H), 4.47-4.53 (m, 1H
1H), 4.18-4.24 (m, 1H), 3.80 (s, 2H), 2.47-2.52 (m, 2H), 2.1
6-2.24 (m, 1H), 1.88-1.94 (m, 1H), 1.48-1.68 (m, 3H), 0.92-
0.94 (m, 6H) Rf value: 0.29 (developing solvent A): 0.26 (developing solvent B) (Example 41) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3 (2-Fluorophenyl) thio] propylamide (Compound (81)) Compound (34) synthesized in Reference Example 34 in place of compound (16) synthesized in Reference Example 16 by a method similar to that in Example 21.
Using 1.35 g, 0.96 g of the title compound (81) was obtained as an oil.
【0142】NMR(δ,CDCl3 ):9.54(d,J=6.7
3,1H),7.31-7.40(m,5H),7.22-7.29(m,2H),7.03-7.12(m,
1H),5.17(d,J=7.81Hz,1H),5.11(s,1H),4.55-4.60(m,1
H),4.20-4.30(m,1H),2.89-2.94(m,2H),2.10-2.20(m,1
H),1.84-1.95(m,1H),1.49-1.73(m,3H),0.93-0.96(m,6H) Rf値:0.42(展開溶媒A) :0.40(展開溶媒B) (実施例42)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3(2−クロロフェ
ニル)チオ〕プロピルアミド(化合物(82)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例35で合成した化合物(35)
1.25gを用いて標記化合物(82)0.58gを得
た。NMR (δ, CDCl 3 ): 9.54 (d, J = 6.7)
3,1H), 7.31-7.40 (m, 5H), 7.22-7.29 (m, 2H), 7.03-7.12 (m,
1H), 5.17 (d, J = 7.81Hz, 1H), 5.11 (s, 1H), 4.55-4.60 (m, 1
H), 4.20-4.30 (m, 1H), 2.89-2.94 (m, 2H), 2.10-2.20 (m, 1
H), 1.84-1.95 (m, 1H), 1.49-1.73 (m, 3H), 0.93-0.96 (m, 6H) Rf value: 0.42 (developing solvent A): 0.40 (developing solvent B) ( Example 42) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3 (2-chlorophenyl) thio] propylamide (compound (82)) Synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (35) synthesized in Reference Example 35 instead of compound (16)
Using 1.25 g, 0.58 g of the title compound (82) was obtained.
【0143】融点(℃):109.5〜149.0(分
解) NMR(δ,CDCl3 ):9.54(s,1H),7.12-7.40(m,9
H),6.62-6.85(m,1H),5.09-5.15(m,3H),4.54-4.60(m,1
H),4.21-4.25(m,1H),2.94-3.00(m,2H),2.27-3.40(m,1
H),1.90-2.02(m,1H),1.49-1.71(m,3H),0.93-0.95(m,6H) Rf値:0.27(展開溶媒A) :0.27(展開溶媒B) (実施例43)L−N−ベンジルオキシカルボニルロイ
シン−(2S)−〔1−ホルミル−3(4−クロロフェ
ニル)チオ〕プロピルアミド(化合物(83)) 実施例21に準ずる方法で参考例16で合成した化合物
(16)の代りに参考例36で合成した化合物(36)
1.58gを用いて標記化合物(83)0.71gを油
状物質として得た。Melting point (° C.): 109.5 to 149.0 (decomposition) NMR (δ, CDCl 3 ): 9.54 (s, 1H), 7.12 to 7.40 (m, 9
H), 6.62-6.85 (m, 1H), 5.09-5.15 (m, 3H), 4.54-4.60 (m, 1H
H), 4.21-4.25 (m, 1H), 2.94-3.00 (m, 2H), 2.27-3.40 (m, 1
H), 1.90-2.02 (m, 1H), 1.49-1.71 (m, 3H), 0.93-0.95 (m, 6H) Rf value: 0.27 (developing solvent A): 0.27 (developing solvent B) ( Example 43) LN-benzyloxycarbonylleucine- (2S)-[1-formyl-3 (4-chlorophenyl) thio] propylamide (compound (83)) Synthesized in Reference Example 16 by a method similar to that in Example 21. Compound (36) synthesized in Reference Example 36 instead of compound (16)
0.71 g of the title compound (83) was obtained as an oil using 1.58 g.
【0144】NMR(δ,CDCl3 ):9.52(d,J=7.2
1Hz,1H),7.32(s,5H),7.25(s,4H),6.72-6.90(m,1H),5.14
-5.17(m,1H),5.10(d,J=4.88Hz,2H),4.53-4.60(m,1H),4.
15-4.25(m,1H),2.88-2.93(m,2H),2.20-2.35(m,1H),1.82
-1.98(m,1H),1.49-1.68(m,3H),0.93-0.98(m,6H) Rf値:0.30(展開溶媒A) :0.30(展開溶媒B) (試験例1)カルパイン阻害活性の測定 カルパインは、日本白色種ウサギ骨格筋より、Tsuj
iとImahori(J.Biochem.90,23
3−240(1981))の方法に従って部分精製し、
実験に使用した。NMR (δ, CDCl 3 ): 9.52 (d, J = 7.2)
1Hz, 1H), 7.32 (s, 5H), 7.25 (s, 4H), 6.72-6.90 (m, 1H), 5.14
-5.17 (m, 1H), 5.10 (d, J = 4.88Hz, 2H), 4.53-4.60 (m, 1H), 4.
15-4.25 (m, 1H), 2.88-2.93 (m, 2H), 2.20-2.35 (m, 1H), 1.82
-1.98 (m, 1H), 1.49-1.68 (m, 3H), 0.93-0.98 (m, 6H) Rf value: 0.30 (developing solvent A): 0.30 (developing solvent B) (Test Example 1) Measurement of Calpain Inhibitory Activity Calpain was obtained from Japanese white rabbit skeletal muscle by Tsuj
i and Imahori (J. Biochem. 90, 23)
3-240 (1981)).
Used for experiments.
【0145】抗カルパイン活性の測定はYoshimu
ra(J.Biol.Chem.258,8883−8
889(1983))等の方法に従って行った。即ち、
4%カゼイン溶液0.05ml,50mMシステイン溶液
0.05ml,カルパイン溶液0.05ml,精製水0.0
25ml被験薬溶液(10%ジメチルスルホオキシド溶
液)0.025ml及び200mMイミダゾール塩酸緩衝
液(pH7.5)0.25mlを含む混合液を30℃で3分
間加温した。その後、50mM塩化カルシウム溶液0.
05mlを加えて反応を開始した。30℃,30分間反応
した後、5%トリクロロ酢酸0.5mlを加えて反応を停
止した。カルパインにより加水分解されたカゼインのト
リクロロ酢酸可溶画分中のタンパク量をRossとSc
hatz(Anal.Biochem.54,304−
306(1973))の方法に従って測定し、吸光度
(a)を求めた。同時に被験薬溶液の代わりに10%ジ
メチルスルホオキシド溶液のみを用いた盲検の吸光度
(b)を測定した。カルパイン阻害率は、次式〔(b−
a)/b〕×100により計算し、50%阻害に必要な
量〔IC50〕をプロビット法より算出した。各実施例で
製造した化合物を被験薬とし、測定結果を表1に示す。The measurement of anti-calpain activity was carried out by Yoshimu.
ra (J. Biol. Chem. 258, 8883-8)
889 (1983)). That is,
4% casein solution 0.05ml, 50mM cysteine solution 0.05ml, calpain solution 0.05ml, purified water 0.0
A mixture containing 0.025 ml of a 25 ml test drug solution (10% dimethyl sulfoxide solution) and 0.25 ml of a 200 mM imidazole hydrochloride buffer (pH 7.5) was heated at 30 ° C. for 3 minutes. Then, a 50 mM calcium chloride solution was added.
The reaction was started by adding 05 ml. After reacting at 30 ° C. for 30 minutes, 0.5 ml of 5% trichloroacetic acid was added to stop the reaction. The amount of protein in the fraction soluble in trichloroacetic acid of casein hydrolyzed by calpain was determined by Ross and Sc.
hatz (Anal. Biochem. 54, 304-
306 (1973)), and the absorbance (a) was determined. At the same time, the absorbance (b) of a blind test using only a 10% dimethyl sulfoxide solution instead of the test drug solution was measured. The calpain inhibition rate was calculated by the following formula [(b-
a) / b] × 100, and the amount [IC 50 ] required for 50% inhibition was calculated by the probit method. The compounds produced in each Example were used as test drugs, and the measurement results are shown in Table 1.
【0146】[0146]
【表1】 [Table 1]
【0147】(試験例2)血小板凝集抑制作用の測定 ウサギ多血小板血漿の調製及び血小板凝集の測定は、B
ornとCross(J.Phystol.168,1
78〜195(1963))の方法に従って行った。即
ち、日本白色種ウサギ頸動脈より、無麻酔下、3.8%
クエン酸ナトリウム溶液1容量に対し、9容量採血し
た。直ちに、200×g,20℃,15分間遠心分離し
上清の多血小板血漿(以下、PRPと略す)を得た。P
RPは、自動血球計数機(日本光電:MEK−415
0)で血小板数を測定し、1μlあたり55×104 個
以上のものを使用した。Test Example 2 Measurement of Platelet Aggregation Inhibitory Effect The preparation of rabbit platelet-rich plasma and the measurement of platelet aggregation
orn and Cross (J. Physol. 168, 1)
78-195 (1963)). That is, 3.8% from the carotid artery of a Japanese white rabbit under no anesthesia
9 volumes of blood were collected per 1 volume of the sodium citrate solution. Immediately, the mixture was centrifuged at 200 × g at 20 ° C. for 15 minutes to obtain supernatant platelet-rich plasma (hereinafter abbreviated as PRP). P
RP is an automatic blood cell counter (Nihon Kohden: MEK-415)
In 0), the number of platelets was measured, and those having 55 × 10 4 or more per μl were used.
【0148】血小板凝集抑制作用は、PRP200μl
に対して被験薬溶液10μlを加え、37℃で5分間加
温後、22μg/mlコラーゲンを10μl添加して血小
板の凝集反応をアグリコメーター(NKK,PAT−4
A)を用いて測定した。同時に、被験薬溶液の代わり
に、被験薬溶解用溶媒のみを用いた時を最大凝集率10
0%として被験薬群の抑制率を求めると共に50%阻害
に必要な量〔IC50〕をプロビット法より算出した。The platelet aggregation-inhibiting effect was confirmed by PRP 200 μl
To the platelet, heated at 37 ° C. for 5 minutes, and added 10 μl of 22 μg / ml collagen to determine the agglutination of platelets by an aggregometer (NKK, PAT-4).
It measured using A). At the same time, the maximum agglutination rate was 10 when only the solvent for dissolving the test drug was used instead of the test drug solution.
The inhibition rate of the test drug group was determined as 0%, and the amount [IC 50 ] required for 50% inhibition was calculated by the probit method.
【0149】但し、被験薬は、ジメチルスルホオキシド
及びポリオキシエチレン60硬化ヒマシ油/エタノール
溶液(1:1)に溶解し、生理食塩水で希釈して使用し
た。また、ジメチルスルホオキシド及びポリオキシエチ
レン60硬化ヒマシ油は、それぞれ最終濃度が1%以下
になる様に調製した。各実施例で製造した化合物を被験
薬とし、測定結果を表2に示す。However, the test drug was dissolved in dimethyl sulfoxide and polyoxyethylene 60 hydrogenated castor oil / ethanol solution (1: 1) and diluted with physiological saline before use. In addition, dimethyl sulfoxide and polyoxyethylene 60 hydrogenated castor oil were each prepared so that the final concentration was 1% or less. The compounds produced in each Example were used as test drugs, and the measurement results are shown in Table 2.
【0150】[0150]
【表2】 [Table 2]
【0151】(試験例3)カルパイン以外のプロテアー
ゼ阻害活性の測定 抗トリプシン活性の測定 抗トリプシン活性の測定は、Aoyagi(J.Ant
ibiotics,22,558〜568(1969)
等の方法を一部改良して行った。(Test Example 3) Measurement of protease inhibitory activity other than calpain Measurement of anti-trypsin activity The measurement of anti-trypsin activity was performed using Aoyagi (J. Ant)
ibiotics, 22, 558-568 (1969).
Were carried out with some improvements.
【0152】2%カゼイン溶液0.5ml,50mM塩化
カルシウム0.05ml,被験薬溶液(10%ジメチルス
ルホオキシド含有)0.05ml,精製水0.1ml及び7
0mMホウ酸緩衝液(pH7.4)0.25mlを含む混合
液を37℃で3分間加温した。その後0.1mg/mlトリ
プシン溶液を加えて反応を開始した。37℃,30分間
反応した後、1.7N過塩素酸1mlを加えて反応を停止
した。60分間室温で放置した後、3,000rpm ,1
0分間遠心分離した後上清の280nmの吸光度(a)
を測定した。同時に被験薬溶液の代わりに10%ジメチ
ルスルホオキシド溶液のみを用いた盲検の吸光度(b)
を測定した。トリプシン阻害率は次式〔(b−a)/
b〕×100により計算した。0.5 ml of a 2% casein solution, 0.05 ml of 50 mM calcium chloride, 0.05 ml of a test drug solution (containing 10% dimethyl sulfoxide), 0.1 ml of purified water and 7 ml
A mixture containing 0.25 ml of 0 mM borate buffer (pH 7.4) was heated at 37 ° C. for 3 minutes. Thereafter, a 0.1 mg / ml trypsin solution was added to start the reaction. After reacting at 37 ° C. for 30 minutes, 1 ml of 1.7N perchloric acid was added to stop the reaction. After standing at room temperature for 60 minutes, 3,000 rpm, 1
After centrifugation for 0 minutes, the absorbance of the supernatant at 280 nm (a)
Was measured. Simultaneously, a blind absorbance using only a 10% dimethyl sulfoxide solution instead of the test drug solution (b)
Was measured. The trypsin inhibition rate was calculated by the following formula [(ba) /
b] × 100.
【0153】実施例で製造した化合物(61),(6
3),(76)及び(83)を被験薬とした。Compounds (61) and (6) produced in Examples
3), (76) and (83) were used as test drugs.
【0154】いずれの化合物も10-5Mの濃度で阻害活
性を示さなかった。None of the compounds showed any inhibitory activity at a concentration of 10 -5 M.
【0155】 抗α−キモトリプシン活性の測定 抗α−キモトリプシン活性の測定は、Erlange
r,B.F.(Ach.Biochem.Biophy
s.115,206−210(1966)等の方法を一
部改良して行った。即ち、10mMグルタリル−L−フ
ェニルアラニン−p−ニトロアニリド溶液(10%ジメ
チルスルホオキシド−10%ポリオキシエチレン60硬
化ヒマシ油含有)0.05ml,50mM塩化カルシウム
溶液0.1ml,精製水0.25ml,被験薬溶液(10%
ジメチルスルホオキシド−10%ポリオキシエチレン6
0硬化ヒマシ油含有)0.05ml及び100mMトリス
塩酸緩衝液(pH7.8)0.5mlを含む混合液を25℃
で3分間加温した。その後、2mg/mlα−キモトリプシ
ン(タイプ−II)を加えて反応を開始し、直ちに25℃
での405nmの吸光度の増加を経時的に測定して1分間
当りの吸光度の変化率(a)を求めた。同時に、被験薬
溶液の代わりに10%ジメチルスルホオキシド−10%
ポリオキシエチレン60硬化ヒマシ油溶液のみを用いた
盲検の1分間当りの吸光度の変化率(b)を測定した。
α−キモトリプシン阻害率は次式〔(b−a)/b〕×
100により計算し、50%阻害に必要な量〔IC50〕
をプロビット法より算出した。比較として特開平1−1
21257号で製造された化合物SUAM−14541
を用い測定を行った。結果を表3に示す。Measurement of anti-α-chymotrypsin activity The measurement of anti-α-chymotrypsin activity was determined according to Erlange.
r, B. F. (Ach. Biochem. Biophy
s. 115, 206-210 (1966) and the like. That is, 0.05 ml of a 10 mM glutaryl-L-phenylalanine-p-nitroanilide solution (containing 10% dimethyl sulfoxide-10% polyoxyethylene 60 hydrogenated castor oil), 0.1 ml of a 50 mM calcium chloride solution, 0.25 ml of purified water, Test drug solution (10%
Dimethyl sulfoxide-10% polyoxyethylene 6
A mixture containing 0.05 ml of 0 hydrogenated castor oil) and 0.5 ml of 100 mM Tris-HCl buffer (pH 7.8) was heated at 25 ° C.
For 3 minutes. Thereafter, 2 mg / ml α-chymotrypsin (Type-II) was added to start the reaction, and immediately
The change in absorbance per minute (a) was determined by measuring the increase in absorbance at 405 nm over time. At the same time, instead of the test drug solution, 10% dimethyl sulfoxide-10%
The rate of change in absorbance per minute (b) in a blind test using only polyoxyethylene 60 hydrogenated castor oil solution was measured.
The α-chymotrypsin inhibition rate was calculated by the following formula [(ba) / b] ×
The amount required for 50% inhibition [IC 50 ] calculated by 100
Was calculated by the probit method. For comparison, see JP-A-1-1
Compound SUAM-14541 prepared in No. 21257
Was used for the measurement. Table 3 shows the results.
【0156】[0156]
【表3】 [Table 3]
【0157】[0157]
【発明の効果】本発明の前記一般式(I)で表わされる
アルデヒド誘導体は、選択的なカルパイン活性阻害作用
及び血小板凝集抑制作用を示す。そのためカルパインの
活性異常により引き起こされる虚血性疾患の治療に用い
ることが期待できる。The aldehyde derivative represented by the general formula (I) of the present invention exhibits a selective calpain activity inhibitory action and a platelet aggregation inhibitory action. Therefore, it can be expected to be used for treatment of ischemic diseases caused by abnormal activity of calpain.
Claims (1)
水素基、複素環基、置換アルキル基又は環状アルキル
基、R2 は、水素原子、アルキル基又は芳香族炭化水素
基、R3 は、水素原子又はアルキル基、R4 は、アルコ
キシカルボニル基、アシル基、カルバモイル基、スルホ
ニル基、Xは、酸素原子又は−S(O)m −で表される
基、ここでmは0,1又は2であり、nは、1〜5であ
る。)。1. A compound of the general formula Wherein R 1 is an aromatic hydrocarbon group, a heterocyclic group, a substituted alkyl group or a cyclic alkyl group, R 2 is a hydrogen atom, an alkyl group or an aromatic hydrocarbon group, and R 3 is , A hydrogen atom or an alkyl group, R 4 is an alkoxycarbonyl group, an acyl group, a carbamoyl group, a sulfonyl group, X is an oxygen atom or a group represented by —S (O) m —, wherein m is 0,1 Or 2, and n is 1 to 5.)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP18474592A JP2697495B2 (en) | 1991-06-19 | 1992-06-19 | Aldehyde derivatives |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP17337791 | 1991-06-19 | ||
JP3-173377 | 1991-06-19 | ||
JP18474592A JP2697495B2 (en) | 1991-06-19 | 1992-06-19 | Aldehyde derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH06287167A JPH06287167A (en) | 1994-10-11 |
JP2697495B2 true JP2697495B2 (en) | 1998-01-14 |
Family
ID=26495374
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP18474592A Expired - Lifetime JP2697495B2 (en) | 1991-06-19 | 1992-06-19 | Aldehyde derivatives |
Country Status (1)
Country | Link |
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JP (1) | JP2697495B2 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2412436C (en) * | 2000-06-05 | 2013-05-21 | The Trustees Of Columbia University In The City Of New York | Identification and use of human bone marrow-derived endothelial progenitor cells to improve myocardial function after ischemic injury |
US20030199464A1 (en) | 2002-04-23 | 2003-10-23 | Silviu Itescu | Regeneration of endogenous myocardial tissue by induction of neovascularization |
KR100967833B1 (en) * | 2008-05-20 | 2010-07-05 | 아이디비켐(주) | A method for preparing high-purity polyethyleneglycol aldehyde derivatives |
NZ700733A (en) * | 2012-04-16 | 2016-07-29 | Allergan Inc | (2-ureidoacetamido)alkyl derivatives as formyl peptide receptor 2 modulators |
-
1992
- 1992-06-19 JP JP18474592A patent/JP2697495B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPH06287167A (en) | 1994-10-11 |
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