JPH05222085A - Sialic acid oligosaccharide derivative and fine particulate carrier - Google Patents

Sialic acid oligosaccharide derivative and fine particulate carrier

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Publication number
JPH05222085A
JPH05222085A JP4005955A JP595592A JPH05222085A JP H05222085 A JPH05222085 A JP H05222085A JP 4005955 A JP4005955 A JP 4005955A JP 595592 A JP595592 A JP 595592A JP H05222085 A JPH05222085 A JP H05222085A
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JP
Japan
Prior art keywords
compound
mixture
added
meoh
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
JP4005955A
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Japanese (ja)
Other versions
JPH0826057B2 (en
Inventor
Akira Nakabayashi
暁 中林
Hitoshi Yamauchi
仁史 山内
Akira Hasegawa
明 長谷川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
D D S KENKYUSHO KK
Original Assignee
D D S KENKYUSHO KK
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Application filed by D D S KENKYUSHO KK filed Critical D D S KENKYUSHO KK
Priority to JP4005955A priority Critical patent/JPH0826057B2/en
Publication of JPH05222085A publication Critical patent/JPH05222085A/en
Publication of JPH0826057B2 publication Critical patent/JPH0826057B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

PURPOSE:To provide the subject new compound effective in avoiding the reticulo-endothelial system in living body as a constituent component of a fine particulate carrier and, accordingly, giving a fine particulate carrier exhibiting remarkably excellent action as a drug carrier. CONSTITUTION:The compound of formula I [X is O or S; W is group of formula II or formula III (R<10> is OH, NH2, etc.; R<11> and R<12> are H or OH-protecting group), etc.; m is 1-8; R<0> is N3, NH2, etc.; R<1> is H, lower alkyl, etc.; R<2> to R<4> are H or OH-protecting group; R<5> is OH, H, etc.], e.g. 2-palmitoylamido-ethyl- O-(5-acetamido-3,5-dideoxy-D-glucero-alpha-D-galacto-2nonulopyranosylonic acid)-(2 6)-beta-D-glucopyranoside. The compound can be produced e.g. by reacting the sialic acid oligosaccharide compound of formula IV with an azidoalkanol, reducing the resultant azide derivative of formula V with hydrogen and reacting the obtained amino derivative with a hydroxysuccinimide ester of a fatty acid.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は、新規なシアル酸オリゴ
糖誘導体及びそれを構成成分として含有する微粒子キャ
リヤーに関する。この微粒子キャリヤーは生体内におい
て細網内皮系を回避する効果を有する。TECHNICAL FIELD The present invention relates to a novel sialic acid oligosaccharide derivative and a fine particle carrier containing it as a constituent. This particulate carrier has the effect of avoiding the reticuloendothelial system in vivo.

【０００２】[0002]

【従来の技術】薬物送達システムの開発を行う場合、リ
ポソーム、リピッドマイクロスフェアーなどの微粒子キ
ャリヤーを薬物担体として利用することは既によく知ら
れているところである。しかし、微粒子キャリヤーを静
脈内投与した場合に、これが肝臓、脾蔵などの細網内皮
系に捕捉されやすいこともよく知られており、このこと
が微粒子キャリヤーを製剤として薬物送達システムに応
用する際の解決すべき課題となっている。2. Description of the Related Art When developing a drug delivery system, it is already well known to utilize fine particle carriers such as liposomes and lipid microspheres as drug carriers. However, it is well known that when a fine particle carrier is administered intravenously, it is easily trapped in the reticuloendothelial system of the liver, spleen, and the like, which means that when the fine particle carrier is applied as a formulation to a drug delivery system. Has become a problem to be solved.

【０００３】従来からリポソームを用いた細網内皮系回
避の研究は、下記文献1)〜9)に示されるように、細胞膜
由来の糖脂質であるガングリオシドや赤血球膜由来の蛋
白質であるグリコホリンをリポソーム膜内に再構成する
形でなされ、その結果微小循環性が改善されたと報告さ
れている。[0003] Conventionally, studies on evasion of reticuloendothelial system using liposomes have been carried out, as shown in the following references 1) to 9), in which ganglioside which is a cell membrane-derived glycolipid and glycophorin which is a protein derived from an erythrocyte membrane are liposomes. It was reported to be reconstituted in the membrane, resulting in improved microcirculation.

【０００４】1) T.M.Allen et al.,FEBS Lett.,233,42
(1987) 2) A.Gabizon et al.,Proc.Natl.Acad.Sci.USA,85,694
9(1988) 3) T.M.Allen et al.,Biochim.Biophys.Acta,981,27(1
989) 4) T.M.Allen,US Patent No.4,837,028(June 6,1989) 5) A.Gabizon,Annals of the New York Academy of Sc
iences,507,64(1987) 6) 内海英雄他「第９回生体膜と薬物の相互作用シンポ
ジウム講演要旨集」p.193(1986) 7) K.Saito et al.,Chem.Pham.Bull.,36,4187(1988) 8) J.Sunamoto et al.,Chemistry Letters,p.1781(198
8) 9) T.M.Allen,"Liposomes in the Therapy of Infecti
ous Disease and Cancer",Alan R Liss,Inc.,New York
(1988),p.405 これらの文献によると、リポソームの微小循環性を改良
し、リポソームを細網内皮系にできるだけ捕捉されない
ようにするためにはリポソーム膜表面にシアル酸が存在
することが重要であると示唆される。とりわけAllen ら
が報告したＧＭ1 修飾リポソームは細胞内皮系を回避
し、微小循環性がよい性質を有するリポソームであると
考えられいる。また、最近では下記文献 10)〜11) に示
されるように、ポリエチレングリコールに脂質を結合
し、これでリポソームを修飾することによりＧＭ1 と同
様の性質が得られると報告されている。1) TMAllen et al., FEBS Lett., 233, 42
(1987) 2) A.Gabizon et al., Proc.Natl.Acad.Sci.USA, 85,694
9 (1988) 3) TMAllen et al., Biochim.Biophys.Acta, 981,27 (1
989) 4) TMAllen, US Patent No. 4,837,028 (June 6,1989) 5) A. Gabizon, Annals of the New York Academy of Sc
iences, 507, 64 (1987) 6) Hideo Utsumi et al., "Proceedings of the 9th Symposium on Interactions between Membranes and Drugs" p.193 (1986) 7) K. Saito et al., Chem. Pham. Bull. , 36, 4187 (1988) 8) J. Sunamoto et al., Chemistry Letters, p. 1781 (198)
8) 9) TMAllen, "Liposomes in the Therapy of Infecti
ous Disease and Cancer ", Alan R Liss, Inc., New York
(1988), p. 405. According to these references, the presence of sialic acid on the surface of the liposome membrane is important in order to improve the microcirculation of the liposome and prevent the liposome from being trapped in the reticuloendothelial system as much as possible. Is suggested. In particular, the GM 1 -modified liposome reported by Allen et al. Is considered to be a liposome that avoids the cell endothelium system and has a property of good microcirculation. Further, recently, as shown in the following documents 10) to 11), it has been reported that a property similar to GM 1 can be obtained by binding a lipid to polyethylene glycol and modifying the liposome with this.

【０００５】10) A.L.Klibanov et al.,FEBS Lett.,26
8,235(1990) 11) A.L.Klibanov et al.,Biochim.Biophys.Acta,1062,
142(1991)10) ALKlibanov et al., FEBS Lett., 26
8,235 (1990) 11) ALKlibanov et al., Biochim.Biophys.Acta, 1062,
142 (1991)

【０００６】[0006]

【発明が解決しようとする課題】前記した従来技術の状
況にかんがみ、本発明は、微粒子キャリヤーに配合した
とき、これに細網内皮系を顕著に回避する性質を付与す
る物質を見出すこと、及びこのような物質を配合して調
製される微粒子キャリヤーを提供することを目的とす
る。In view of the above-mentioned state of the art, the present invention finds a substance which, when incorporated into a particulate carrier, imparts to it a property of significantly avoiding the reticuloendothelial system, and It is an object to provide a fine particle carrier prepared by incorporating such a substance.

【０００７】[0007]

【課題を解決するための手段】本発明者は、前記した課
題を解決するための手段について検討した結果、新規物
質として合成した糖部分が二又は三糖よりなるシアル酸
オリゴ糖脂質が所期の目的を達成することを見出し、本
発明を完成するに至った。Means for Solving the Problems As a result of studying means for solving the above-mentioned problems, the present inventor has found that a sialic acid oligoglycolipid whose sugar moiety synthesized as a novel substance is composed of di- or trisaccharide is desired. The inventors have found that the object of (1) is achieved and completed the present invention.

【０００８】以下に本発明を詳細に説明する。The present invention will be described in detail below.

【０００９】本発明物質は式（Ｉ）によって示されるシ
アル酸オリゴ糖誘導体である。The substance of the present invention is a sialic acid oligosaccharide derivative represented by the formula (I).

【００１０】[0010]

【化４】 [Chemical 4]

【００１１】まず、式（Ｉ）はシアル酸が当該誘導体の
末端に位置していることを示す。シアル酸部分について
説明すると次のごとくになる。該シアル酸の２位におけ
る波状線はα結合又はβ結合を表しており、そのいずれ
でもよいことを意味する。同様に、８位における波状線
は８位におけるエピマーが式（Ｉ）に含まれることを表
す。Ｒ1 はＨ、好ましくは炭素数１〜２の低級アルキル
基又はアルカリ金属を表し、Ｒ2 〜Ｒ4 は同一又は異な
っていてもよく、それぞれＨ又は水酸基の保護基例えば
アセチル基を表し、Ｒ5 はＯＨ、ＯＡｃ又はＨを表す。
Ｒ5 がＨの場合は９−デオキシシアル酸を示し、従って
本発明物質におけるシアル酸部分は９−デオキシシアル
酸を含むものであることを意味する。First, formula (I) shows that sialic acid is located at the end of the derivative. The sialic acid moiety is explained as follows. The wavy line at the 2-position of the sialic acid represents an α bond or a β bond, which means that either one may be used. Similarly, the wavy line at position 8 represents that the epimer at position 8 is included in formula (I). R 1 represents H, preferably a lower alkyl group having 1 to 2 carbon atoms or an alkali metal, and R 2 to R 4 may be the same or different and each represents H or a hydroxyl-protecting group such as acetyl group; 5 represents OH, OAc or H.
When R 5 is H, it represents 9-deoxysialic acid, which means that the sialic acid moiety in the substance of the present invention contains 9-deoxysialic acid.

【００１２】ＸはＯ又はＳを表し、Ｗは下記式（II）〜
(VII) のいずれかによって示される単糖又は二糖の糖残
基を残す。従って、式（Ｉ）はシアル酸を末端に有する
二又は三糖のオリゴ糖を構成部分とする誘導体を示して
おり、末端シアル酸のグリコシド結合はＳ−グリコシド
結合が含まれることを意味する。X represents O or S, and W represents the following formula (II).
Retain the mono- or disaccharide sugar residues represented by either (VII). Therefore, the formula (I) shows a derivative having a di- or trisaccharide oligosaccharide having sialic acid at the terminal as a constituent part, and means that the glycosidic bond of the terminal sialic acid contains an S-glycoside bond.

【００１３】[0013]

【化５】 [Chemical 5]

【００１４】[0014]

【化６】 [Chemical 6]

【００１５】式（II）はシアル酸残基を示し、式中Ｒ6
はＨ、好ましくは炭素数１〜２の低級アルキル基又はア
ルカリ金属を表し、Ｒ7 〜Ｒ9 は同一又は異なっていて
もよく、それぞれＨ又は水酸基の保護基例えばアセチル
基を表す。該シアル酸単位の１位における波状線はα結
合またはβ結合を表しており、そのいずれでもよいこと
を意味する。Formula (II) represents a sialic acid residue, where R 6
Represents H, preferably a lower alkyl group having 1 to 2 carbon atoms or an alkali metal, and R 7 to R 9 may be the same or different and each represents H or a hydroxyl protecting group such as an acetyl group. The wavy line at the 1-position of the sialic acid unit represents an α bond or a β bond, which means that either of them may be used.

【００１６】式(III) はガラクトース残基を示し、式
（IV）はグルコース残基を示す。各式中、Ｒ10はＯＨ、
ＯＡｃ、ＮＨ2 又はＮＨＡｃを表す。従って式(III) の
ガラクトース残基とはガラクトサミン残基を含み、ま
た、式（IV）のグルコース残基とはグルコサミン残基を
含むものである。Ｒ11及びＲ12は同一又は異なっていて
もよく、それぞれＨ又は水酸基の保護基例えばアセチル
基を表す。各糖単位の１位における波状線はα結合また
はβ結合を表しており、そのいずれでもよいことを意味
する。The formula (III) represents a galactose residue, and the formula (IV) represents a glucose residue. In each formula, R 10 is OH,
Represents OAc, NH 2 or NHAc. Therefore, the galactose residue of the formula (III) includes a galactosamine residue, and the glucose residue of the formula (IV) includes a glucosamine residue. R 11 and R 12 may be the same or different and each represents H or a hydroxyl-protecting group such as an acetyl group. The wavy line at the 1-position of each sugar unit represents an α bond or a β bond, which means that either one may be used.

【００１７】式（Ｖ）及び(VII) はガラクトシルグルコ
ース残基を示し、式（VI）はグロシルグルコース残基を
示す。式（Ｖ）及び(VI)の残基は末端シアル酸と（２→
６）結合をなし、式(VII) の残基は末端シアル酸と（２
→３）結合をなしている。各式中、Ｒ10〜Ｒ15は同一又
は異なっていてもよく、それぞれＨ又は水酸基の保護基
例えばアセチル基を表す。残基中の各糖単位の１位にお
ける波状線はα結合またはβ結合を表しており、そのい
ずれでもよいことを意味する。Formulas (V) and (VII) represent galactosyl glucose residues, and formula (VI) represents grosyl glucose residues. Residues of formulas (V) and (VI) are combined with terminal sialic acid (2 →
6) forms a bond, and the residue of formula (VII) is linked to the terminal sialic acid (2
→ 3) The bond is made. In each formula, R 10 to R 15 may be the same or different and each represents H or a hydroxyl-protecting group such as an acetyl group. The wavy line at the 1-position of each sugar unit in the residue represents an α bond or a β bond, which means that either of them may be used.

【００１８】式（Ｉ）におけるＲ0 はＮ3 、ＮＨ2 又は
ＮＨＲを表し、ここでＲは、好ましくは炭素数12〜18の
直鎖又は分枝鎖のアシル基、ベンジルオキシカルボニル
基、ｔ−ブトキシカルボニル基又はトリメチルシリル基
を表す。本発明の最終目的物はＲ0 がＮＨＲであって、
かつＲが好ましくは炭素数12〜18の直鎖又は分枝鎖のア
シル基である物質である。該物質以外の物質は最終目的
物を生産するための合成中間体となり得るが、最終目的
物と共に本発明物質に属する。R 0 in formula (I) represents N 3 , NH 2 or NHR, wherein R is preferably a straight chain or branched chain acyl group having 12 to 18 carbon atoms, a benzyloxycarbonyl group, t -Represents a butoxycarbonyl group or a trimethylsilyl group. The final object of the present invention is that R 0 is NHR,
Further, R is a substance in which R is preferably a linear or branched acyl group having 12 to 18 carbon atoms. Substances other than the substance can be synthetic intermediates for producing the final product, but belong to the substance of the present invention together with the final product.

【００１９】本発明の最終目的物は、前記したシアル酸
を末端に有する二又は三糖のオリゴ糖を構成部分とする
こと以外に直鎖又は分子鎖のアシル基を有しており、従
って詳しくはシアル酸オリゴ糖脂質誘導体である。脂質
部分は該最終目的物を微粒子キャリヤーの構成成分とし
て使用するために必要な部分であり、例えばパルミトイ
ル基が汎用される。The final product of the present invention has a straight-chain or molecular-chain acyl group in addition to having the above-mentioned di- or trisaccharide oligosaccharide having sialic acid at the terminal as a constituent part, and therefore, in detail, Is a sialic acid oligoglycolipid derivative. The lipid portion is a portion necessary for using the final product as a constituent component of the fine particle carrier, and for example, a palmitoyl group is commonly used.

【００２０】オリゴ糖部分と脂質部分とはスペーサーと
しての−Ｏ（ＣＨ2 ）m −を介して結合し、このスペー
サー部分は他の合成中間体においても構成部分となる。
ｍは１〜８の整数を表し、２、４、６及び８の偶数、特
に２が汎用される。The oligosaccharide moiety and the lipid moiety are bound via -O (CH 2 ) m- as a spacer, and this spacer moiety also serves as a constituent part in other synthetic intermediates.
m represents an integer of 1 to 8, and even numbers of 2, 4, 6 and 8 are used, and 2 is commonly used.

【００２１】本発明物質は特徴的な構成部分を有してい
るので、それぞれＮＭＲの分析値等によって特定するこ
とができる。Since the substance of the present invention has a characteristic constituent part, it can be specified by the NMR analysis value or the like.

【００２２】本発明物質の製造は一般的には例えば次の
ように行えばよい。The production of the substance of the present invention may be carried out generally as follows.

【００２３】シアル酸オリゴ糖部分が既に合成されてお
り、例えば既知の合成手段によって下記式（ａ）に示す
化合物（ただし、糖部分の水酸基を保護基によって保
護）を出発物質として用意することができる場合には、
これにアジドアルカノールを例えば三弗化ホウ素ジエチ
ルエーテルの存在下に反応させ、下記式（ｂ）に示すア
ジド誘導体を得る。The sialic acid oligosaccharide moiety has already been synthesized, and for example, a compound represented by the following formula (a) (provided that the hydroxyl group of the sugar moiety is protected by a protecting group) is prepared as a starting material by a known synthetic means. If you can,
This is reacted with an azidoalkanol in the presence of, for example, boron trifluoride diethyl ether to obtain an azido derivative represented by the following formula (b).

【００２４】[0024]

【化７】 [Chemical 7]

【００２５】このアジド誘導体をリンドラー触媒の存在
下に水素還元してアミノ誘導体を得る。次に、これに脂
肪酸活性体、例えば脂肪酸のヒドロキシコハク酸イミド
エステルを反応させ、最後に糖部分の水酸基を脱保護す
れば最終目的物である脂質誘導体を得ることができる。
或いはまた、アジド誘導体の段階で予め糖部分の水酸基
を脱保護してから、水素還元し、次に脂肪酸活性体を反
応させても同様に最終目的物を得ることができる。This azido derivative is hydrogenated in the presence of a Lindlar catalyst to give an amino derivative. Next, a fatty acid active substance, for example, a hydroxysuccinimide ester of a fatty acid is reacted with this, and finally the hydroxyl group of the sugar moiety is deprotected to obtain a lipid derivative as a final target.
Alternatively, the final target product can be obtained in the same manner by deprotecting the hydroxyl groups of the sugar moiety in advance at the stage of the azide derivative, reducing with hydrogen, and then reacting with a fatty acid active substance.

【００２６】シアル酸オリゴ糖のスペーサー側の末端糖
単位がアセチルグルコサミン、アセチルガラクトサミン
のように２−アセチルアミノ基を有する場合には、糖部
分の水酸基を保護してからこれにトリメチルシリルトリ
フルオロメタンスルホン酸を反応させ、次にアジドアル
カノールを反応させてアジド誘導体を得ることができ
る。得られたアジド誘導体は上記と同じ要領の処理を加
えてアミノ誘導体および最終目的物としての脂質誘導体
に変換することができる。When the terminal sugar unit on the spacer side of the sialic acid oligosaccharide has a 2-acetylamino group such as acetylglucosamine and acetylgalactosamine, the hydroxyl group of the sugar moiety is protected and then trimethylsilyltrifluoromethanesulfonic acid is added thereto. Can be reacted and then reacted with an azidoalkanol to give an azido derivative. The obtained azide derivative can be converted into an amino derivative and a lipid derivative as a final product by applying the same procedure as above.

【００２７】或いはまた、オリゴ糖部分の合成を経由し
て次のように行ってもよい。Alternatively, the following may be carried out via the synthesis of the oligosaccharide moiety.

【００２８】下記式（ｃ）に示す単糖化合物（ただし、
ＹはＳＭｅの又はハロゲンを示し、また糖部分の水酸基
を保護基によって保護）を出発物質として用意し、これ
に上記と同じ要領でアジドアルカノールを反応させて下
記式（ｄ）に示す該単糖のアジド誘導体を得て、これを
脱保護する。次に、これに下記式（ｅ）に示すシアル酸
を縮合せしめ、その結果（２→９）Ｏ−グリコシド結合
によって二糖化したシアル酸オリゴ糖のアジド誘導体を
得る。これ以後は前記したと同じ要領の処理を加えて最
終目的物を得る。A monosaccharide compound represented by the following formula (c) (however,
Y represents SMe or halogen, and the hydroxyl group of the sugar moiety is protected by a protecting group) as a starting material, and this is reacted with an azidoalkanol in the same manner as above to give the monosaccharide represented by the following formula (d). The azido derivative of is obtained and deprotected. Next, this is condensed with a sialic acid represented by the following formula (e), and as a result, an azide derivative of a sialic acid oligosaccharide disaccharide-ized by a (2 → 9) O-glycoside bond is obtained. Thereafter, the same procedure as described above is applied to obtain the final object.

【００２９】[0029]

【化８】 [Chemical 8]

【００３０】或いは、下記式（ｆ）に示す単糖化合物
（糖部分の水酸基を保護基によって保護。ただし、９位
の水酸基をＴｓ基によって保護）のアジド誘導体を合成
し、次にこれに下記式（ｇ）に示すシアル酸を縮合せし
め、その結果（２→９）Ｓ−グリコシド結合によって二
糖化したシアル酸オリゴ糖のアジド誘導体を得ることが
でき、これ以後は前記したと同じ要領の処理を加えて最
終目的物を得る。Alternatively, an azido derivative of the monosaccharide compound represented by the following formula (f) (wherein the hydroxyl group of the sugar moiety is protected by a protecting group, but the 9-position hydroxyl group is protected by the Ts group) is synthesized and then By condensing the sialic acid represented by the formula (g), as a result, an azide derivative of a sialic acid oligosaccharide disaccharide-ized by the (2 → 9) S-glycoside bond can be obtained, and thereafter, the same procedure as described above is performed. To obtain the final product.

【００３１】[0031]

【化９】 [Chemical 9]

【００３２】同様に式（ｆ）の変わりに下記式（ｈ）に
示す単糖化合物（糖部分の水酸基を保護基によって保
護。ただし、６位の水酸基をＴｓ基によって保護）のア
ジド誘導体を合成し、次にこれに下記式（ｇ）に示すシ
アル酸を縮合せしめ、その結果（２→６）Ｓ−グリコシ
ド結合によって二糖化したシアル酸オリゴ糖のアジド誘
導体を得ることができ、これ以後は前記したと同じ要領
の処理を加えて最終目的物を得る。Similarly, instead of the formula (f), an azide derivative of the following formula (h) (a hydroxyl group of the sugar moiety is protected by a protecting group, but the 6-position hydroxyl group is protected by a Ts group) is synthesized. Then, this is condensed with a sialic acid represented by the following formula (g), and as a result, an azide derivative of a sialic acid oligosaccharide disaccharide-ized by a (2 → 6) S-glycoside bond can be obtained. The same procedure as described above is applied to obtain the final product.

【００３３】[0033]

【化１０】 [Chemical 10]

【００３４】本発明微粒子キャリヤーは前記式（Ｉ）に
よって示されるシアル酸オリゴ糖誘導体のうちの脂質誘
導体を配合して得られる微粒子キャリヤーであって、該
物質の特定の性質を専ら利用する物である。The fine particle carrier of the present invention is a fine particle carrier obtained by blending a lipid derivative of the sialic acid oligosaccharide derivatives represented by the above formula (I), and is a product which utilizes the specific property of the substance exclusively. is there.

【００３５】本発明微粒子キャリヤーは具体的にはリポ
ソーム、リピッドマイクロスフェアー、ミセル、エマル
ジョンを挙げることができる。これらキャリヤーの調製
はそれぞれ従来公知の方法に従って行えばよく、基本的
には本発明物質を両親媒性物質である他の膜成分と共に
溶媒に溶解または分散して混合する。Specific examples of the fine particle carrier of the present invention include liposomes, lipid microspheres, micelles and emulsions. Each of these carriers may be prepared by a conventionally known method, and basically, the substance of the present invention is dissolved or dispersed in a solvent and mixed with other membrane components which are amphiphilic substances.

【００３６】例えば、リポソームの場合には、ホスファ
チジルコリン、スフィンゴミエリン、ホスファチジルエ
タノールアミン等のリン脂質やジアルキル型合成界面活
性剤等の膜成分物質と本発明物質とを予め混合し、これ
を公知の方法(Ann.Rev.Biophys.Bioeng., 9,467(1980))
にしたがいリポソームの水分散液を調製する。かかるリ
ポコームは膜安定化剤としてコレステロール等のステロ
ール類、ジアルキルリン酸、ステアリルアミン等の荷電
物質およびトコフェロール等の酸化防止剤を含んでいて
もよい。For example, in the case of liposomes, phospholipids such as phosphatidylcholine, sphingomyelin and phosphatidylethanolamine, and membrane component substances such as dialkyl-type synthetic surfactants are mixed in advance with the substance of the present invention, and the mixture is subjected to a known method. (Ann. Rev. Biophys. Bioeng., 9, 467 (1980))
An aqueous dispersion of liposomes is prepared according to the above. Such lipocomb may contain sterols such as cholesterol, charged substances such as dialkylphosphoric acid and stearylamine, and antioxidants such as tocopherol as a membrane stabilizer.

【００３７】リピッドマイクロスフェアーの場合には、
ホスファチジルコリンと本発明物質とを予め混合し、こ
れに大豆油を加えて公知のリピッドマイクロスフェアー
の調製方法に従い処理することにより目的のリピッドマ
イクロスフェアーを得ることができる。In the case of lipid microspheres,
The desired lipid microspheres can be obtained by previously mixing phosphatidylcholine and the substance of the present invention, adding soybean oil to the mixture, and treating the mixture according to a known method for preparing lipid microspheres.

【００３８】ミセルの場合には、ポリオキシソルビタン
脂肪酸エステル、脂肪酸ナトリウムポリオキシエチレン
硬化ヒマシ油等の界面活性剤と本発明物質を予め混合
し、公知のミセルの調製方法に従い処理することにより
目的のミセルを製造することができる。In the case of micelles, a surfactant such as polyoxysorbitan fatty acid ester, fatty acid sodium polyoxyethylene hydrogenated castor oil or the like is preliminarily mixed with the substance of the present invention, and treated according to a known method for preparing micelles. Micelles can be manufactured.

【００３９】エマルジョンの場合には、ポリオキシソル
ビタン脂肪酸エステル、脂肪酸ナトリウム、ポリオキシ
エチレン硬化ヒマシ油等の界面活性剤と本発明物質を予
め混合し、これに大豆油等の油脂を加えて公知のエマル
ジョンの調製方法に従い処理することにより目的のエマ
ルジョンを製造することができる。In the case of an emulsion, a surfactant such as polyoxysorbitan fatty acid ester, sodium fatty acid, polyoxyethylene hydrogenated castor oil, etc. and the substance of the present invention are mixed in advance, and fats and oils such as soybean oil are added to the emulsion to obtain a known emulsion. The target emulsion can be produced by treating according to the method for preparing the emulsion.

【００４０】上記のようにして製造される微粒子キャリ
ヤーにおいて本発明物質が全脂質膜成分に対して占める
割合は約1/40モル比以上、好ましくは1/20モル比以上と
するのが望ましい。In the fine particle carrier produced as described above, the ratio of the substance of the present invention to the total lipid membrane components is preferably about 1/40 molar ratio or more, preferably 1/20 molar ratio or more.

【００４１】かかる微粒子キャリヤーが保持しうる薬物
には特に制限はなく、水溶性薬物でも脂溶性薬物でもよ
く、例えばシトシンアラビノシド、ダウノルビシン及び
メトトレキセートに代表される制癌剤、ペニシリンＧに
代表される抗生物質、インシュリン、インターフェロン
及び組織プラスミノーゲンアクチベータに代表される生
理活性物質などを挙げることができる。There is no particular limitation on the drug that the fine particle carrier can hold, and it may be a water-soluble drug or a fat-soluble drug. Examples include substances, insulin, interferons, and physiologically active substances represented by tissue plasminogen activator.

【００４２】[0042]

【作用】後記実験例によって示されるごとく、本発明物
質を配合した本発明微粒子キャリヤーは細網内皮系を回
避する性質があり、従って薬物運搬体として顕著に優れ
た作用を有する。As will be shown by the experimental examples described below, the fine particle carrier of the present invention containing the substance of the present invention has the property of avoiding the reticuloendothelial system, and therefore has a remarkably excellent action as a drug carrier.

【００４３】[0043]

【実施例】旋光度はすべてPerkin-Elmer Model 241 pol
arimeterを使用し、25℃で測定した。シリカゲルカラム
クロマトグラフィーは、半井Silica gel 60 またはYMC-
GEL を、ＴＬＣプレートはSilica Gel F254 (Merck,Dar
mstadt) を使用した。 1Ｈ−ＮＭＲはVXR-500S（バリア
ン社製）及びJeol JNM-GX 270 （日本電子社製）を使用
し、特徴的なピークのみをδ(ppm) で表記した。また、
質量分析はJEOL JMS-HX110/HX-110 （日本電子社製）
を、赤外線吸収スペクトルはJasco A-100 （日本分光社
製）を使用して測定した。[Example] All optical rotations are Perkin-Elmer Model 241 pol
It measured at 25 degreeC using the arimeter. Silica gel column chromatography can be performed with Hanai Silica gel 60 or YMC-
GEL, TLC plate is Silica Gel F 254 (Merck, Dar
mstadt) was used. For 1 H-NMR, VXR-500S (manufactured by Varian) and Jeol JNM-GX 270 (manufactured by JEOL Ltd.) were used, and only characteristic peaks were represented by δ (ppm). Also,
Mass spectrometry is JEOL JMS-HX110 / HX-110 (made by JEOL Ltd.)
The infrared absorption spectrum was measured using Jasco A-100 (manufactured by JASCO Corporation).

【００４４】実施例１：2-Palmitoylamido-ethyl O-(5-
acetamido-3,5-dideoxy-D-glycero-α-D-Galacto-2-non
ulopyranosylonic acid)- (2→6)- β-D-Glucopyranosi
de（化合物(4) の合成） 本実施例に含まれる反応式を図１に示す。 Example 1 : 2-Palmitoylamido-ethyl O- (5-
acetamido-3,5-dideoxy-D-glycero-α-D-Galacto-2-non
ulopyranosylonic acid)-(2 → 6)-β-D-Glucopyranosi
de (Synthesis of Compound (4)) The reaction formula contained in this example is shown in FIG.

【００４５】(a) 化合物（１）(70mg,0.076mmol)とア
ジトエタノール(20mg)を塩化メチレン(2ml) に溶解し、
「モレキュラーシーブ４Ａ」(300mg) を加え、室温で１
時間攪拌した。０℃に冷却し、三フッ化ホウ素ジエチル
エーテル(0.02ml)を加え、０℃で３時間攪拌した。(A) Compound (1) (70 mg, 0.076 mmol) and azidoethanol (20 mg) were dissolved in methylene chloride (2 ml),
Add "Molecular Sieve 4A" (300mg) and add 1 at room temperature.
Stir for hours. The mixture was cooled to 0 ° C., boron trifluoride diethyl ether (0.02 ml) was added, and the mixture was stirred at 0 ° C. for 3 hours.

【００４６】セライトろ過し、ろ液と洗液はあわせて塩
化メチレンで抽出し、炭酸水素ナトリウム水溶液で洗
浄、無水硫酸ナトリウムで脱水後減圧濃縮した。得られ
たシロップはシリカゲルカラムクロマトグフィー (CHCl
3 -MeOH 70:1) にて生成し、化合物（２）を得た。After filtration through Celite, the filtrate and washings were combined, extracted with methylene chloride, washed with an aqueous solution of sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained syrup is silica gel column chromatography (CHCl
It was generated with 3- MeOH 70: 1) to obtain the compound (2).

【００４７】RF =0.48(CHCl3 -MeOH 20:1) 。R F = 0.48 (CHCl 3 -MeOH 20: 1).

【００４８】［α］D +5.6°(C=1.8, CHCl3 ) 。[Α] D + 5.6 ° (C = 1.8, CHCl 3 ).

【００４９】(b) 化合物（２）(50mg,0.06mmol) とｐ
−トルエンスルホン酸・水和物(19mg,0.1mmol)をエタノ
ール(2ml) に溶解し、リンドラー触媒(135mg) を加え、
室温で２時間水素(48psi) にて還元した。触媒をろ去
後、ろ液を減圧乾固した。ついで、アセトニトリル溶液
とし、パルミチン酸Ｎ−ヒドロキシコハク酸イミドエス
テル及びトリエチルアミンンを加え、室温にて一晩攪拌
した。(B) Compound (2) (50 mg, 0.06 mmol) and p
-Toluenesulfonic acid hydrate (19 mg, 0.1 mmol) is dissolved in ethanol (2 ml), Lindlar catalyst (135 mg) is added,
Reduction with hydrogen (48 psi) for 2 hours at room temperature. After removing the catalyst by filtration, the filtrate was dried under reduced pressure. Next, an acetonitrile solution was prepared, palmitic acid N-hydroxysuccinimide ester and triethylamine were added, and the mixture was stirred overnight at room temperature.

【００５０】減圧濃縮後、シリカゲルカラムクロマトグ
ラフィー (CHCl3 -MeOH 30:1) にて精製して化合物
（３）を35mg得た。After concentration under reduced pressure, the residue was purified by silica gel column chromatography (CHCl 3 -MeOH 30: 1) to obtain 35 mg of compound (3).

【００５１】RF =0.48(CHCl3 -MeOH 20:1) 。R F = 0.48 (CHCl 3 -MeOH 20: 1).

【００５２】［α］D +2.8°(C=1.0, CHCl3 ) 。[Α] D + 2.8 ° (C = 1.0, CHCl 3 ).

【００５３】1H-NMR(CDCl3 ) δ：5.18(t,1H,J=9.3H
z)，5.13(dd,1H,J=9.3Hz) ，4.95(dd,1H,J=7.8,9.3Hz)
， 4.87(m,1H) ，4.46(d,1H,J=7.8Hz)，4.29(dd,1H,J=
2.7,12.5Hz)，3.80(s,3H)，2.60(dd,1H,J=4.6,12.7H
z)， 1.92(t,1H,J=12.7Hz)，0.88(t,3H,J=7.6Hz)。 1 H-NMR (CDCl 3 ) δ: 5.18 (t, 1H, J = 9.3H
z), 5.13 (dd, 1H, J = 9.3Hz), 4.95 (dd, 1H, J = 7.8,9.3Hz)
, 4.87 (m, 1H), 4.46 (d, 1H, J = 7.8Hz), 4.29 (dd, 1H, J =
2.7,12.5Hz), 3.80 (s, 3H), 2.60 (dd, 1H, J = 4.6,12.7H
z), 1.92 (t, 1H, J = 12.7Hz), 0.88 (t, 3H, J = 7.6Hz).

【００５４】(c) 化合物（３）をメタノールに溶解
し、ソジウムメトキシドを加えて室温で２時間攪拌し
た。ついで、１Ｎ水酸化ナトリウムを加え、室温でさら
に一晩攪拌した。(C) The compound (3) was dissolved in methanol, sodium methoxide was added, and the mixture was stirred at room temperature for 2 hours. Then, 1N sodium hydroxide was added, and the mixture was further stirred at room temperature overnight.

【００５５】「アンバーリスト１５」にて中和後ろ過
し、減圧濃縮した。カラムクロマトグラフィー（「セフ
ァデックスLH-20 」，MeOH）にて精製して化合物（４）
を得た。After being neutralized with "Amberlyst 15", it was filtered and concentrated under reduced pressure. Compound (4) purified by column chromatography (“Sephadex LH-20”, MeOH)
Got

【００５６】RF =0.77(CHCl3 -MeOH- H2 O 10:10:3)。R F = 0.77 (CHCl 3 —MeOH—H 2 O 10: 10: 3).

【００５７】［α］D -7.0°(C=0.53,MeOH) 。[Α] D -7.0 ° (C = 0.53, MeOH).

【００５８】1H-NMR(CD3 OD) δ：4.24(d,1H,J=7.8H
z)，4.05(dd,1H,J=4.8,10.8Hz)，3.19(dd,1H,J=7.8,9.3
Hz) ，2.86(dd,1H,J=4.4,12.2Hz)，2.20(t,2H,J=7.6H
z)，2.01(s,3H)，0.90(t,3H,J=7.0Hz)。 1 H-NMR (CD 3 OD) δ: 4.24 (d, 1H, J = 7.8H
z), 4.05 (dd, 1H, J = 4.8,10.8Hz), 3.19 (dd, 1H, J = 7.8,9.3
Hz), 2.86 (dd, 1H, J = 4.4,12.2Hz), 2.20 (t, 2H, J = 7.6H
z), 2.01 (s, 3H), 0.90 (t, 3H, J = 7.0Hz).

【００５９】実施例２：2-Palmitoylamido-ethyl O-5-a
cetamido-3,5-dideoxy-D-glycero- α-D-galacto-2-non
ulopyranosylonic acid)- (2→6)-O- β-D-galactopyra
nosyl-(1→4)- β-D-glucopyranoside（化合物（８）の
合成） 本実施例に含まれる反応式を図２に示す。 Example 2 : 2-Palmitoylamido-ethyl O-5-a
cetamido-3,5-dideoxy-D-glycero- α-D-galacto-2-non
ulopyranosylonic acid)-(2 → 6) -O-β-D-galactopyra
nosyl- (1 → 4) -β-D-glucopyranoside (Synthesis of Compound (8)) The reaction formula contained in this example is shown in FIG.

【００６０】(a) 化合物（５）(190mg,0.157mmol) と
アジドエタノール(55mg)を塩化メチレン(3ml) に溶解
し、「モレキュラーシーブ４Ａ」(400mg) を加え、室温
で一晩攪拌した。０℃に冷却し、三フッ化ホウ素ジエチ
ルエーテル(0.04ml)を加え、０℃で３時間攪拌した。(A) Compound (5) (190 mg, 0.157 mmol) and azidoethanol (55 mg) were dissolved in methylene chloride (3 ml), "Molecular Sieve 4A" (400 mg) was added, and the mixture was stirred overnight at room temperature. The mixture was cooled to 0 ° C., boron trifluoride diethyl ether (0.04 ml) was added, and the mixture was stirred at 0 ° C. for 3 hours.

【００６１】それからセライトろ過し、ろ液と洗液はあ
わせて塩化メチレンで抽出し、重曹水で洗浄、無水硫酸
ナトリウムで脱水後減圧濃縮した。得られたシロップは
シリカゲルカラムクロマトグラフィー (CHCl3 -MeOH 8
0:1) にて精製し、化合物（６）を得た。Then, the mixture was filtered through Celite, and the filtrate and washings were combined, extracted with methylene chloride, washed with aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained syrup was subjected to silica gel column chromatography (CHCl 3 -MeOH 8
The compound (6) was obtained by purification with 0: 1).

【００６２】RF =0.47(CHCl3 -MeOH 20:1) 。R F = 0.47 (CHCl 3 -MeOH 20: 1).

【００６３】［α］D -17.9°(C=1.82,CHCl3 ) 。[Α] D -17.9 ° (C = 1.82, CHCl 3 ).

【００６４】1H-NMR(CDCl3 ) δ： 5.41(m,1H) ， 5.31
(m,2H) ，5.21(bt,1H,J=9.3Hz) ，5.08(dd,1H,J=8.5,1
0.5Hz) ， 4.99(dd,1H,J=3.4,10.5Hz) ，4.94(t,1H,8.3
Hz)， 4.86(m,1H) ， 4.58(d,1H,8.5Hz) ，4.56(d,1H,J
=8.3Hz)，4.53(bd,1H) ，4.30(bd,1H,J=11.7Hz)，4.15
(dd,1H,J=5.4,12.0Hz)，3.8(s,3H) ，2.54(dd,1H,J=4.
6,12.7Hz)。 1 H-NMR (CDCl 3 ) δ: 5.41 (m, 1H), 5.31
(m, 2H), 5.21 (bt, 1H, J = 9.3Hz), 5.08 (dd, 1H, J = 8.5,1
0.5Hz), 4.99 (dd, 1H, J = 3.4,10.5Hz), 4.94 (t, 1H, 8.3
Hz), 4.86 (m, 1H), 4.58 (d, 1H, 8.5Hz), 4.56 (d, 1H, J
= 8.3Hz), 4.53 (bd, 1H), 4.30 (bd, 1H, J = 11.7Hz), 4.15
(dd, 1H, J = 5.4,12.0Hz), 3.8 (s, 3H), 2.54 (dd, 1H, J = 4.
6,12.7Hz).

【００６５】(b) 化合物（６）(20mg,0.02mmol) とｐ
−トルエンスルホン酸・水和物(10mg)をエタノール(2m
l) に溶解し、リンドラー触媒(70mg)を加え、室温で２
時間水素(48psi) にて還元した。触媒をろ去後、ろ液を
減圧乾固した。ついで、アセトニトリル溶液とし、パル
ミチン酸Ｎ−ヒドロキシコハク酸イミドエステル(11mg,
0.03mmol) 及びトリエチルアミンを加え、室温にて一晩
攪拌した。(B) Compound (6) (20 mg, 0.02 mmol) and p
-Toluenesulfonic acid hydrate (10 mg) was added to ethanol (2 m
l), add Lindlar's catalyst (70 mg), and add 2 at room temperature.
Reduced with hydrogen (48 psi) for hours. After removing the catalyst by filtration, the filtrate was dried under reduced pressure. Then, an acetonitrile solution was prepared, and palmitic acid N-hydroxysuccinimide ester (11 mg,
0.03 mmol) and triethylamine were added, and the mixture was stirred at room temperature overnight.

【００６６】減圧濃縮後、シリカゲルカラムクロマトグ
ラフィー (CHCl3 -MeOH 30:1) にて精製して化合物
（７）を19mg得た。After concentration under reduced pressure, the residue was purified by silica gel column chromatography (CHCl 3 -MeOH 30: 1) to obtain 19 mg of compound (7).

【００６７】RF =0.44(CHCl3 -MeOH 20:1) 。R F = 0.44 (CHCl 3 -MeOH 20: 1).

【００６８】［α］D -9.1°(C=1.27,CHCl3 ) 。[Α] D -9.1 ° (C = 1.27, CHCl 3 ).

【００６９】1H-NMR(CDCl3 ) δ： 5.41(m,1H) ， 5.31
(m,2H) ，5.22(t,1H,J=9.5Hz)，5.12(bd,1H,J=10.8H
z)， 5.08(dd,1H,J=7.8,10.3Hz) ， 5.00(dd,1H,J=3.5,
10.3Hz) ，4.90(dd,1H,J=8.1,9.5Hz) ， 4.87(m,1H) ，
4.57(d,1H,J=7.8Hz) ，4.52(dd,1H,J=1.9,11.9Hz)，4.
47(d,1H,J=8.1Hz)，4.30(bd,1H,J=13.4Hz)，4.16(dd,1
H,J=5.6,12.0Hz,) ，4.08(bd,J=10.7Hz) ， 3.98(dt,1
H,J=10.3Hz) ，3.90(bt,J=6.4Hz)，3.85(t,1H,J=9.3H
z)，3.81(s,3H)，2.54(dd,1H,J=4.0,13.0Hz)，0.88(t,3
H,J=6.8Hz)。 1 H-NMR (CDCl 3 ) δ: 5.41 (m, 1H), 5.31
(m, 2H), 5.22 (t, 1H, J = 9.5Hz), 5.12 (bd, 1H, J = 10.8H
z), 5.08 (dd, 1H, J = 7.8,10.3Hz), 5.00 (dd, 1H, J = 3.5,
10.3Hz), 4.90 (dd, 1H, J = 8.1,9.5Hz), 4.87 (m, 1H),
4.57 (d, 1H, J = 7.8Hz), 4.52 (dd, 1H, J = 1.9,11.9Hz), 4.
47 (d, 1H, J = 8.1Hz), 4.30 (bd, 1H, J = 13.4Hz), 4.16 (dd, 1
H, J = 5.6,12.0Hz,) 4.08 (bd, J = 10.7Hz), 3.98 (dt, 1
H, J = 10.3Hz), 3.90 (bt, J = 6.4Hz), 3.85 (t, 1H, J = 9.3H
z), 3.81 (s, 3H), 2.54 (dd, 1H, J = 4.0,13.0Hz), 0.88 (t, 3
H, J = 6.8Hz).

【００７０】(c) 化合物（７）をメタノールに溶解
し、ソジウムメトキシドを加えて室温で２時間攪拌し
た。ついで、１Ｎ水酸化ナトリウムを加え、室温でさら
に一晩攪拌した。(C) The compound (7) was dissolved in methanol, sodium methoxide was added, and the mixture was stirred at room temperature for 2 hours. Then, 1N sodium hydroxide was added, and the mixture was further stirred at room temperature overnight.

【００７１】「アンバーリスト１５」にて中和後ろ過
し、減圧濃縮した。カラムクロマトグラフィー（「セフ
ァデックスLH-20 」，MeOH）にて精製して化合物（８）
を得た。After neutralization with "Amberlyst 15", the mixture was filtered and concentrated under reduced pressure. Compound (8) purified by column chromatography (“Sephadex LH-20”, MeOH)
Got

【００７２】RF =0.68(CHCl3 -MeOH- H2 O 10:10:3)。R F = 0.68 (CHCl 3 —MeOH—H 2 O 10: 10: 3).

【００７３】［α］D -2.40°(C=0.83,MeOH) 。[Α] D -2.40 ° (C = 0.83, MeOH).

【００７４】1H-NMR(CD3 OD) δ： 4.32(d,2H,J=7.6Hz)
，4.01(dd,1H,J=7.1,9.8Hz) ，2.81(dd,1H,J=4.6,12.0
Hz)，2.20(t,2H,J=7.6Hz)， 1.65(t,1H,J=12.0Hz)，0.9
0(t,3H,J=6.8Hz)。 1 H-NMR (CD 3 OD) δ: 4.32 (d, 2H, J = 7.6Hz)
, 4.01 (dd, 1H, J = 7.1,9.8Hz), 2.81 (dd, 1H, J = 4.6,12.0
Hz), 2.20 (t, 2H, J = 7.6Hz), 1.65 (t, 1H, J = 12.0Hz), 0.9
0 (t, 3H, J = 6.8Hz).

【００７５】実施例３：8-Palmitoylamido-octyl O-(5-
acetaido-3,5-didexy-D-glycero-β-D-galacto-2-nonul
opyranosylonic acid)- (2→9)-5-acetamido-3,5-dideo
xy-D-glycero- α-D-galacto-2-nonulopyranosylonic a
cid （化合物（13）の合成） 本実施例に含まれる反応式は図３に示す。 Example 3 : 8-Palmitoylamido-octyl O- (5-
acetaido-3,5-didexy-D-glycero-β-D-galacto-2-nonul
opyranosylonic acid)-(2 → 9) -5-acetamido-3,5-dideo
xy-D-glycero- α-D-galacto-2-nonulopyranosylonic a
cid (Synthesis of Compound (13)) The reaction formula contained in this example is shown in FIG.

【００７６】(a) 化合物（９）(1.142ｇ，190mmol)を
アセトニトリル(5ml) に溶解し、「モレキュラシーブ３
Ａ」(870mmol) を入れ、室温で１夜攪拌した。−45℃に
冷却後、ジメチル（メチルチオ）スルホニウムトリフレ
イトＤＭＴＳＴ(3.658ｇ) を加え、−45℃で５分間攪拌
した。そこに、8-アジドオクタノール(9.1ｇ）をアセト
ニトリル(5ml) に溶解し、「モレキュラシーブ３Ａ」(8
00mg) を入れ、室温で１夜攪拌したものを加え、−20℃
で１夜攪拌した。(A) Compound (9) (1.142 g, 190 mmol) was dissolved in acetonitrile (5 ml), and "Molecular Sieve 3
A ”(870 mmol) was added and the mixture was stirred at room temperature overnight. After cooling to −45 ° C., dimethyl (methylthio) sulfonium triflate DMTST (3.658 g) was added, and the mixture was stirred at −45 ° C. for 5 minutes. 8-Azidooctanol (9.1 g) was dissolved in acetonitrile (5 ml), and "Molecular Sieve 3A" (8
(00mg), stirred at room temperature overnight, added, and added at -20 ° C.
It was stirred overnight.

【００７７】TLC(CH2 Cl2 ：MeOH=20:1)で反応の終了を
確認後、セライト濾過し、塩化メチレンで抽出後塩化メ
チレン層を炭酸水素ナトリウム水溶液にて洗浄し、無水
硫酸ナトリウムにて脱水した。この後、これを濾別し、
塩化メチレンで洗浄し、濾液と洗液を合して減圧濃縮を
行った。得られたシロップをカラムクロマトグラフィー
（CH2 Cl2 ：MeOH=100:1) にて精製して化合物（10)(10
15mg，72.8％) とそのβ体(190mg，13.6％) を得た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 : MeOH = 20: 1), the reaction mixture was filtered through Celite, extracted with methylene chloride, and the methylene chloride layer was washed with an aqueous solution of sodium hydrogen carbonate to obtain anhydrous sodium sulfate. And dehydrated. After this, this is filtered off,
It was washed with methylene chloride, the filtrate and the washing solution were combined, and concentrated under reduced pressure. The resulting syrup was purified by column chromatography (CH 2 Cl 2 : MeOH = 100: 1) to give compound (10) (10
15 mg, 72.8%) and its β-form (190 mg, 13.6%) were obtained.

【００７８】元素分析：Ｃ28Ｈ44Ｏ13Ｎ4 としての計算
値Ｃ，52.17 ；Ｈ，6.88；Ｎ，8.69に対し実験値はＣ，
51.99 ；Ｈ，6.88；Ｎ，8.54であった。Elemental analysis: Calculated value as C 28 H 44 O 13 N 4 C, 52.17; H, 6.88; N, 8.69, experimental value is C,
51.99; H, 6.88; N, 8.54.

【００７９】ＩＲmax filmcm-1：3280，2100，1750，12
30，1670，1550。IR max film cm −1 : 3280, 2100, 1750, 12
30, 1670, 1550.

【００８０】α体［α］D -8.62° (CH2 Cl2 ,C=1.2
0)。Α-form [α] D -8.62 ° (CH 2 Cl 2 , C = 1.2
0).

【００８１】β体［α］D -12.40° (CH2 Cl2 ，C=9.5
0) 。Β-form [α] D -12.40 ° (CH 2 Cl 2 , C = 9.5
0).

【００８２】270MHz 1H NMR(CDCl3 ) ：α体 δ 1.31-1.62(m,16H)，1.88(s,3H)，2.03，2.0
4，2.14，2.15(4s,12H)，2.58(dd,1H,J=12.83Hz,J=4.39
Hz)，3.79(s,3H)，4.31(dd,1H,J=12.46Hz,J=2.56Hz)，
4.84(ddd,1H,J=7.7Hz,J=9.9Hz) ， 5.19(d,1H,J=9.53H
z)，5.30-5.42(m,2H,H-7) 。270 MHz 1 H NMR (CDCl 3 ): α-form δ 1.31-1.62 (m, 16H), 1.88 (s, 3H), 2.03, 2.0
4, 2.14, 2.15 (4s, 12H), 2.58 (dd, 1H, J = 12.83Hz, J = 4.39
Hz), 3.79 (s, 3H), 4.31 (dd, 1H, J = 12.46Hz, J = 2.56Hz),
4.84 (ddd, 1H, J = 7.7Hz, J = 9.9Hz), 5.19 (d, 1H, J = 9.53H
z), 5.30-5.42 (m, 2H, H-7).

【００８３】β体 δ 1.25-1.62(m,16H)，1.88(s,3
H)，2.02，2.03，2.07，2.15(4s,12H)，2.46(dd,1H,J=1
2.83Hz,J=4.76Hz)，3.80(s,3H)，4.81(dd,1H,J=12.46H
z,J=2.19Hz)，5.16-5.49(m,4H,H-4,7,8) 。 Β-body δ 1.25-1.62 (m, 16H), 1.88 (s, 3
H), 2.02, 2.03, 2.07, 2.15 (4s, 12H), 2.46 (dd, 1H, J = 1
2.83Hz, J = 4.76Hz), 3.80 (s, 3H), 4.81 (dd, 1H, J = 12.46H
z, J = 2.19Hz), 5.16-5.49 (m, 4H, H-4,7,8).

【００８４】化合物(10)をソジウムメトキシドを用いて
脱アセチル化して化合物（10′）を得た。The compound (10) was deacetylated with sodium methoxide to obtain the compound (10 ').

【００８５】(b) 化合物（10′）(194mg,0.34mmol)と
化合物（９）(353mg,0.68mmol)をアセトニトリル(3ml)
に溶解し、「モレキュラーシーブ３Ａ」(400mg) を加
え、室温で一晩攪拌した。−45℃に冷却後、ジメチル
（メチルチオ）スルホニウムトリフレート（1.13ｇ）を
加え、−20℃で一日攪拌した。(B) Compound (10 ') (194 mg, 0.34 mmol) and compound (9) (353 mg, 0.68 mmol) were added to acetonitrile (3 ml).
, "Molecular Sieve 3A" (400 mg) was added, and the mixture was stirred at room temperature overnight. After cooling to −45 ° C., dimethyl (methylthio) sulfonium triflate (1.13 g) was added, and the mixture was stirred at −20 ° C. for one day.

【００８６】反応終了後セライトろ過し、ろ液と洗液は
あわせて塩化メチレンで抽出し、重曹水で洗浄、無水硫
酸ナトリウムで脱水後減圧濃縮した。得られたシロップ
はシリカゲルカラムクロマトグラフィー (CHCl3 -MeOH
50:1) にて精製し、化合物（11）を得た。収量 129mg。
(α体：205mg)。After completion of the reaction, the mixture was filtered through Celite, and the filtrate and washings were combined, extracted with methylene chloride, washed with aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained syrup was subjected to silica gel column chromatography (CHCl 3 -MeOH
The compound (11) was obtained by purification with 50: 1). Yield 129mg.
(α form: 205 mg).

【００８７】［α］D -32.7°(C=0.96,CH2 Cl2 ) 。[Α] D -32.7 ° (C = 0.96, CH 2 Cl 2 ).

【００８８】1H-NMR(CDCl3 ) δ：6.26(d,1H,J=7.7H
z)，6.08(d,1H,J=9.9Hz)，5.21(ddd,1H)，3.89(s,3H)，
3,80(s,3H)，2.83(dd,1H) ，2.54(dd,1H) ，2.14(s,3
H)，2.07(s,3H)，2.03(s,3H)，2.00(s,3H)，1.98(s,3
H)，1.87(s,3H)。 1 H-NMR (CDCl 3 ) δ: 6.26 (d, 1H, J = 7.7H
z), 6.08 (d, 1H, J = 9.9Hz), 5.21 (ddd, 1H), 3.89 (s, 3H),
3,80 (s, 3H), 2.83 (dd, 1H), 2.54 (dd, 1H), 2.14 (s, 3
H), 2.07 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3
H), 1.87 (s, 3H).

【００８９】(c) ついで、常法により脱エステル化し
て化合物（12）を得た。化合物（12）(5.8mgをエタノー
ル(1.5ml) 及び水(0.15ml)の混液に溶解し、リンドラー
触媒(42mg)を加え、室温で２時間水素(48psi) にて還元
した。触媒をろ去後、ろ液を減圧乾固した。クロロホル
ム−メタノール−水(10:10:3 1ml) の溶液と、パルミチ
ン酸Ｎ−ヒドロキシコハク酸イミドエステル(3.5mg) を
加え、室温で一晩攪拌した。(C) Then, the compound (12) was obtained by deesterification by a conventional method. Compound (12) (5.8 mg was dissolved in a mixed solution of ethanol (1.5 ml) and water (0.15 ml), Lindlar catalyst (42 mg) was added, and the mixture was reduced with hydrogen (48 psi) at room temperature for 2 hours. Then, the filtrate was evaporated to dryness under reduced pressure, a solution of chloroform-methanol-water (10: 10: 3 1 ml) and palmitic acid N-hydroxysuccinimide ester (3.5 mg) were added, and the mixture was stirred at room temperature overnight.

【００９０】反応終了後、カラムクロマトグラフィー
（「セファデックスLH-20 」，CHCl3-MeOH- H3 O 10:1
0:3)にて精製して化合物（13）を得た。After completion of the reaction, column chromatography (“Sephadex LH-20”, CHCl 3 —MeOH—H 3 O 10: 1)
The compound (13) was obtained by purification at 0: 3).

【００９１】RF =0.70(CHCl3 -MeOH- H2 O 10:10:3)。R F = 0.70 (CHCl 3 —MeOH—H 2 O 10: 10: 3).

【００９２】［α］D -3.0°(C=0.33,MeOH) 。[Α] D -3.0 ° (C = 0.33, MeOH).

【００９３】1H-NMR(CD3 OD) δ：2.82(bd,1H,J=12H
z)，2.42(bd,1H,J=12Hz)，2.16(t,2H,J=7.6Hz)，2.01
(s,6H)，0.90(t,3H,J=6.8Hz)。 1 H-NMR (CD 3 OD) δ: 2.82 (bd, 1H, J = 12H
z), 2.42 (bd, 1H, J = 12Hz), 2.16 (t, 2H, J = 7.6Hz), 2.01
(s, 6H), 0.90 (t, 3H, J = 6.8Hz).

【００９４】実施例４：8-Palmitoylamido-etyl O-(5-a
cetamido-3,5-dideoxy-L-glycero- α-D-galacto-2-non
ulopyranosylonic acid)- (2→3)-O- β-D-galactopyra
nosyl-(1→4)- β-D-glucopyranoside（化合物（17）の
合成） 本実施例に含まれる反応式を図４に示す。 Example 4 : 8-Palmitoylamido-etyl O- (5-a
cetamido-3,5-dideoxy-L-glycero- α-D-galacto-2-non
ulopyranosylonic acid)-(2 → 3) -O-β-D-galactopyra
nosyl- (1 → 4) -β-D-glucopyranoside (Synthesis of Compound (17)) The reaction formula contained in this example is shown in FIG.

【００９５】(a) 化合物（14）(100mg,0.07mmol)とア
ジドエタノール(20mg)を塩化メチレン(3ml) に溶解し、
「モレキュラーシーブ４ＡタイプAW300 」(2.0ｇ) を加
え、室温で一晩攪拌した。０℃に冷却し、三フッ化ホウ
素ジエチルエーテル(0.04ml)を加え、０℃で４時間攪拌
した。(A) Compound (14) (100 mg, 0.07 mmol) and azidoethanol (20 mg) were dissolved in methylene chloride (3 ml),
"Molecular sieve 4A type AW300" (2.0 g) was added, and the mixture was stirred at room temperature overnight. The mixture was cooled to 0 ° C., boron trifluoride diethyl ether (0.04 ml) was added, and the mixture was stirred at 0 ° C. for 4 hours.

【００９６】セライトろ過し、ろ液と洗液はあわせて塩
化メチレンで抽出し、重曹水で洗浄、無水硫酸ナトリウ
ムで脱水後減圧濃縮した。得られたシロップはシリカゲ
ルカラムクロマトグラフィー(AcOEt-C6 H14 3:2) にて
精製し、化合物（15）を82mg得た。After filtration through Celite, the filtrate and washings were combined, extracted with methylene chloride, washed with aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained syrup was purified by silica gel column chromatography (AcOEt-C 6 H 14 3: 2) to obtain 82 mg of compound (15).

【００９７】［α］D -7.8°(C=0.98,CHCl3 ) 。[Α] D -7.8 ° (C = 0.98, CHCl 3 ).

【００９８】1H-NMR(CDCl3 ) δ：5.47(t,1H)，5.25(d
d,1H) ，5.23(dd,1H) ，5.15(d,1H)，5.08(dd,1H) ，4.
93(d,1H)，4.86(dd,1H) ，4.70(d,1H)，3.80(s,3H)，3.
60(dd,1H) ，2.60(dd,1H) ，1.74(t,1H)。 1 H-NMR (CDCl 3 ) δ: 5.47 (t, 1H), 5.25 (d
d, 1H), 5.23 (dd, 1H), 5.15 (d, 1H), 5.08 (dd, 1H), 4.
93 (d, 1H), 4.86 (dd, 1H), 4.70 (d, 1H), 3.80 (s, 3H), 3.
60 (dd, 1H), 2.60 (dd, 1H), 1.74 (t, 1H).

【００９９】(b) ついで、常法により脱エステル化し
て化合物（16）を得た。 RF =0.57(CHCl3 -MeOH- H2 O
10:10:3)。化合物（16）(12mg)をエタノール(2.5ml) 及
び水(0.25ml)の混液に溶解し、リンドラー触媒(100mg)
を加え、室温で７時間水素(48psi) にて還元した。触媒
をろ去後、ろ液を減圧乾固した。クロロホルム−メタノ
ール−水(10:10:3、2ml)の溶液とし、パルミチン酸Ｎ−
ヒドロキシコハク酸イミドエステル(3.5mg) 及びトリエ
チルアミンを加え、室温で一晩攪拌した。(B) Then, deesterification was carried out by a conventional method to obtain the compound (16). R F = 0.57 (CHCl 3 -MeOH- H 2 O
10: 10: 3). Compound (16) (12 mg) was dissolved in a mixture of ethanol (2.5 ml) and water (0.25 ml), and Lindlar catalyst (100 mg)
Was added and reduced with hydrogen (48 psi) for 7 hours at room temperature. After removing the catalyst by filtration, the filtrate was dried under reduced pressure. A solution of chloroform-methanol-water (10: 10: 3, 2 ml) was prepared, and palmitic acid N-
Hydroxysuccinimide ester (3.5 mg) and triethylamine were added, and the mixture was stirred at room temperature overnight.

【０１００】反応終了後、減圧にて乾固し、カラムクロ
マトグラフィー（「セファデックスLH-20 」，MeOH）に
て精製して化合物（17）を得た。After completion of the reaction, the mixture was dried under reduced pressure and purified by column chromatography (“Sephadex LH-20”, MeOH) to obtain compound (17).

【０１０１】RF =0.56(CHCl3 -MeOH- H2 O 10:10:3)。R F = 0.56 (CHCl 3 —MeOH—H 2 O 10: 10: 3).

【０１０２】［α］D -1.7°(C=0.88,CHCl3 -MeOH- H2
O 10:10:3)。[Α] D -1.7 ° (C = 0.88, CHCl 3 -MeOH-H 2
O 10: 10: 3).

【０１０３】1H-NMR(CD3 OD) δ：4.42(d,1H,J=7.8H
z)， 4.31(d,1H,J=7.8Hz) ，2.73(dd,1H,J=4.4,12.2H
z)，2.19(t,2H,J=7.6Hz)，1.99(s,3H)， 1.73(t,1H,J=1
2.0Hz)，0.90(t,3H,J=7.0Hz)。 1 H-NMR (CD 3 OD) δ: 4.42 (d, 1H, J = 7.8H
z), 4.31 (d, 1H, J = 7.8Hz), 2.73 (dd, 1H, J = 4.4,12.2H
z), 2.19 (t, 2H, J = 7.6Hz), 1.99 (s, 3H), 1.73 (t, 1H, J = 1
2.0Hz), 0.90 (t, 3H, J = 7.0Hz).

【０１０４】実施例５：2-Palmitoylamido-ethyl S-(5-
acetamido-3,5-dieoxy-D-glycero- α-D-galacto-2-non
ulopyranosylonic acid)- (2→6)-6-thio-β-D-galacto
pyranoside（化合物（21）の合成） 本実施例に含まれる反応式を図５に示す。 Example 5 : 2-Palmitoylamido-ethyl S- (5-
acetamido-3,5-dieoxy-D-glycero- α-D-galacto-2-non
ulopyranosylonic acid)-(2 → 6) -6-thio-β-D-galacto
pyranoside (Synthesis of Compound (21)) The reaction formula contained in this example is shown in FIG.

【０１０５】(a) S-(Methyl 5-acetamido-4,7,8,9-tet
ra-O-acetyl-3,5-dideoxy-D-glycero- α-D-galacto-2-
nonulopyranosylonate)- (2→6)-2,3,4-tri-O-acetyl-6
-thio- α-D-galactopyranosyl trichloroacetimidate
（18）(180m,0.19mmol) とアジドエタノール(50mg)を塩
化メチレン(4ml) に溶解し、「モレキュラーシーブ４
Ａ」(300mg) を加え、室温で４時間攪拌した。０℃に冷
却し、三フッ化ホウ素ジエチルエーテル(0.03ml)を加
え、０℃で２時間攪拌した。(A) S- (Methyl 5-acetamido-4,7,8,9-tet
ra-O-acetyl-3,5-dideoxy-D-glycero- α-D-galacto-2-
nonulopyranosylonate)-(2 → 6) -2,3,4-tri-O-acetyl-6
-thio- α-D-galactopyranosyl trichloroacetimidate
(18) (180m, 0.19mmol) and azidoethanol (50mg) were dissolved in methylene chloride (4ml), and "Molecular sieve 4
A ”(300 mg) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was cooled to 0 ° C., boron trifluoride diethyl ether (0.03 ml) was added, and the mixture was stirred at 0 ° C. for 2 hours.

【０１０６】セライトろ過し、ろ液と洗液はあわせて塩
化メチレンで抽出し、重曹水で洗浄、無水硫酸ナトリウ
ムで脱水後減圧濃縮した。得られたシロップはシリカゲ
ルカカラムクロマトグラフィー (CH2 Cl2 -MeOH 90:1)
にて精製し、化合物（19）を125mg得た。After filtration through Celite, the filtrate and washings were combined, extracted with methylene chloride, washed with aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained syrup was subjected to silica gel column chromatography (CH 2 Cl 2 -MeOH 90: 1).
The compound (19) was obtained in an amount of 125 mg.

【０１０７】［α］D -9.4°(C=0.89,CHCl3 ) 。[Α] D -9.4 ° (C = 0.89, CHCl 3 ).

【０１０８】1H-NMR(CDCl3 ) δ：5.56(d,1H)，5.0(dd,
1H)，5.09(dd,1H) ，4.93(ddd,1H)，4.74(d,1H)，4.29
(dd,1H) ，3.82(s,3H)，2.72(dd,1H) ，2.20(s,3H)，2.
16(s,3H)，2.14(s,3H)，2.06(s,3H)，2.05(s,3H)，2.03
(s,3H)，1.97(s,3H)，1.90(s,3H)。 1 H-NMR (CDCl 3 ) δ: 5.56 (d, 1H), 5.0 (dd,
1H), 5.09 (dd, 1H), 4.93 (ddd, 1H), 4.74 (d, 1H), 4.29
(dd, 1H), 3.82 (s, 3H), 2.72 (dd, 1H), 2.20 (s, 3H), 2.
16 (s, 3H), 2.14 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 2.03
(s, 3H), 1.97 (s, 3H), 1.90 (s, 3H).

【０１０９】(b) ついで、常法により脱エステル化し
て化合物（20）を得た。 RF =0.58(CHCl3 -MeOH- H2 O
10:10:3)。化合物（20）(17mg)をエタノール(3.0ml) に
溶解し、リンドラー触媒(140mg) を加え、室温で一晩水
素(48psi) にて還元した。触媒をろ去後、ろ液を減圧乾
固した。クロロホルム−メタノール−水(10:10:3、2ml)
の溶液とし、パルミチン酸Ｎ−ヒドロキシコハク酸イミ
ドエステル(12mg)及びトリエチルアミンを加え室温で一
晩攪拌した。(B) Then, deesterification was carried out by a conventional method to obtain the compound (20). R F = 0.58 (CHCl 3 -MeOH-H 2 O
10: 10: 3). The compound (20) (17 mg) was dissolved in ethanol (3.0 ml), the Lindlar catalyst (140 mg) was added, and the mixture was reduced with hydrogen (48 psi) at room temperature overnight. After removing the catalyst by filtration, the filtrate was dried under reduced pressure. Chloroform-methanol-water (10: 10: 3, 2 ml)
The resulting solution was added with palmitic acid N-hydroxysuccinimide ester (12 mg) and triethylamine, and the mixture was stirred at room temperature overnight.

【０１１０】反応終了後、減圧にて乾固し、カラムクロ
マトグラフィー（「セファデックスLH-20 」，MeOH）に
て精製して化合物（21）を得た。After completion of the reaction, the mixture was dried under reduced pressure and purified by column chromatography (“Sephadex LH-20”, MeOH) to obtain compound (21).

【０１１１】RF =0.83(CHCl3 -MeOH- H2 O 10:10:3)。R F = 0.83 (CHCl 3 —MeOH—H 2 O 10: 10: 3).

【０１１２】［α］D +2.1°(C=0.19,MeOH) 。[Α] D + 2.1 ° (C = 0.19, MeOH).

【０１１３】1H-NMR(CD3 OD) δ：4.26(d,1H,J=7.6H
z)，2.89(dd,1H,J=4.6,12.2Hz)，2.19(t,2H,J=7.7Hz)，
2.01(s,3H)， 1.63(dd,1H,J=10.7,12.2Hz)，0.90(t,3H,
J=7.0Hz)。 1 H-NMR (CD 3 OD) δ: 4.26 (d, 1H, J = 7.6H
z), 2.89 (dd, 1H, J = 4.6,12.2Hz), 2.19 (t, 2H, J = 7.7Hz),
2.01 (s, 3H), 1.63 (dd, 1H, J = 10.7,12.2Hz), 0.90 (t, 3H,
J = 7.0Hz).

【０１１４】実施例６：2-Palmitoylamido-ethyl S-(5-
acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-non
ulopyranosylonic acid)- (2→6)-2-acetamido-2-deoxy
-6-thio-β-D-glucopyranoside（化合物（30）の合成） 本実施例に含まれる反応式を図６に示す。 Example 6 : 2-Palmitoylamido-ethyl S- (5-
acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-non
ulopyranosylonic acid)-(2 → 6) -2-acetamido-2-deoxy
-6-thio-β-D-glucopyranoside (Synthesis of Compound (30)) The reaction formula contained in this example is shown in FIG.

【０１１５】(a) 2-Acetamido-1,3,4,6-tetra-O-acety
l-2-deoxy- β-D-glucopyranose（22）(4.6ｇ,1.8mmol)
を用いて、トリメチルシリルトリフルオロメタンスル
フォネート法によりオキサゾリン体（23）を得た。(A) 2-Acetamido-1,3,4,6-tetra-O-acety
l-2-deoxy-β-D-glucopyranose (22) (4.6 g, 1.8 mmol)
Was used to obtain an oxazoline derivative (23) by the trimethylsilyltrifluoromethanesulfonate method.

【０１１６】このオキサゾリン体を塩化メチレン（20m
l）に溶解し、アジドエタノール (1.53ｇ，17.6mmol)
及び「モレキュラーシーブ４Ａ」(3g)を加え室温で 1.5
時間攪拌した。０℃に冷却し、窒素気流中にて触媒量の
硫酸を加え、室温にて８時間攪拌した。This oxazoline derivative was converted into methylene chloride (20 m
l) dissolved in azidoethanol (1.53g, 17.6mmol)
And "Molecular Sieve 4A" (3g) were added and the mixture was stirred at room temperature for 1.5
Stir for hours. After cooling to 0 ° C., a catalytic amount of sulfuric acid was added in a nitrogen stream, and the mixture was stirred at room temperature for 8 hours.

【０１１７】セライトろ過し、ろ液と洗液はあわせて塩
化メチレンで抽出し、重曹水で洗浄、無水硫酸ナトリウ
ムで脱水後減圧濃縮した。得られたシロップはシリカゲ
ルカラムクロマトグラフィー(AcOEt-C6 H14 1:1) にて
精製し、化合物（24）を3.12ｇ得た。After filtration through Celite, the filtrate and washings were combined, extracted with methylene chloride, washed with aqueous sodium hydrogen carbonate, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained syrup was purified by silica gel column chromatography (AcOEt-C 6 H 14 1: 1) to obtain 3.12 g of compound (24).

【０１１８】1H-NMR(CDCl3 ) δ：5.89(d,1H)，5.37(d
d,1H,J=9.4,10.6Hz)，5.07(t,1H)，4.85(d,1H,J=8.4H
z)，4.26(dd,1H，J=12.3,4.8Hz) ，4.16(dd,1H,J=2.3H
z) ，4.05(m,1H)。 1 H-NMR (CDCl 3 ) δ: 5.89 (d, 1H), 5.37 (d
d, 1H, J = 9.4,10.6Hz), 5.07 (t, 1H), 4.85 (d, 1H, J = 8.4H
z), 4.26 (dd, 1H, J = 12.3,4.8Hz), 4.16 (dd, 1H, J = 2.3H
z), 4.05 (m, 1H).

【０１１９】(b) ついで、常法により化合物（24）(2.
5ｇ) を脱エステルして化合物（25）を1.67ｇ得た。(B) Then, the compound (24) (2.
(5 g) was deesterified to obtain 1.67 g of compound (25).

【０１２０】［α］D -51.2℃(C=1.1,MeOH)。[Α] D -51.2 ° C. (C = 1.1, MeOH).

【０１２１】1H-NMR(CD3 OD) δ：4.49(d,1H,J=8.4H
z)，1.97(s,3H)。 1 H-NMR (CD 3 OD) δ: 4.49 (d, 1H, J = 8.4H
z), 1.97 (s, 3H).

【０１２２】(c) 化合物（25）(500mg,1.72mmol)をピ
リジン(8ml) に溶解し、０℃に冷却した後、ｐ−トルエ
ンスルホニルクロリド(430mg,2.26mmol)を加え、０℃に
て４時間攪拌した。反応終了後メタノールを加え、減圧
濃縮した。ついで、ピリジン−無水酢酸(2:1、 9ml) を
加え一晩放置した。(C) Compound (25) (500 mg, 1.72 mmol) was dissolved in pyridine (8 ml), cooled to 0 ° C, p-toluenesulfonyl chloride (430 mg, 2.26 mmol) was added, and the mixture was added at 0 ° C. Stir for 4 hours. After completion of the reaction, methanol was added and the mixture was concentrated under reduced pressure. Then, pyridine-acetic anhydride (2: 1, 9 ml) was added and left overnight.

【０１２３】減圧濃縮後、通常の処理をしてシリカゲル
カラムクロマトグラフィー(AcOEt-C6 H14 2:1) にて精
製し、化合物（26）を 620mg得た。After concentration under reduced pressure, the mixture was subjected to usual treatment and purified by silica gel column chromatography (AcOEt-C 6 H 14 2: 1) to obtain 620 mg of compound (26).

【０１２４】［α］D -7.2°(C=0.87,CH2 Cl2 ) 。[Α] D -7.2 ° (C = 0.87, CH 2 Cl 2 ).

【０１２５】1H-NMR(CDCl3 ) δ：5.86(d,1H)，5.34(d
d,1H,J=10.4,9.2Hz)，4.90(t,1H)，4.80(d,1H,J=8.3H
z)，2.46(s,3H)。 1 H-NMR (CDCl 3 ) δ: 5.86 (d, 1H), 5.34 (d
d, 1H, J = 10.4,9.2Hz), 4.90 (t, 1H), 4.80 (d, 1H, J = 8.3H
z), 2.46 (s, 3H).

【０１２６】(d) 化合物（26）(300mg,0.57mmol)及びM
etyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideox
y-2-thio-D-glycero-α-D-galacto-2-nonulopyranosylo
nateのＳ−ナトリウム塩（27）(450mg,0.85mmol)をN,N-
ジメチルホルムアミド(5ml)に溶解し、45℃にて１日間
攪拌した。ついで、ピリジン−無水酢酸(2:1、7.5ml)を
加え一晩放置した。(D) Compound (26) (300 mg, 0.57 mmol) and M
etyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideox
y-2-thio-D-glycero-α-D-galacto-2-nonulopyranosylo
nate S-sodium salt (27) (450 mg, 0.85 mmol) was added to N, N-
It was dissolved in dimethylformamide (5 ml) and stirred at 45 ° C for 1 day. Then pyridine-acetic anhydride (2: 1, 7.5 ml) was added and left overnight.

【０１２７】減圧濃縮後、通常の処理をしてシリカゲル
カラムクロマトグラフィー(AcOEt-C6 H14 3:1) にて精
製し、化合物（28）を 370mg得た。After concentration under reduced pressure, the mixture was subjected to usual treatment and purified by silica gel column chromatography (AcOEt-C 6 H 14 3: 1) to obtain 370 mg of compound (28).

【０１２８】［α］D +19.5°(C=0.83,CH2 Cl2 ) 。[Α] D + 19.5 ° (C = 0.83, CH 2 Cl 2 ).

【０１２９】1H-NMR(CDCl3 ) δ：6.18(d,1H)，4.92(d,
1H)，4.72(d,1H,J=8.2Hz)，3.81(s,3H)，2.71(dd,1H,J=
13.0Hz)。 1 H-NMR (CDCl 3 ) δ: 6.18 (d, 1H), 4.92 (d,
1H), 4.72 (d, 1H, J = 8.2Hz), 3.81 (s, 3H), 2.71 (dd, 1H, J =
13.0Hz).

【０１３０】(e) ついで、常法により脱エステル化し
て化合物（29）を得た。(E) Then, deesterification was carried out by a conventional method to obtain the compound (29).

【０１３１】RF =0.64(CHCl3 -MeOH- H2 O 10:10:3)。R F = 0.64 (CHCl 3 —MeOH—H 2 O 10: 10: 3).

【０１３２】［α］D +21.0°(C=0.56,MeOH) 。[Α] D + 21.0 ° (C = 0.56, MeOH).

【０１３３】1H-NMR(CDCl3 ) δ：4.43(d,1H,J=8.4H
z)，2.01(s,3H)，1.97(s,3H)， 1.69(t,1H,J=11.8Hz)。 1 H-NMR (CDCl 3 ) δ: 4.43 (d, 1H, J = 8.4H
z), 2.01 (s, 3H), 1.97 (s, 3H), 1.69 (t, 1H, J = 11.8Hz).

【０１３４】(f) 化合物（29）(13.8mg)をエタノール
(2.5ml) 及び水(0.25ml)の混液に溶解し、リンドラー触
媒(178mg) を加え、室温で５時間水素(48psi) にて還元
した。触媒をろ去後、ろ液を減圧乾固した。クロロホル
ム−メタノール−水(10:10:3、2ml) の溶液とし、パル
ミチン酸Ｎ−ヒドロキシコハク酸イミドエステル(15mg)
及びトリエチルアミンを加え、室温で一晩攪拌した。(F) Compound (29) (13.8 mg) was added to ethanol.
(2.5 ml) and water (0.25 ml) were dissolved in the mixture, Lindlar's catalyst (178 mg) was added, and the mixture was reduced with hydrogen (48 psi) at room temperature for 5 hours. After removing the catalyst by filtration, the filtrate was dried under reduced pressure. A solution of chloroform-methanol-water (10: 10: 3, 2 ml) was prepared, and palmitic acid N-hydroxysuccinimide ester (15 mg) was prepared.
And triethylamine were added, and the mixture was stirred overnight at room temperature.

【０１３５】反応終了後、減圧にて乾固し、カラムクロ
マトグラフィー（「セファデックスLH-20 」，MeOH）に
て精製して化合物（30）を得た。After completion of the reaction, the mixture was dried under reduced pressure and purified by column chromatography (“Sephadex LH-20”, MeOH) to obtain compound (30).

【０１３６】RF =0.76(CHCl3 -MeOH- H2 O 10:10:3)。R F = 0.76 (CHCl 3 —MeOH—H 2 O 10: 10: 3).

【０１３７】［α］D +22.4°(C=0.85,CHCl3 -MeOH- H
2 O 10:10:3)。[Α] D + 22.4 ° (C = 0.85, CHCl 3 -MeOH-H
2 O 10: 10: 3).

【０１３８】1H-NMR(CD3 OD) δ：4.33(d,1H,J=8.3H
z)，3.90(m,1H)，2.88(dd,1H,J=4.6,13Hz)，2.19(t,2H,
J=7.7Hz)，2.00(s,3H)，1.97(s,3H)， 1.69(dd,1H,J=1
0.5,12.0Hz)，0.90(t,3H,J=7.1Hz)。 1 H-NMR (CD 3 OD) δ: 4.33 (d, 1H, J = 8.3H
z), 3.90 (m, 1H), 2.88 (dd, 1H, J = 4.6,13Hz), 2.19 (t, 2H,
J = 7.7Hz), 2.00 (s, 3H), 1.97 (s, 3H), 1.69 (dd, 1H, J = 1
0.5,12.0Hz), 0.90 (t, 3H, J = 7.1Hz).

【０１３９】実施例７：2-azidoethyl S-(5-acetamido-
3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranos
ylonic acid)- (2→6)-6-thio-β-D-glucopyranoside
（化合物（33）の合成） 本実施例に含まれる反応式を図７に示す。 Example 7 : 2-azidoethyl S- (5-acetamido-
3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranos
ylonic acid)-(2 → 6) -6-thio-β-D-glucopyranoside
(Synthesis of Compound (33)) The reaction formula included in this example is shown in FIG. 7.

【０１４０】(a) まず、2-Azidoetyl S-(methyl 5-ace
tamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycer
o- α-D-galacto-2-nonulopyranosylonate)- (2→6)-2,
3,4-tri-O-acetyl-6-thio- β-D-glucopyranoside（化
合物（32））を次のようにして合成した。(A) First, 2-Azidoetyl S- (methyl 5-ace
tamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycer
o-α-D-galacto-2-nonulopyranosylonate)-(2 → 6) -2,
3,4-tri-O-acetyl-6-thio-β-D-glucopyranoside (compound (32)) was synthesized as follows.

【０１４１】すなわち、S-(Methyl 5-acetamido-4,7,8,
9-tetara-O-acetyl-3,5-dideoxy-D-glycero-α-Dgalact
o-2-nonulopyrunosylonate)-(2→)-2,3,4-tri-O-acetyl
- α-D-glucopyranosyltrichloroacetimidate(31)(160m
g,0.17mmol) と2-アジドエタノール(45mg,0.51mmol) を
塩化メチレン(3ml) に溶解し、「モレキュラーシーブ４
Ａ」(200mg) を加え、室温にて３時間撹拌した。０℃に
冷却後三フッ化ホウ素ジエチルエーテル（23μl,0.19mm
ol) を加え、０℃にて６時間撹拌した。That is, S- (Methyl 5-acetamido-4,7,8,
9-tetara-O-acetyl-3,5-dideoxy-D-glycero-α-Dgalact
o-2-nonulopyrunosylonate)-(2 →) -2,3,4-tri-O-acetyl
-α-D-glucopyranosyltrichloroacetimidate (31) (160m
g, 0.17 mmol) and 2-azidoethanol (45 mg, 0.51 mmol) were dissolved in methylene chloride (3 ml), and “Molecular sieve 4
A ”(200 mg) was added, and the mixture was stirred at room temperature for 3 hours. After cooling to 0 ℃, boron trifluoride diethyl ether (23μl, 0.19mm
ol) was added and the mixture was stirred at 0 ° C. for 6 hours.

【０１４２】ＴＬＣ（CH2 Cl2 -MeOH 15:1) にて反応の
終了を確認後反応液をセライト濾過し、塩化メチレンに
て洗浄した。濾液と洗液は合せて塩化メチレンにて抽出
し、有機層を炭酸水素ナトリウム水溶液、水の順に洗浄
し、無水硫酸ナトリウムにて脱水した。これを濾別し、
塩化メチレンにて洗浄し、濾液と洗液は合せて減圧濃縮
し、得られたシロップをシリカゲルカラムクロマトグラ
フィー（CH2 Cl2 -MeOH 80:1）にて精製して化合物（3
2）(86mg,58.4％）を得た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 15: 1), the reaction solution was filtered through Celite and washed with methylene chloride. The filtrate and washings were combined and extracted with methylene chloride, and the organic layer was washed with an aqueous solution of sodium hydrogencarbonate and water in this order and dehydrated with anhydrous sodium sulfate. This is filtered off,
The mixture was washed with methylene chloride, and the filtrate and washings were combined and concentrated under reduced pressure. The obtained syrup was purified by silica gel column chromatography (CH 2 Cl 2 -MeOH 80: 1) to give the compound (3
2) (86 mg, 58.4%) was obtained.

【０１４３】元素分析：Ｃ34Ｈ48Ｎ4 Ｏ20Ｓとしての計
算値Ｃ，47.22 ；Ｈ，5.59；Ｎ，6.48に対し実験値は
Ｃ，47,09 ；Ｈ，5.58；Ｎ，6.39であった。Elemental analysis: Calculated values as C 34 H 48 N 4 O 20 S C, 47.22; H, 5.59; N, 6.48, whereas experimental values were C, 47,09; H, 5.58; N, 6.39. It was

【０１４４】［α］D ＝+25.58°(C＝0.43，CHCl3 ）。[Α] D = + 25.58 ° (C = 0.43, CHCl 3 ).

【０１４５】IR νmax Film（cm-1) ：3700-3200 ，21
00，1750，1660，1540。IR ν max Film (cm -1 ): 3700-3200, 21
00, 1750, 1660, 1540.

【０１４６】1H-NMR(CDCl3 ）δ：5.27-5.34(m,3H) ，
5.19(t,1H,J=9.5Hz)，4.98(dd,1H,J=8.1Hz) ，4.87(dd
d,1H,J=11.5,4.6,10.4Hz)，4.57(d,1H)，4.30(dd,1H,J=
2.6,12.6Hz)，4.10(dd,1H,J=4.8Hz) ，2.14，2.13，2.0
8，2.05，2.04，2.03，2.00(7s,21Hz) 。 1 H-NMR (CDCl 3 ) δ: 5.27-5.34 (m, 3H),
5.19 (t, 1H, J = 9.5Hz), 4.98 (dd, 1H, J = 8.1Hz), 4.87 (dd
d, 1H, J = 11.5,4.6,10.4Hz), 4.57 (d, 1H), 4.30 (dd, 1H, J =
2.6,12.6Hz), 4.10 (dd, 1H, J = 4.8Hz), 2.14, 2.13, 2.0
8, 2.05, 2.04, 2.03, 2.00 (7s, 21Hz).

【０１４７】(b) ついで、化合物（32）(86mg,99μmo
l)をメタノール(2ml) に溶解し、触媒量のソジウムメト
キシドの28％メタノール溶液を加え、室温にて６時間撹
拌した後水(0.5ml) を加え、１晩撹拌した。(B) Then, the compound (32) (86 mg, 99 μmo
l) was dissolved in methanol (2 ml), a catalytic amount of 28% methanol solution of sodium methoxide was added, the mixture was stirred at room temperature for 6 hours, water (0.5 ml) was added, and the mixture was stirred overnight.

【０１４８】ＴＬＣ(BuOH-EtOH-H2 O 4:2:1)にて反応の
終了を確認後イオン交換樹脂「アンバーライトIR-120」
（Ｈ型）にて中和し、これを濾別後メタノールにて洗浄
した。濾液と洗液は合せて減圧濃縮し、得られたシロッ
プをカラムクロマトグラフィー（「セファデックス LH-
20」、溶離液メタノール）にて精製して化合物（33）
（55mg，定量的）を得た。After confirming the completion of the reaction by TLC (BuOH-EtOH-H 2 O 4: 2: 1), the ion exchange resin "Amberlite IR-120" was used.
It was neutralized with (H type), filtered, and washed with methanol. The filtrate and washings are combined and concentrated under reduced pressure, and the resulting syrup is subjected to column chromatography (“Sephadex LH-
20 ", eluent methanol) to purify compound (33)
(55 mg, quantitative) was obtained.

【０１４９】元素分析Ｃ19Ｈ32Ｎ4 Ｏ13Ｓとしての計算
値Ｃ，41.00 ；Ｈ，5.80；Ｎ，10.07 に対して実験値は
Ｃ，41.00 ；Ｈ，5.80；Ｎ，10.07 であった。Elemental analysis The calculated values for C 19 H 32 N 4 O 13 S were C, 41.00; H, 5.80; N, 10.07, whereas the experimental values were C, 41.00; H, 5.80; N, 10.07.

【０１５０】［α］D ＝+30.95°(C＝0.42，MeOH）。[Α] D = + 30.95 ° (C = 0.42, MeOH).

【０１５１】IR νmax Film（cm-1) ：3700-3000 ，21
00。IR ν max Film (cm -1 ): 3700-3000, 21
00.

【０１５２】1H-NMR(CD3 OD) δ：4.19(d,1H,J=7.7H
z)，2.72(dd,1H) ，1.81(s,3H)，1.59(t,1H,J=11.2Hz)
。 1 H-NMR (CD 3 OD) δ: 4.19 (d, 1H, J = 7.7H
z), 2.72 (dd, 1H), 1.81 (s, 3H), 1.59 (t, 1H, J = 11.2Hz)
.

【０１５３】実施例８：2-Azidoethyl S-(5-acetamico-
3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranos
ylonic aced)- (2→6)-O-(6-thio- β-D-gulopyranosy
l)-(1→4)- β-D-glucopyranoside（化合物（36）の合
成） 本実施例に含まれる反応式を図８に示す。 Example 8 : 2-Azidoethyl S- (5-acetamico-
3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranos
ylonic aced)-(2 → 6) -O- (6-thio- β-D-gulopyranosy
l)-(1 → 4) -β-D-glucopyranoside (Synthesis of Compound (36)) The reaction formula contained in this example is shown in FIG.

【０１５４】(a) まず、2-Azidoethyl S-(methyl 5-ac
etamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glyce
ro-α-D-galacto-2-nonulopyranosylonate)- (2→6)-O-
(2,3,4-tri-O-acetyl-6-thio-3-D-gulopyranosyl)- (1
→4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside（化合
物（35））を合成した。(A) First, 2-Azidoethyl S- (methyl 5-ac
etamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glyce
ro-α-D-galacto-2-nonulopyranosylonate)-(2 → 6) -O-
(2,3,4-tri-O-acetyl-6-thio-3-D-gulopyranosyl)-(1
→ 4) -2,3,6-tri-O-acetyl-β-D-glucopyranoside (compound (35)) was synthesized.

【０１５５】すなわち、化合物（34）(170mg,138μmol)
と2-アジドエタノール (40mg,459μmol)を塩化メチレン
(3ml) に溶解し、「モレキュラーシーブ４Ａ」(200mg)
を加えて室温にて４時間撹拌した。０℃に冷却後三フッ
化ホウ素ジエチルエーテル (0.02ml,163μmol)を加え、
０℃にて２時間撹拌した。That is, the compound (34) (170 mg, 138 μmol)
And 2-azidoethanol (40 mg, 459 μmol) in methylene chloride
Dissolve in (3 ml), "Molecular Sieve 4A" (200 mg)
Was added and the mixture was stirred at room temperature for 4 hours. After cooling to 0 ° C., boron trifluoride diethyl ether (0.02 ml, 163 μmol) was added,
The mixture was stirred at 0 ° C for 2 hours.

【０１５６】ＴＬＣ（CH2 Cl2 -MeOH 15:1）にて反応の
終了を確認後反応液をセライト濾過し、塩化メチレンに
て洗浄した。濾液と洗液は合せて塩化メチレンにて抽出
し、有機層を炭酸水素ナトリウム水溶液、水の順で洗浄
し、無水硫酸ナトリウムにて脱水した。これを濾別後塩
化メチレンにて洗浄し、濾液と洗液は合せて減圧濃縮
し、得られたシロップをシリカゲルカラムクロマトグラ
フィー（AcOH-C6 H142:1 ）にて精製して化合物（35）
(112mg，70％）を得た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 15: 1), the reaction solution was filtered through Celite and washed with methylene chloride. The filtrate and washings were combined and extracted with methylene chloride, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate and water in this order, and dehydrated with anhydrous sodium sulfate. This is filtered off, washed with methylene chloride, the filtrate and washings are combined and concentrated under reduced pressure, and the syrup thus obtained is purified by silica gel column chromatography (AcOH-C 6 H 14 2: 1) to give the compound ( 35)
(112 mg, 70%) was obtained.

【０１５７】元素分析：Ｃ46Ｈ64Ｎ4 Ｏ28Ｓとしての計
算値Ｃ，47.92 ；Ｈ，5.59；Ｎ，4.86に対して実験値は
Ｃ，47.83 ；Ｈ，5.77；Ｎ，4.85であった。Elemental analysis: Calculated value as C 46 H 64 N 4 O 28 S C, 47.92; H, 5.59; N, 4.86, whereas experimental value was C, 47.83; H, 5.77; N, 4.85. ..

【０１５８】［α］D ＝ +6.76°(C＝0.976 ，CHC
l3 ）。[Α] D = + 6.76 ° (C = 0.976, CHC
l 3 ).

【０１５９】IR νmax Film (cm-1) ：3700-3200 ，21
00，1750，1670，1540。IR ν max Film (cm −1 ): 3700-3200, 21
00, 1750, 1670, 1540.

【０１６０】1H-NMR(CDCl3 ) δppm ：5.26(m,2H)，4.8
5(m,1H)，4.19(dd,1H,J=2.8Hz,J=13.0Hz)，3.78(s,3
H)，2.68(dd,1H,J=4.6Hz,J=12.4Hz)，1.83(s,3H)，5.35
(t,1H)，5.19(t,1H,J=9.5Hz)，4.94(dd,1H,J=8.1Hz) ，
4.81(d,1H)，4.70(d,1H)，4.52(d,1H,J=7.7Hz)，4.39(d
d,1H) ，4.23(dd,1H,J=5.0Hz,J=12.5Hz)，3.23，3.44(2
m,2H) ，2.81(dd,1H,J=13.7Hz,J=7.9Hz)，2.63(dd,1H,J
=5.3Hz) ，2.12，2.12，2.09，2.07，2.07，2.04，2.0
1，1.99，1.99，1.92(10s,30H) 。 1 H-NMR (CDCl 3 ) δppm: 5.26 (m, 2H), 4.8
5 (m, 1H), 4.19 (dd, 1H, J = 2.8Hz, J = 13.0Hz), 3.78 (s, 3
H), 2.68 (dd, 1H, J = 4.6Hz, J = 12.4Hz), 1.83 (s, 3H), 5.35
(t, 1H), 5.19 (t, 1H, J = 9.5Hz), 4.94 (dd, 1H, J = 8.1Hz),
4.81 (d, 1H), 4.70 (d, 1H), 4.52 (d, 1H, J = 7.7Hz), 4.39 (d
d, 1H), 4.23 (dd, 1H, J = 5.0Hz, J = 12.5Hz), 3.23,3.44 (2
m, 2H), 2.81 (dd, 1H, J = 13.7Hz, J = 7.9Hz), 2.63 (dd, 1H, J
= 5.3Hz), 2.12, 2.12, 2.09, 2.07, 2.07, 2.04, 2.0
1, 1.99, 1.99, 1.92 (10s, 30H).

【０１６１】(b) ついで、化合物（35）(110mg，95μm
ol)をメタノール(3ml) に溶解し、触媒量のソジウムメ
トキシドの28％メタノール溶液を加え、室温にて５時間
撹拌した後水(0.5ml) を加え、１晩攪拌した。(B) Then, the compound (35) (110 mg, 95 μm
ol) was dissolved in methanol (3 ml), a catalytic amount of 28% methanol solution of sodium methoxide was added, the mixture was stirred at room temperature for 5 hours, water (0.5 ml) was added, and the mixture was stirred overnight.

【０１６２】ＴＬＣ(BuOH-EtOH-H2 O 4:2:1 ）にて反応
の終了を確認後イオン交換樹脂「アンバーライトIR-12
0」（Ｈ型）にて中和し、これを濾別後メタノールにて
洗浄した。濾液と洗液は合せて減圧濃縮し、得られたシ
ロップをカラムクロマトグラフィー（「セファデックス
LH-20 」、溶離液メタノール）にて化合物（36）（68m
g，定量的）を得た。After confirming the completion of the reaction by TLC (BuOH-EtOH-H 2 O 4: 2: 1), the ion exchange resin "Amberlite IR-12" was used.
It was neutralized with 0 "(H type), filtered, and washed with methanol. The filtrate and washings are combined and concentrated under reduced pressure, and the resulting syrup is subjected to column chromatography (“Sephadex”).
LH-20 ", eluent methanol) with compound (36) (68m
g, quantitative).

【０１６３】元素分析：Ｃ25Ｈ42Ｎ4 Ｏ18Ｓとしての計
算値Ｃ，41.78 ；Ｈ，5.89；Ｎ，7.80に対して実験値は
Ｃ，41.77 ；Ｈ，5.64；Ｎ，7.49であった。Elemental analysis: Calculated value as C 25 H 42 N 4 O 18 S C, 41.78; H, 5.89; N, 7.80, whereas experimental value was C, 41.77; H, 5.64; N, 7.49. ..

【０１６４】［α］D ＝ +7.50°(C＝0.4 ，MeOH） IR νmax KBr (cm-1) ：3700-3100 ，2100。[Α] D = + 7.50 ° (C = 0.4, MeOH) IR ν max KBr (cm −1 ): 3700-3100, 2100.

【０１６５】1H-NMR(CD3 OD) δppm ： 2.79(dd,1H)，
1.93(s,3H)，1.56(t,1H,J=11.4Hz)， 4.66(d,1H,J=8.4H
z) ，4.30(d,1H,J=7.9Hz)，2.87(m,2H)。 1 H-NMR (CD 3 OD) δppm: 2.79 (dd, 1H),
1.93 (s, 3H), 1.56 (t, 1H, J = 11.4Hz), 4.66 (d, 1H, J = 8.4H
z), 4.30 (d, 1H, J = 7.9Hz), 2.87 (m, 2H).

【０１６６】実施例９：2-Azidoethyl S-(5-acetamido-
3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranos
ylonic acid)- (2→6)-O-(6-thio- β-D-galactopyrano
syl)-(1→4)- β-D-glucopyranoside（化合物（39）の
合成） 本実施例に含まれる反応式を図９に示す。 Example 9 : 2-Azidoethyl S- (5-acetamido-
3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranos
ylonic acid)-(2 → 6) -O- (6-thio-β-D-galactopyrano
syl)-(1 → 4) -β-D-glucopyranoside (Synthesis of Compound (39)) The reaction formula contained in this example is shown in FIG. 9.

【０１６７】(a) 2-Azidoethyl S-(methyl 5-acetamid
o-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycro- α-
D-galacto-2-nonulopyranosylonate)- (2→6)-O-(2,3,4
-tri-O-acetyl-6-thio-β-D-galactopyranosyl)- (1→
4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside（化合物
（38））を合成した。(A) 2-Azidoethyl S- (methyl 5-acetamid
o-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycro- α-
D-galacto-2-nonulopyranosylonate)-(2 → 6) -O- (2,3,4
-tri-O-acetyl-6-thio-β-D-galactopyranosyl)-(1 →
4) -2,3,6-tri-O-acetyl-β-D-glucopyranoside (compound (38)) was synthesized.

【０１６８】すなわち、S-(methyl 5-acetamido-4,7,8.
9-tetra-O-acetyl-3,5-dideoxy-D-glycero- α-D-galac
to-2-nonulopyranosylonate)- (2→6)-O-(2,3,4-tri-O-
acetyl-6-thio-β-D-galactopyranosyl)- (1→4)-2,3,6
-tri-O-acetyl-β-D-glucopyranosyl trichloroacetimi
date(37)(190mg,155μmol)と2-アジドエタノール (40m
g,459μmol)を塩化メチレン（5ml)に溶解し、「モレキ
ュラーシーブ４Ａ」(500mg) を加え、室温にて４時間攪
拌した。０℃にて冷却後、三フッ化ホウ素ジエチルエー
テル (25μl, 203μmol)を加え、０℃にて３時間攪拌し
た。ＴＬＣ（CH2Cl2 -MeOH 15:1）にて反応の終了を確
認後反応液をセライト濾過し、塩化メチレンにて洗浄し
た。濾液と洗液は合せて塩化メチレンにて抽出し、有機
層を炭酸水素ナトリウム水溶液、水の順で洗浄し、無水
硫酸ナトリウムにて脱水した。これを濾別後塩化メチレ
ンにて洗浄し、濾液と洗液は合せて減圧濃縮し、得られ
たシロップをシリカゲルカラムクロマトグラフィー（CH
2 Cl2 -MeOH 80:1）にて精製して化合物（38）(125mg，
70.5％) を得た。That is, S- (methyl 5-acetamido-4,7,8.
9-tetra-O-acetyl-3,5-dideoxy-D-glycero- α-D-galac
to-2-nonulopyranosylonate)-(2 → 6) -O- (2,3,4-tri-O-
Acetyl-6-thio-β-D-galactopyranosyl)-(1 → 4) -2,3,6
-tri-O-acetyl-β-D-glucopyranosyl trichloroacetimi
date (37) (190 mg, 155 μmol) and 2-azido ethanol (40 m
g, 459 μmol) was dissolved in methylene chloride (5 ml), “Molecular Sieve 4A” (500 mg) was added, and the mixture was stirred at room temperature for 4 hours. After cooling at 0 ° C, boron trifluoride diethyl ether (25 µl, 203 µmol) was added, and the mixture was stirred at 0 ° C for 3 hours. After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 15: 1), the reaction solution was filtered through Celite and washed with methylene chloride. The filtrate and washings were combined and extracted with methylene chloride, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate and water in this order, and dehydrated with anhydrous sodium sulfate. This is separated by filtration, washed with methylene chloride, the filtrate and washings are combined and concentrated under reduced pressure, and the obtained syrup is subjected to silica gel column chromatography (CH
Compound (38) (125 mg, purified by 2 Cl 2 -MeOH 80: 1)
70.5%) was obtained.

【０１６９】元素分析：Ｃ46Ｈ64Ｎ4 Ｏ28Ｓとしての計
算値Ｃ，47.92 ；Ｈ，5.59；Ｎ，4.86に対して実験値は
Ｃ47.88 ；Ｈ，5.72；Ｎ，4.69であった。Elemental analysis: Calculated value as C 46 H 64 N 4 O 28 S C, 47.92; H, 5.59; N, 4.86, whereas experimental value was C 47.88; H, 5.72; N, 4.69. ..

【０１７０】［α］D ＝-11.95°(C＝7.30，CHCl3 ）。[Α] D = -11.95 ° (C = 7.30, CHCl 3 ).

【０１７１】IR νmax Film (cm-1) ：3700-3200 ，21
00，1750，1670，1540。IR ν max Film (cm -1 ): 3700-3200, 21
00, 1750, 1670, 1540.

【０１７２】1H-NMR(CDCl3 ) δppm ：4.93(m,1H)，4.2
8(dd,1H,J=2.6Hz,J=12.3Hz)，4.16(dd,1H,J=3.5Hz) ，
3.86(s,3H)，2.72(dd,1H,J=4.6Hz,J=12.8Hz)，1.90(s,3
H)，5.54(d,1H,)，5.20(t,1H,J=9.5Hz)，4.97(dd,1H,J=
7.9Hz) ，4.71(d,1H,J=6.8Hz,) ，4.55(d,1H)，3.69，
3.48，3.27(3m,3H) ，2.80(dd,1H,J=6.8Hz,J=14.3Hz)，
2.53(dd,1H,J=7.7Hz) ，2.20，2.18，2.13，2.10，2.0
5，2.05，2.05，2.04，2.04，1.94(10s,30H) 。 1 H-NMR (CDCl 3 ) δppm: 4.93 (m, 1H), 4.2
8 (dd, 1H, J = 2.6Hz, J = 12.3Hz), 4.16 (dd, 1H, J = 3.5Hz),
3.86 (s, 3H), 2.72 (dd, 1H, J = 4.6Hz, J = 12.8Hz), 1.90 (s, 3
H), 5.54 (d, 1H,), 5.20 (t, 1H, J = 9.5Hz), 4.97 (dd, 1H, J =
7.9Hz), 4.71 (d, 1H, J = 6.8Hz,), 4.55 (d, 1H), 3.69,
3.48, 3.27 (3m, 3H), 2.80 (dd, 1H, J = 6.8Hz, J = 14.3Hz),
2.53 (dd, 1H, J = 7.7Hz), 2.20, 2.18, 2.13, 2.10, 2.0
5, 2.05, 2.05, 2.04, 2.04, 1.94 (10s, 30H).

【０１７３】(b) ついで、化合物（38）(90mg,78μmo
l)をメタノール(2ml) に溶解し、触媒量のソジウムメト
キシドの28％メタノール溶液を加え、室温にて５時間攪
拌した後水(0.5ml) を加え、１晩攪拌した。(B) Then, the compound (38) (90 mg, 78 μmo
l) was dissolved in methanol (2 ml), a catalytic amount of 28% methanol solution of sodium methoxide was added, and the mixture was stirred at room temperature for 5 hours, water (0.5 ml) was added, and the mixture was stirred overnight.

【０１７４】ＴＬＣ(BuOH-EtOH-H2 O 4:2:1 ）にて反応
の終了を確認後イオン交換樹脂「アンバーライトIR-12
0」（Ｈ型）にて中和し、これを濾別後メタノールにて
洗浄し、濾液と洗液を合せて減圧濃縮し、得られたシロ
ップをカラムクロマトグラフィー（「セファデックス L
H-20」、溶離液メタノール）にて化合物（39）(40mg,71
％）を得た。After confirming the completion of the reaction by TLC (BuOH-EtOH-H 2 O 4: 2: 1), the ion exchange resin "Amberlite IR-12" was used.
Neutralize with "0" (H type), filter and wash with methanol, combine the filtrate and washings and concentrate under reduced pressure. The resulting syrup was subjected to column chromatography ("Sephadex L
H-20 ", eluent methanol) with compound (39) (40 mg, 71
%) Was obtained.

【０１７５】元素分析：Ｃ25Ｈ42Ｎ4 Ｏ18Ｓとしての計
算値Ｃ，41.08 ；Ｈ，5.89；Ｎ，7.80に対して実測値は
Ｃ，41.75 ；Ｈ，6.03；Ｎ，7.99であった。Elemental analysis: Calculated value as C 25 H 42 N 4 O 18 S C, 41.08; H, 5.89; N, 7.80, whereas actual value was C, 41.75; H, 6.03; N, 7.99. ..

【０１７６】［α］D ＝+27.00°(C＝0.4 ，MeOH）。[Α] D = + 27.00 ° (C = 0.4, MeOH).

【０１７７】IR νmax KBr (cm-1) ：3700-3000 ，21
00。IR ν max KBr (cm −1 ): 3700-3000, 21
00.

【０１７８】1H-NMR(CD3 OD) δppm ： 2.88(dd,1H,J=
4.2Hz,J=12.3Hz) ，2.01(s,3H)，1.64(t,1H)， 440(d,1
H,J=6.2Hz)，4.37(d,1H,J=7.5Hz)，2.99(m,2H)。 1 H-NMR (CD 3 OD) δppm: 2.88 (dd, 1H, J =
4.2Hz, J = 12.3Hz), 2.01 (s, 3H), 1.64 (t, 1H), 440 (d, 1
H, J = 6.2Hz), 4.37 (d, 1H, J = 7.5Hz), 2.99 (m, 2H).

【０１７９】実施例10：2-Azidoethyl O-(5-acetamido-
3,5,9-trideoxy-D-glycero- α-D-galacto-2-nonulopyr
anosylonic acid)-(2 →3)-O- β-D-galactopyranosyl)
-(1 →4)- β-D-gucopyranoside （化合物（42）の合
成） 本実施例に含まれる反応式を図10に示す。 Example 10 : 2-Azidoethyl O- (5-acetamido-
3,5,9-trideoxy-D-glycero- α-D-galacto-2-nonulopyr
anosylonic acid)-(2 → 3) -O-β-D-galactopyranosyl)
-(1 → 4)-β-D-gucopyranoside (Synthesis of Compound (42)) FIG. 10 shows the reaction formula contained in this example.

【０１８０】(a) まず、2-Azidoethyl O-(methyl 5-ac
etamido-4,7,8-tri-O-acetyl-3,5,9-trideoxy-D-glycer
o- α-D-galacto-2-nonulopyranosylonate)-(2 →3)-O-
(2,4-di-O-acetyl-6-O-benzoyl-β-D-galactopyranosy
l)-(1 →4)-3-O-acetyl-2,6-di-O-benzoyl- β-D-gluco
pyranoside（化合物（41））を合成した。(A) First, 2-Azidoethyl O- (methyl 5-ac
etamido-4,7,8-tri-O-acetyl-3,5,9-trideoxy-D-glycer
o-α-D-galacto-2-nonulopyranosylonate)-(2 → 3) -O-
(2,4-di-O-acetyl-6-O-benzoyl-β-D-galactopyranosy
l)-(1 → 4) -3-O-acetyl-2,6-di-O-benzoyl- β-D-gluco
Pyranoside (compound (41)) was synthesized.

【０１８１】すなわち、化合物（40）(90mg,0.07mmol)
と2-アジドエタノール(20mg,0.23mmol) を塩化メチレン
(3ml) に溶解し、「モレキュラーシーブ４Ａ」タイプAW
300(2ｇ) を加えて室温にて30分間攪拌した。次いで、
氷冷下三フッ化ホウ素ジエチルエーテル(0.02ml)を滴下
し、０℃にて３時間攪拌した。That is, the compound (40) (90 mg, 0.07 mmol)
And 2-azidoethanol (20 mg, 0.23 mmol) in methylene chloride
Dissolve in (3 ml), "Molecular Sieve 4A" type AW
300 (2 g) was added and stirred at room temperature for 30 minutes. Then
Boron trifluoride diethyl ether (0.02 ml) was added dropwise under ice cooling, and the mixture was stirred at 0 ° C. for 3 hours.

【０１８２】ＴＬＣ（CH2 Cl2 -MeOH 18:1）にて反応の
終了を確認後、反応液をセライト濾過し、濾液と洗液を
合わせて塩化メチレンで抽出し、塩化メチレン層を炭酸
水素ナトリウム水溶液、水で洗浄した。無水硫酸ナトリ
ウムで脱水後、これを濾別し、塩化メチレンで洗浄し、
濾液と洗液を合わせ、得られたシロップをカラムクロマ
トグラフィー（CH2 Cl2 -MeOH 80:1）にて精製して化合
物（41）(80mg,94.2％) を得た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 18: 1), the reaction solution was filtered through Celite, the filtrate and the washing solution were combined, and the mixture was extracted with methylene chloride. It was washed with an aqueous solution of sodium and water. After dehydration with anhydrous sodium sulfate, this was filtered off and washed with methylene chloride,
The filtrate and washings were combined, and the obtained syrup was purified by column chromatography (CH 2 Cl 2 —MeOH 80: 1) to obtain compound (41) (80 mg, 94.2%).

【０１８３】元素分析：Ｃ59Ｈ68Ｎ4 Ｏ27としての計算
値Ｃ，56.01 ；Ｈ，5.42；Ｎ，4.43に対して実験値は
Ｃ，56.30 ；Ｈ，5.55；Ｎ，4.58であった。Elemental analysis: Calculated values for C 59 H 68 N 4 O 27 C, 56.01; H, 5.42; N, 4.43, whereas experimental values were C, 56.30; H, 5.55; N, 4.58.

【０１８４】［α］D ＝ +9.61°(C＝0.62，CHCl3 ) 。[Α] D = + 9.61 ° (C = 0.62, CHCl 3 ).

【０１８５】IR νmax Film (cm-1) ：3700-3140 ，31
40-2800 ，2100，1740，1670，1540，710 。IR ν max Film (cm -1 ): 3700-3140, 31
40-2800, 2100, 1740, 1670, 1540, 710.

【０１８６】1H-NMR(CDCl3 ) δppm ：8.08-7.38(m,15
H)，5.48(t,1H,J=9.53Hz) ，5.24(dd,1H,J=7.88Hz)，5.
04(dd,1H,J=7.88Hz,J=10.26Hz)，4.99(d,1H)，4.86(d,1
H)，4.72(d,1H)，4.55(dd,1H,J=3.30Hz)，3.90，3.65，
3.37，3.22(4m,4H) ，5.39(m,1H,J=9.71Hz) ，5.15(dd,
1H,J=2.93Hz)，4.08(q,1H)，3.72(s,3H)，3.58(dd,1H,J
=10.62Hz) ，2.56(dd,1H,J=12.45Hz,J=4.58Hz)，2.20-
1.83(7s,21H) ，1.09(d,3H,J=6.23Hz) 。 1 H-NMR (CDCl 3 ) δppm: 8.08-7.38 (m, 15
H), 5.48 (t, 1H, J = 9.53Hz), 5.24 (dd, 1H, J = 7.88Hz), 5.
04 (dd, 1H, J = 7.88Hz, J = 10.26Hz), 4.99 (d, 1H), 4.86 (d, 1
H), 4.72 (d, 1H), 4.55 (dd, 1H, J = 3.30Hz), 3.90, 3.65,
3.37, 3.22 (4m, 4H), 5.39 (m, 1H, J = 9.71Hz), 5.15 (dd,
1H, J = 2.93Hz), 4.08 (q, 1H), 3.72 (s, 3H), 3.58 (dd, 1H, J
= 10.62Hz), 2.56 (dd, 1H, J = 12.45Hz, J = 4.58Hz), 2.20-
1.83 (7s, 21H), 1.09 (d, 3H, J = 6.23Hz).

【０１８７】(b) ついで、化合物（41）(80mg,0.063mm
ol)をメタノール(3ml) に溶解し、ソジウムメトキシド
の28％メタノール溶液（５滴）を加え、室温にて24時間
攪拌した後水(0.5ml) を加え、さらに12時間攪拌した。(B) Then, the compound (41) (80 mg, 0.063 mm
was dissolved in methanol (3 ml), 28% methanol solution of sodium methoxide (5 drops) was added, and the mixture was stirred at room temperature for 24 hours, water (0.5 ml) was added, and the mixture was further stirred for 12 hours.

【０１８８】ＴＬＣ(BuOH-EtOH-H2 O 4:2:1 ）にて反応
の終了を確認後、イオン交換樹脂「アンバーライトIR-1
20」（Ｈ型）にて中和し、濾過後減圧濃縮した。得られ
たシロップは「セファデックス LH-20」によるゲル濾過
を行なって化合物（42）を得た。After confirming the completion of the reaction by TLC (BuOH-EtOH-H 2 O 4: 2: 1), the ion exchange resin "Amberlite IR-1" was used.
It was neutralized with 20 "(H type), filtered and concentrated under reduced pressure. The obtained syrup was subjected to gel filtration with "Sephadex LH-20" to obtain a compound (42).

【０１８９】元素分析：Ｃ25Ｈ42Ｎ4 Ｏ18としての計算
値Ｃ，47.73 ；Ｈ，6.17；Ｎ，8.16に対して実験値は
Ｃ；43.69 ；Ｈ，6.42；Ｎ，8.14であった。Elemental analysis: Calculated as C 25 H 42 N 4 O 18 C, 47.73; H, 6.17; N, 8.16, whereas experimental values were C; 43.69; H, 6.42; N, 8.14.

【０１９０】［α］D ＝ -1.59°(C＝1.0 ， MeOH-CH2
Cl2 1:1 ）。[Α] D = -1.59 ° (C = 1.0, MeOH-CH 2
Cl 2 1: 1).

【０１９１】IR νmax KBr (cm-1) ：3800-2800 ，29
50，2870，2100，1720，1660，1540。IR ν max KBr (cm −1 ): 3800-2800, 29
50, 2870, 2100, 1720, 1660, 1540.

【０１９２】1H-NMR(CDCl3 ) δppm ：4.43(d,1H,J=7.6
9Hz) ，4.37(d,1H,J=7.69Hz) ，2.85(broad,1H)，2.03
(s,3H)，1.74(broad,1H)，1.27(d,1H,J=5.86Hz) 。 1 H-NMR (CDCl 3 ) δppm: 4.43 (d, 1H, J = 7.6
9Hz), 4.37 (d, 1H, J = 7.69Hz), 2.85 (broad, 1H), 2.03
(s, 3H), 1.74 (broad, 1H), 1.27 (d, 1H, J = 5.86Hz).

【０１９３】実施例11：2-Azidoethyl O-(5-acetamido-
3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranos
ylonic acid) -(2→6)-O-2-acetamido-2-deoxy- β-D-g
lucopyranaside（化合物（45）の合成） 本実施例に含まれる反応式を図11に示す。 Example 11 : 2-Azidoethyl O- (5-acetamido-
3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranos
ylonic acid)-(2 → 6) -O-2-acetamido-2-deoxy-β-Dg
lucopyranaside (Synthesis of Compound (45)) FIG. 11 shows the reaction formula contained in this example.

【０１９４】(a) まず、2-Azidoethyl O-(methyl 5-ac
etamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glyce
ro-α-D-galacto-2-nonulopyranosylonate)- (2→6)-O-
2-acetamide-4-O-acetyl-3-O-benzoyl-2-deoxy-β-D-gl
ucopyranoside（化合物（44））を合成した。(A) First, 2-Azidoethyl O- (methyl 5-ac
etamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glyce
ro-α-D-galacto-2-nonulopyranosylonate)-(2 → 6) -O-
2-acetamide-4-O-acetyl-3-O-benzoyl-2-deoxy-β-D-gl
ucopyranoside (compound (44)) was synthesized.

【０１９５】すなわち、化合物（43）(100mg,0.122mmo
l) を塩化メチレン(5ml) に溶解し、2-アジドエタノー
ル(20mg)と乾燥剤「ドライアライト」(2ｇ) を加え、室
温で２時間攪拌した。トリフルオロ酢酸ＴＦＡ(0.1ml)
を加え、室温で３日間攪拌した。That is, compound (43) (100 mg, 0.122 mmo
l) was dissolved in methylene chloride (5 ml), 2-azidoethanol (20 mg) and desiccant "Dry Alite" (2 g) were added, and the mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid TFA (0.1 ml)
Was added and the mixture was stirred at room temperature for 3 days.

【０１９６】反応の終了をＴＬＣ(EtOAc) にて確認後セ
ライト濾過し、濾液と洗液は合せて塩化メチレンで抽出
した。塩化メチレン層は炭酸水素ナトリウム水溶液、水
にて洗浄し、無水硫酸ナトリウムにて脱水し、これを濾
過後減圧濃縮した。得られたシロップはカラムクロマト
グラフィー（CH2 Cl2 -MeOH 80:1）にて精製して化合物
（44）(98mg,88.6％）を得た。After confirming the completion of the reaction by TLC (EtOAc), the reaction mixture was filtered through Celite, and the filtrate and washings were combined and extracted with methylene chloride. The methylene chloride layer was washed with an aqueous sodium hydrogen carbonate solution and water, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained syrup was purified by column chromatography (CH 2 Cl 2 —MeOH 80: 1) to obtain the compound (44) (98 mg, 88.6%).

【０１９７】元素分析：Ｃ39Ｈ51Ｎ5 Ｏ20として計算値
Ｃ，51.48 ；Ｈ，5.65；Ｎ，7.70に対し実験値はＣ，5
1.55 ；Ｈ，6.73；Ｎ，7.68であった。Elemental analysis: Calculated as C 39 H 51 N 5 O 20 C, 51.48; H, 5.65; N, 7.70, whereas experimental value was C, 5
It was 1.55; H, 6.73; N, 7.68.

【０１９８】［α］D ＝-23.37°(C＝0.89，CHCl3 ) 。[Α] D = -23.37 ° (C = 0.89, CHCl 3 ).

【０１９９】IR νmax Film (cm-1) ：3700-3150 ，21
00，1750，1220，1660，1550，710。IR ν max Film ( cm -1 ): 3700-3150, 21
00, 1750, 1220, 1660, 1550, 710.

【０２００】(b) ついで、化合物（44）(95mg,0.104mm
ol)をメタノール(5ml) に溶解し、０℃にてソジウムメ
トキシドの28％メタノール溶液を４滴加え、室温で５時
間攪拌した。さらに水(0.5ml) を加え、10時間攪拌し
た。(B) Then, the compound (44) (95 mg, 0.104 mm
ol) was dissolved in methanol (5 ml), 4 drops of 28% methanol solution of sodium methoxide was added at 0 ° C., and the mixture was stirred at room temperature for 5 hours. Water (0.5 ml) was further added, and the mixture was stirred for 10 hours.

【０２０１】ＴＬＣ（CH2 Cl2 -MeOH 3:1 ）にて反応の
終了を確認後イオン交換樹脂「アンバーライトIR-120」
（Ｈ型）にて中和後濾過し、減圧濃縮した。得られたシ
ロップは「セファデックス LH-20」によるゲル濾過を行
い、化合物（45）(50mg,82.3％）を得た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 3: 1), ion exchange resin "Amberlite IR-120"
After being neutralized with (H type), it was filtered and concentrated under reduced pressure. The obtained syrup was subjected to gel filtration with "Sephadex LH-20" to obtain a compound (45) (50 mg, 82.3%).

【０２０２】元素分析：Ｃ21Ｈ35Ｎ5 Ｏ14としての計算
値Ｃ，43.37 ；Ｈ，6.07；Ｎ，12.04 に対して実験値は
Ｃ，43.28 ；Ｈ，6.23；Ｎ，12.14 であった。Elemental analysis: Calculated values for C 21 H 35 N 5 O 14 C, 43.37; H, 6.07; N, 12.04, whereas experimental values were C, 43.28; H, 6.23; N, 12.14.

【０２０３】［α］D ＝-27.60°(C＝0.92，MeOH）。[Α] D = -27.60 ° (C = 0.92, MeOH).

【０２０４】IR νmax KBr (cm-1) ：3500-2900 ，21
00，1650，1500。IR ν max KBr (cm -1 ): 3500-2900, 21
00, 1650, 1500.

【０２０５】実施例12：S-(5-Acetamido-3,5-dideoxy-D
-glycero- α-D-galacto-2-nonulopyranosylonic acid)
-(2 →9)-(2-azidoethyl 5-acetamido-3,5-dideoxy-D-g
lycero- α-D-galacto-2-nonulopyranosid)onic acid
（化合物(53)の合成） 本実施例に含まれる反応式を図12に示す。 Example 12 : S- (5-Acetamido-3,5-dideoxy-D
-glycero- α-D-galacto-2-nonulopyranosylonic acid)
-(2 → 9)-(2-azidoethyl 5-acetamido-3,5-dideoxy-Dg
lycero- α-D-galacto-2-nonulopyranosid) onic acid
(Synthesis of Compound (53)) The reaction formula included in this example is shown in FIG.

【０２０６】(a) まず、Methyl(2-azidoethyl 5-acetam
ido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-D
-galacto-2-nonulopyranosid)onate( 化合物 47)を合成
した。(A) First, Methyl (2-azidoethyl 5-acetam
ido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-D
-galacto-2-nonulopyranosid) onate (compound 47) was synthesized.

【０２０７】すなわち、Methyl 5-acetamido-4,7,8,9-t
etra-O-acetyl-2-chloro-2,3,5-trideoxy-D-glycero-β
-D-galacto-2-nonulopyranosonate(46)(4.78g,0.37mmo
l) を塩化メチレン(50ml)に溶解し、「モレキュラーシ
ーブ 4A 」(3g)を加えて５時間攪拌した。一方、2-アジ
ドエタノール(2.45g,28.1mmol)を塩化メチレン(50ml)に
溶解し、炭酸銀(5.17g,18.7mmol)と過塩素酸銀(0.2g,0.
96mmol) と「モレキュラーシーブ 4A 」(4g)を加え、暗
所にて５時間攪拌した。前者を後者に加えて暗所にて１
晩攪拌した。That is, Methyl 5-acetamido-4,7,8,9-t
etra-O-acetyl-2-chloro-2,3,5-trideoxy-D-glycero-β
-D-galacto-2-nonulopyranosonate (46) (4.78g, 0.37mmo
l) was dissolved in methylene chloride (50 ml), "Molecular Sieve 4A" (3 g) was added, and the mixture was stirred for 5 hours. On the other hand, 2-azidoethanol (2.45 g, 28.1 mmol) was dissolved in methylene chloride (50 ml), and silver carbonate (5.17 g, 18.7 mmol) and silver perchlorate (0.2 g, 0.
96 mmol) and "Molecular Sieve 4A" (4 g) were added, and the mixture was stirred in the dark for 5 hours. 1 in the dark with the former added to the latter
Stir overnight.

【０２０８】ＴＬＣ（CH2 Cl2 -MeOH 15:1）にて反応の
終了を確認後反応液をセライト濾過し、塩化メチレンに
て洗浄した。濾液と洗液は合せて減圧濃縮し、得られた
シロップをシリカゲルカラムクロマトグラフィー（CH2
Cl2 -MeOH 150:1)にて精製して化合物(47)（3.8g, 72.3
％）を得た。この化合物のαとβの比率はＮＭＲより約
10:9であった。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 15: 1), the reaction solution was filtered through Celite and washed with methylene chloride. The filtrate and washings are combined and concentrated under reduced pressure, and the resulting syrup is subjected to silica gel column chromatography (CH 2
Cl 2 -MeOH 150: 1) and then the compound (47) (3.8g, 72.3
%) Was obtained. The ratio of α to β of this compound is about
It was 10: 9.

【０２０９】元素分析：Ｃ22Ｈ32Ｎ4 Ｏ13としての計算
値Ｃ，47.14 ；Ｈ，5.75；Ｎ，10.00 に対して実験値は
C,47.41 ；H,5.86；N,9.85であった。Elemental analysis: Calculated value as C 22 H 32 N 4 O 13 C, 47.14; H, 5.75; N, 10.00
C, 47.41; H, 5.86; N, 9.85.

【０２１０】IRνmax Film（cm-1) ：3700-3200 ，210
0，1740，1660,1540 。IR ν max Film (cm -1 ): 3700-3200, 210
0, 1740, 1660, 1540.

【０２１１】(b) 次に、Methyl(2-azidoethyl 5-acetam
ido-3,5-dideoxy-D-glycero-D-galacto-2-nonulopyrano
sid)onate(化合物(48)) を合成した。(B) Next, Methyl (2-azidoethyl 5-acetam
ido-3,5-dideoxy-D-glycero-D-galacto-2-nonulopyrano
sid) onate (compound (48)) was synthesized.

【０２１２】すなわち、化合物(47)(2g,3.57mmol) をメ
タノール(15ml)に溶解し、触媒量のソジウムメトキシド
を加え、室温にて１晩攪拌した。That is, the compound (47) (2 g, 3.57 mmol) was dissolved in methanol (15 ml), a catalytic amount of sodium methoxide was added, and the mixture was stirred overnight at room temperature.

【０２１３】ＴＬＣ（CH2 Cl2 -MeOH 5:1 ）にて反応の
終了を確認後反応液をイオン交換樹脂「アンバーライト
IR-120」（Ｈ型）にて中和し、これを濾別後、メタノー
ルにて洗浄した。濾液と洗液は合せて減圧濃縮し、化合
物(48)(1.4g,定量的) を得た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 5: 1), the reaction solution was treated with an ion exchange resin "Amberlite".
It was neutralized with "IR-120" (H type), filtered, and washed with methanol. The filtrate and washings were combined and concentrated under reduced pressure to obtain compound (48) (1.4 g, quantitative).

【０２１４】元素分析：Ｃ14Ｈ24Ｎ4 Ｏ9 としての計算
値Ｃ，42.86 ；Ｈ，6.17；Ｎ，14.28 に対して実験値は
Ｃ，43.00 ；Ｈ，6.15；Ｎ，14.26 であった。Elemental analysis: Calculated values for C 14 H 24 N 4 O 9 C, 42.86; H, 6.17; N, 14.28, whereas experimental values were C, 43.00; H, 6.15; N, 14.26.

【０２１５】(c) ついで、Methyl [2-azidoethyl 5-ace
tamido-3,5-dideoxy-9-O-(p-toluenesulfonyl)-D-glyce
ro- α-D-galacto-2-nonulopyranosid]onate（化合物(4
9)）及びMethyl [2-azidoethyl 5-acetamido-3,5-dideo
xy--9-O-(p-toluenesulfonyl)-D-glycero-β-D-galacto
-2-nonulopyranosid]onate（化合物(50)）を合成した。(C) Then, Methyl [2-azidoethyl 5-ace
tamido-3,5-dideoxy-9-O- (p-toluenesulfonyl) -D-glyce
ro-α-D-galacto-2-nonulopyranosid] onate (compound (4
9)) and Methyl [2-azidoethyl 5-acetamido-3,5-dideo
xy--9-O- (p-toluenesulfonyl) -D-glycero-β-D-galacto
-2-nonulopyranosid] onate (compound (50)) was synthesized.

【０２１６】すなわち、化合物(48)(1g,2.55mmol) をピ
リジン(10ml)に溶解し、０℃に冷却後p-トルトエンスル
ホニルクロリド(0.63g,3.30mmol)を加え、０℃にて 2.5
時間攪拌した。That is, the compound (48) (1 g, 2.55 mmol) was dissolved in pyridine (10 ml), cooled to 0 ° C, p-tortoenesulfonyl chloride (0.63 g, 3.30 mmol) was added, and the mixture was added at 2.5 ° C at 2.5 ° C.
Stir for hours.

【０２１７】ＴＬＣ（CH2 Cl2 -MeOH 10:1）にて反応の
終了を確認後メタノールを加え、減圧濃縮した。得られ
たシロップはシルカゲルカラムクロマトグラフィー「CH
2 Cl2 -MeOH 55:1）にて精製して化合物(49)(365mg, 2
6.2％）及び化合物(50)(330mg, 23.7％）を得た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 10: 1), methanol was added and the mixture was concentrated under reduced pressure. The resulting syrup is silica gel column chromatography "CH
2 Cl 2 -MeOH 55: 1) and then the compound (49) (365 mg, 2
6.2%) and compound (50) (330 mg, 23.7%) were obtained.

【０２１８】元素分析：Ｃ21Ｈ30Ｎ4 Ｏ11Ｓとしての計
算値Ｃ，46.15 ；Ｈ，5.53；Ｎ，10.25 に対して実験値
はＣ，46.30 ；Ｈ，5.49；Ｎ，10.33 であった。Elemental analysis: Calculated values for C 21 H 30 N 4 O 11 S C, 46.15; H, 5.53; N, 10.25, whereas experimental values were C, 46.30; H, 5.49; N, 10.33. ..

【０２１９】IRνmax Film((cm-1) ：3700-3100 ，210
0，1740，1660,1540 ，730 。IR ν max Film ((cm -1 ): 3700-3100, 210
0, 1740, 1660, 1540, 730.

【０２２０】化合物(49) ［α］D ＝＋1.10°（Ｃ＝0.902,CHCl3 ）。 Compound (49) [α] D = + 1.10 ° (C = 0.902, CHCl 3 ).

【０２２１】1H-NMR(CDCl3 ) δppm ：7.35-7.79(m,4H)
，6.70(d,1H,J=6.0Hz)，3.84(s,3H)，3.25-3.58(m,4H)
，2.78(dd,1H) ，2.45(s,3H),2.04(s,3H) ，1.85(t,1
H,J=11.6Hz) 。 1 H-NMR (CDCl 3 ) δppm: 7.35-7.79 (m, 4H)
、 6.70 (d, 1H, J = 6.0Hz) 、 3.84 (s, 3H) 、 3.25-3.58 (m, 4H)
, 2.78 (dd, 1H), 2.45 (s, 3H), 2.04 (s, 3H), 1.85 (t, 1
H, J = 11.6Hz).

【０２２２】化合物(50) ［α］D ＝-14.50°（Ｃ＝1.034,CHCl3 ）。 Compound (50) [α] D = -14.50 ° (C = 1.034, CHCl 3 ).

【０２２３】1H-NMR(CDCl3 ) δppm ：7.34-7.79(m,4H)
，6.85(d,1H)，3.78(s,3H)，3.27-3.50(m,4H) ，2.05
(s,3H)，1.73(t,1H)。 1 H-NMR (CDCl 3 ) δppm: 7.34-7.79 (m, 4H)
, 6.85 (d, 1H), 3.78 (s, 3H), 3.27-3.50 (m, 4H), 2.05
(s, 3H), 1.73 (t, 1H).

【０２２４】(d) 次に、Methyl [2-azidoethyl 5-aceta
mido-4,7,8-tri-O-acetyl-3,5-dideoxy-9-O-(p-toluene
sulfonyl)-D-galacto-α-D-galacto-2-nonulopyranosi
d]onate（化合物(51)）を合成した。(D) Next, Methyl [2-azidoethyl 5-aceta
mido-4,7,8-tri-O-acetyl-3,5-dideoxy-9-O- (p-toluene
sulfonyl) -D-galacto-α-D-galacto-2-nonulopyranosi
d] onate (compound (51)) was synthesized.

【０２２５】すなわち、化合物(49)(250mg,0.46mmol)を
ピリジン(4ml) に溶解し、無水酢酸(2ml) を加え、室温
にて１晩攪拌した。That is, the compound (49) (250 mg, 0.46 mmol) was dissolved in pyridine (4 ml), acetic anhydride (2 ml) was added, and the mixture was stirred at room temperature overnight.

【０２２６】ＴＬＣ（CH2 Cl2 -MeOH 20:1）にて反応の
終了を確認後メタノールを加えて減圧濃縮し、得られた
シロップをシルカゲルカラムクロマトグラフィー（CH2
Cl2-MeOH 120:1 ）にて精製して化合物(51)(287mg, 93.
3％）を得た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 20: 1), methanol was added and the mixture was concentrated under reduced pressure, and the obtained syrup was subjected to silica gel column chromatography (CH 2
Cl 2 -MeOH 120: 1) and then the compound (51) (287 mg, 93.
3%).

【０２２７】元素分析：Ｃ27Ｈ36Ｎ4 Ｏ14Ｓとしての計
算値Ｃ，48.21 ；Ｈ，5.39；Ｎ，8.33に対して実験値は
Ｃ，48.32 ；Ｈ，5.40；Ｎ，8.06であった。Elemental analysis: Calculated value as C 27 H 36 N 4 O 14 S C, 48.21; H, 5.39; N, 8.33, whereas experimental value was C, 48.32; H, 5.40; N, 8.06. ..

【０２２８】［α］D ＝−15.40 °（Ｃ＝0.714,CHC
l3 ）。[Α] D = -15.40 ° (C = 0.714, CHC
l 3 ).

【０２２９】IRνmax Film (cm-1) ：3700-3200 ，210
0，1750，1660,1540 ，730 。IR ν max Film (cm -1 ): 3700-3200, 210
0, 1750, 1660, 1540, 730.

【０２３０】1H-NMR(CDCl3 ) δppm ：7.32-7.78(m,4H)
，5.32(m,2H)，4.90(ddd,1H,J=12.1Hz,J=46Hz,J=10.1H
z) ，4.34(dd,1H,J=2.2Hz,J=1.6Hz) ，4.10(dd,1H,J=1
0.6Hz)，3.82(s,3H)，3.26-3.53(2m,3H)，2.64(dd,1H,J
=12.8Hz)，2.08,2.07,2.02,1.88(4s,12H) 。 1 H-NMR (CDCl 3 ) δppm: 7.32-7.78 (m, 4H)
, 5.32 (m, 2H), 4.90 (ddd, 1H, J = 12.1Hz, J = 46Hz, J = 10.1H
z), 4.34 (dd, 1H, J = 2.2Hz, J = 1.6Hz), 4.10 (dd, 1H, J = 1
0.6Hz), 3.82 (s, 3H), 3.26-3.53 (2m, 3H), 2.64 (dd, 1H, J
= 12.8Hz), 2.08,2.07,2.02,1.88 (4s, 12H).

【０２３１】(e) ついで、Methyl S-(methyl 5-acetami
do-4,7,8,9-tetra-O-acetyl-3,5-dideo xy-D-galacto-
α-D-galacto-2-nonulopyranosid]onate)-(2→9)-(2-az
idoethyl 5-acetamido-4,7,8-tri-O-acetyl-3,5-dideox
y-9-thio-D-glycero- α-D-galacto-2-nonulopyranosi
d)onate（化合物(52)）を合成した。(E) Next, Methyl S- (methyl 5-acetami
do-4,7,8,9-tetra-O-acetyl-3,5-dideo xy-D-galacto-
α-D-galacto-2-nonulopyranosid] onate)-(2 → 9)-(2-az
idoethyl 5-acetamido-4,7,8-tri-O-acetyl-3,5-dideox
y-9-thio-D-glycero- α-D-galacto-2-nonulopyranosi
d) onate (compound (52)) was synthesized.

【０２３２】すなわち、Methyl 5-acetamido-4,7,8-tet
ra-O-acetyl-3,5-dideoxy-2-thio-D-glycero- α-D-gal
acto-2-nonulopyranosonate(27)(295mg,0.56mmol) のナ
トリウム塩と化合物(51)(250mg,0.37mmol)とをＮ，Ｎ−
ジメチルホルムアミド(4ml)に溶解し、窒素気流中40℃
にて１晩攪拌した。That is, Methyl 5-acetamido-4,7,8-tet
ra-O-acetyl-3,5-dideoxy-2-thio-D-glycero- α-D-gal
Acto-2-nonulopyranosonate (27) (295 mg, 0.56 mmol) sodium salt and compound (51) (250 mg, 0.37 mmol) were combined with N, N-
Dissolve in dimethylformamide (4ml), 40 ℃ in nitrogen stream
The mixture was stirred overnight at.

【０２３３】ＴＬＣ（CH2 Cl2 -MeOH 15:1）にて反応の
終了を確認後反応液を減圧濃縮し、得られたシロップを
シルカゲルカラムクロマトグラフィー（CH2 Cl2 -MeOH
45:1）にて精製して化合物(52)(110mg, 29.4％）を得
た。After confirming the completion of the reaction by TLC (CH 2 Cl 2 -MeOH 15: 1), the reaction solution was concentrated under reduced pressure, and the obtained syrup was subjected to silica gel column chromatography (CH 2 Cl 2 -MeOH).
The compound (52) (110 mg, 29.4%) was obtained by purification at 45: 1).

【０２３４】元素分析：Ｃ40Ｈ57Ｎ5 Ｏ23Ｓとしての計
算値Ｃ，47.66 ；Ｈ，5.70；Ｎ，6.95に対して実験値は
Ｃ，46.49 ；Ｈ，5.93；Ｎ，7.03であった。Elemental analysis: Calculated value as C 40 H 57 N 5 O 23 S C, 47.66; H, 5.70; N, 6.95, whereas experimental value was C, 46.49; H, 5.93; N, 7.03. ..

【０２３５】［α］D ＝＋51.10 °（Ｃ＝0.544,CHC
l3 ）。[Α] D = + 51.10 ° (C = 0.544, CHC
l 3 ).

【０２３６】IRνmax Film（cm-1) ：3700-3200 ，210
0，1750，1660,1540 。IR ν max Film (cm -1 ): 3700-3200, 210
0, 1750, 1660, 1540.

【０２３７】1H-NMR(CDCl3 ) δppm ：5.89(d,1H,J=9.2
Hz)，5.23(d,1H,J=10.1Hz) ，5.18(dd,1H) ，5.15(dd,1
H) ，5.11(m,1H)，4.85(m,2H)，3.88, 3.83(2n,6H) ，
3.54, 3.36(2m,3H) ，3.22(dd,1H,J=10.1Hz,J=14.8Hz)
，2.99(dd,1H) ，2.69(dd,1H,J=4.8Hz,J=12.6Hz)，2.6
5(dd,1H,J=4.4Hz,J=12.6Hz)，2.27, 2.16, 2.10, 2.07,
2.05, 2.03, 2.03(7s,21H)，1.89, 1.88(2s,6H) 。 1 H-NMR (CDCl 3 ) δppm: 5.89 (d, 1H, J = 9.2
Hz), 5.23 (d, 1H, J = 10.1Hz), 5.18 (dd, 1H), 5.15 (dd, 1
H), 5.11 (m, 1H), 4.85 (m, 2H), 3.88, 3.83 (2n, 6H),
3.54, 3.36 (2m, 3H), 3.22 (dd, 1H, J = 10.1Hz, J = 14.8Hz)
, 2.99 (dd, 1H), 2.69 (dd, 1H, J = 4.8Hz, J = 12.6Hz), 2.6
5 (dd, 1H, J = 4.4Hz, J = 12.6Hz), 2.27, 2.16, 2.10, 2.07,
2.05, 2.03, 2.03 (7s, 21H), 1.89, 1.88 (2s, 6H).

【０２３８】(f) 最後に、化合物(52)(110mg,0.11mmol)
をメタノール(2ml) に溶解し、触媒量のソジウムメトキ
シドの28％メタノール溶液を加え、室温にて８時間攪拌
した後、水(0.5ml) を加え、１晩攪拌した。(F) Finally, the compound (52) (110 mg, 0.11 mmol)
Was dissolved in methanol (2 ml), a catalytic amount of 28% methanol solution of sodium methoxide was added, the mixture was stirred at room temperature for 8 hours, water (0.5 ml) was added, and the mixture was stirred overnight.

【０２３９】ＴＬＣ(BuOH-EtOH-H2 O ４：２：１）にて
反応の終了を確認後イオン交換樹脂「アンバーライトIR
-120」のＨ型にて中和し、これを濾別後メタノールにて
洗浄した。After confirming the completion of the reaction by TLC (BuOH-EtOH-H 2 O 4: 2: 1), the ion exchange resin "Amberlite IR
It was neutralized with H-form of "-120", separated by filtration, and washed with methanol.

【０２４０】濾液と洗液は合せて減圧濃縮し、得られた
シロップはカラムクロマトグラフィー（「セファデック
スＬＨ−20」、容離液メタノール）にて化合物(53)(66m
g,88.2％）を得た。The filtrate and washings were combined and concentrated under reduced pressure, and the syrup thus obtained was subjected to column chromatography (“Sephadex LH-20”, methanol as eluent) to give compound (53) (66 m).
g, 88.2%) was obtained.

【０２４１】元素分析：Ｃ24Ｈ39Ｎ5 Ｏ16Ｓとしての計
算値Ｃ，42.04 ；Ｈ，5.73；Ｎ，10.21 に対して実験値
はＣ，42.00 ；Ｈ，5.59；Ｎ，10.08 であった。Elemental analysis: Calculated values as C 24 H 39 N 5 O 16 S C, 42.04; H, 5.73; N, 10.21, whereas experimental values were C, 42.00; H, 5.59; N, 10.08. ..

【０２４２】［α］D ＝＋7.72°（Ｃ＝1.32, MeOH）。[Α] D = + 7.72 ° (C = 1.32, MeOH).

【０２４３】1H-NMR(CD3 OD) δppm ：3.02(m,2H)，2.8
4(m,2H)，2.05, 2.02(2s,6H) ，1.72, 1.72(2m,2H) 。 1 H-NMR (CD 3 OD) δppm: 3.02 (m, 2H), 2.8
4 (m, 2H), 2.05, 2.02 (2s, 6H), 1.72, 1.72 (2m, 2H).

【０２４４】実施例13 Ｌ−α−ジパルミトイルホスファチジルコリン60μmol
、コレステロール60μmol 、及び実施例４で得られた
化合物(17)(6μmol)をクロロホルム及びメタノール混液
（容積比2:1 ）に溶かした。次に、窒素ガス気流中で有
機溶媒を除去して遠沈管のガラス壁にリピッドフィルム
を生成させた。ここに予め約45℃に加温した１mMイヌリ
ンのリン酸緩衝化生理食塩水(pH 7.4)６mlを加えて浸盪
し、更に軽く超音波処理してリポソームの懸濁液を調製
した。 Example 13 L-α-Dipalmitoylphosphatidylcholine 60 μmol
, 60 μmol of cholesterol, and the compound (17) (6 μmol) obtained in Example 4 were dissolved in a mixed solution of chloroform and methanol (volume ratio 2: 1). Next, the organic solvent was removed in a nitrogen gas stream to form a lipid film on the glass wall of the centrifuge tube. 6 ml of 1 mM inulin phosphate-buffered saline (pH 7.4) preheated to about 45 ° C. was added thereto, and the mixture was shaken and further sonicated gently to prepare a liposome suspension.

【０２４５】これを45〜60℃に加温し、次いで0.08μm
の孔径を有するポリカーボネート製メンブランフィルタ
ーを通過させ、粒径約0.08μm のリポソームの懸濁液を
調製した。次に、これを超遠心分離（104 ×ｇ，１時
間，３回）し、上澄液を除去することによりリポソーム
に保持されなかったイヌリンを除去し、リン酸緩衝化生
理食塩水(pH 7.4)を加え、全量４mlのリポソーム懸濁液
を得た。This was heated to 45 to 60 ° C., then 0.08 μm
The solution was passed through a polycarbonate membrane filter having a pore size of 1 to prepare a liposome suspension having a particle size of about 0.08 μm. Next, this was subjected to ultracentrifugation (10 4 × g, 1 hour, 3 times) to remove the inulin not retained by the liposomes by removing the supernatant liquid, and phosphate-buffered saline (pH 7.4) was added to obtain a total volume of 4 ml of liposome suspension.

【０２４６】実施例１４ Ｌ−α−ジパルミトイルホスファチジルコリン６０μmo
l 、コレステロール60μmol 、及び実施例６で得られた
化合物(30)(6μmol)をクロロホルム及びメタノール混液
（容積比2:1 ）に溶かした。次に、窒素ガス気流中で有
機溶媒を除去し遠沈管のガラス壁にリピッドフィルムを
生成させた。ここに予め約45℃に加温した１mMイヌリン
のリン酸緩衝化生理食塩水(pH 7.4)６mlを加えて浸盪
し、更に軽く超音波処理してリポソームの懸濁液を調製
した。 Example 14 L-α-dipalmitoylphosphatidylcholine 60 μmo
l, cholesterol 60 μmol, and the compound (30) (6 μmol) obtained in Example 6 were dissolved in a mixture of chloroform and methanol (volume ratio 2: 1). Next, the organic solvent was removed in a nitrogen gas stream to form a lipid film on the glass wall of the centrifuge tube. 6 ml of 1 mM inulin phosphate-buffered saline (pH 7.4) preheated to about 45 ° C. was added thereto, and the mixture was shaken and further sonicated gently to prepare a liposome suspension.

【０２４７】これを45〜60℃に加温し、次いで0.08μm
の孔径を有するポリカーボネート製メンブランフィルタ
ーを通過させ、粒径約0.08μm のリポソームの懸濁液を
調製した。次に、これを超遠心分離（104 ×ｇ，１時
間，３回）し、上澄液を除去することによりリポソーム
に保持されなかったイヌリンを除去し、リン酸緩衝化生
理食塩水(pH 7.4)を加え、全量４mlのリポソーム懸濁液
を得た。This was heated to 45 to 60 ° C., then 0.08 μm
The solution was passed through a polycarbonate membrane filter having a pore size of 1 to prepare a liposome suspension having a particle size of about 0.08 μm. Next, this was subjected to ultracentrifugation (10 4 × g, 1 hour, 3 times) to remove the inulin not retained by the liposomes by removing the supernatant liquid, and phosphate-buffered saline (pH 7.4) was added to obtain a total volume of 4 ml of liposome suspension.

【０２４８】実施例15 実施例６で得られた化合物(30)（６μmol ）の代わりに
実施例２で得られた化合物(8) （６μmol ）を使用した
以外は実施例15におけると同様に処理して、全量４mlの
リポソーム懸濁液を得た。 Example 15 The same procedure as in Example 15 was repeated except that the compound (8) (6 μmol) obtained in Example 2 was used instead of the compound (30) (6 μmol) obtained in Example 6. Then, a total volume of 4 ml of a liposome suspension was obtained.

【０２４９】実施例16 実施例４で得られた化合物(17)（６μmol ）の代わりに
実施例５で得られた化合物(21)（６μmol ）を使用した
以外は実施例８におけると同様に処理して、全量４mlの
リポソーム懸濁液を得た。 Example 16 The same procedure as in Example 8 was repeated except that the compound (21) (6 μmol) obtained in Example 5 was used instead of the compound (17) (6 μmol) obtained in Example 4. Then, a total volume of 4 ml of a liposome suspension was obtained.

【０２５０】実施例17 大豆 500mg、卵黄レシチン60mg及びグリセリン 125mgを
秤取し、注射用蒸留水５ml中に加えてホモジナイサーを
用いて粗乳化を行なった。これに実施例６で得られた化
合物(30)を添加し、更に超音波処理して乳化を行ない、
目的のリピッドマイクロフェアー５mlを得た。 Example 17 Soybean 500 mg, egg yolk lecithin 60 mg and glycerin 125 mg were weighed out, added to 5 ml of distilled water for injection and rough emulsified using a homogenizer. To this, the compound (30) obtained in Example 6 was added, and further treated with ultrasonic waves to emulsify,
5 ml of the desired lipid microsphere was obtained.

【０２５１】試験例１ （イ）試料 実施例13〜16において、１mMイヌリンの代わりに 3Ｈ−
イヌリン 140μＣｉを含有する１mMイヌリンを使用した
以外はそれぞれ実施例13〜16におけると同様に処理し
て、各全量４mlのリポソーム懸濁液を得て、それぞれ検
体試料１〜４として用意した。なお、Ｌ−α−ジパルミ
トイルホスファチジルコリンのコリン基をマーカーとし
て酵素法により定量した。いずれの検体試料も１ml当り
リン脂質を10.0μmol 含有するようにリン酸緩衝化生理
食塩水(pH 7.4)で希釈し、それぞれの検体試料の全量を
4.63ml,4.41ml,5.24ml及び4.46mlとした。 Test Example 1 (a) Sample In Examples 13 to 16, 3 H-in place of 1 mM inulin.
The same procedure as in Examples 13 to 16 was carried out except that 1 mM inulin containing 140 μCi of inulin was used to obtain a total of 4 ml of liposome suspension, which were prepared as specimen samples 1 to 4, respectively. The L-α-dipalmitoylphosphatidylcholine was quantified by the enzymatic method using the choline group as a marker. All sample samples were diluted with phosphate buffered saline (pH 7.4) to contain 10.0 μmol of phospholipid per ml, and the total amount of each sample sample was
It was 4.63 ml, 4.41 ml, 5.24 ml and 4.46 ml.

【０２５２】また、実施例14において、実施例６で得ら
れた化合物(30)の代わりにむジセチルリン酸を使用し、
且つ１mMイヌリンの代わりに 3Ｈ−イヌリン 140μＣｉ
を含有する１mMイヌリンを使用した以外は実施例14にお
けると同様に処理して、全量４mlのリポソーム懸濁液を
得て、対照試料（コントロールリポソーム）として用意
した。なお、Ｌ−α−ジパルミトイルホスファチジルコ
リンのコリン基をマーカーとして酵素法により定量し、
１ml当りリン脂質を10.0μmol 含有するようにリン酸緩
衝化生理食塩水(pH 7.4)で希釈したところ、対照試料は
全量4.85mlとなった。In Example 14, dicetylphosphoric acid was used in place of the compound (30) obtained in Example 6,
And 140 μCi of 3 H-inulin instead of 1 mM inulin
Was treated in the same manner as in Example 14 except that 1 mM inulin containing was used to obtain a total volume of 4 ml of a liposome suspension, which was prepared as a control sample (control liposome). In addition, the choline group of L-α-dipalmitoylphosphatidylcholine was used as a marker for quantification by an enzymatic method,
When diluted with phosphate buffered saline (pH 7.4) so as to contain 10.0 μmol of phospholipid per ml, the total volume of the control sample was 4.85 ml.

【０２５３】（ロ）試験方法 用意した５種の試料をそれぞれＳＤ系雄性ラット（体重
200〜290 ｇ）の後肢静脈内に体重100 ｇ当りＬ−α−
ジパルミトイルホスファチジルコリンの合計として５μ
mol を注入した。(B) Test method Five prepared samples were used for SD male rats (body weight).
200-290 g) Intravenous injection into the hind limb per 100 g body weight L-α-
5μ as the total of dipalmitoylphosphatidylcholine
Mol was injected.

【０２５４】投与後30分、１時間、２時間、４時間、６
時間及び24時間後に上記のカニューレより血液を約 0.2
ml採取し、遠心後血漿約 100μｌをろ紙に採り、乾燥後
燃焼装置にて燃焼し、液体シンチレーション法によりそ
の放射活性を求めた。30 minutes, 1 hour, 2 hours, 4 hours, 6 after administration
After approximately 24 hours and 24 hours,
ml was collected and after centrifugation, about 100 μl of plasma was collected on a filter paper, dried and burned in a burning device, and its radioactivity was determined by a liquid scintillation method.

【０２５５】また、24時間後にラットを屠殺し、肝臓及
びひ臓を各約 400mg、骨髄を約50mg採り、乾燥後燃焼装
置にて燃焼し、液体シンチレーション法によりその放射
活性を求め、組織−血漿間分配計数（以下Kp値と記す）
を次式に従って計算した。すなわち、Also, after 24 hours, the rats were sacrificed, about 400 mg each of liver and spleen and about 50 mg of bone marrow were taken, dried and burned in a combustion apparatus, and their radioactivity was determined by a liquid scintillation method. Distribution count (hereinafter referred to as Kp value)
Was calculated according to the following formula. That is,

【０２５６】[0256]

【数１】 [Equation 1]

【０２５７】（ハ）結果 結果を図13および図14に示す。(C) Results The results are shown in FIGS. 13 and 14.

【０２５８】図13は血漿中濃度の経時的変化を表すグラ
フであり、図中、黒四角を連ねた線、白丸を連ねた線、
白三角を連ねた線、黒丸を連ねた線及び黒三角を連ねた
線はそれぞれ対照試料、検体試料1 、検体試料2 、検体
試料3 および検体試料4 における結果を示す。FIG. 13 is a graph showing changes in plasma concentration over time. In the figure, a line connecting black squares, a line connecting white circles,
The line connecting the white triangles, the line connecting the black circles, and the line connecting the black triangles show the results for the control sample, sample sample 1, sample sample 2, sample sample 3, and sample sample 4, respectively.

【０２５９】図14は臓器毎のKp値を示す棒グラフであ
り、図中、黒色のカラム、白抜きのカラム、斜平行線を
付したカラム、灰色のカラム及び垂直平行線を付したカ
ラムはそれぞれ対照試料、検体試料1 、検体試料2 、検
体試料3 および検体試料4 における結果を示す。FIG. 14 is a bar graph showing Kp values for each organ. In the figure, black columns, white columns, columns with diagonal parallel lines, columns with gray lines and columns with vertical parallel lines are respectively shown. The results for the control sample, specimen sample 1, specimen sample 2, specimen sample 3, and specimen sample 4 are shown.

【０２６０】図13および図14より、本発明のリポソーム
が、コントロールリポソームに比較して高い血中濃度の
維持を可能にしており、更に肝臓、ひ臓及び骨髄でのKp
値が有意に低くなるところから、細網内皮系への補促が
されにくいことが判明した。From FIGS. 13 and 14, the liposome of the present invention is capable of maintaining a high blood concentration as compared with the control liposome, and further, Kp in the liver, spleen and bone marrow is increased.
Since the value was significantly low, it was found that it was difficult to promote the reticuloendothelial system.

【０２６１】[0261]

【発明の効果】新規物質であるシアル酸オリゴ糖誘導体
を構成成分として含有せしめることにより肝臓、ひ臓等
の細網内皮系に捕捉されにくく、血液中での薬物濃度を
長時間維持することのできるリポソーム等の微粒子キャ
リヤーが提供されるところとなった。[Effects of the Invention] By including a sialic acid oligosaccharide derivative, which is a novel substance, as a constituent component, it is difficult to be captured by the reticuloendothelial system of the liver, spleen, etc., and the drug concentration in blood can be maintained for a long time. Nowadays, fine particle carriers such as liposomes are provided.

【図面の簡単な説明】[Brief description of drawings]

【図１】実施例１に含まれる反応式である。FIG. 1 is a reaction formula included in Example 1.

【図２】実施例１に含まれる反応式である。2 is a reaction formula included in Example 1. FIG.

【図３】実施例２に含まれる反応式である。3 is a reaction formula included in Example 2. FIG.

【図４】実施例２に含まれる反応式である。4 is a reaction formula included in Example 2. FIG.

【図５】実施例３に含まれる反応式である。FIG. 5 is a reaction formula included in Example 3.

【図６】実施例３に含まれる反応式である。6 is a reaction formula included in Example 3. FIG.

【図７】実施例３に含まれる反応式である。7 is a reaction formula included in Example 3. FIG.

【図８】実施例４に含まれる反応式である。8 is a reaction formula included in Example 4. FIG.

【図９】実施例４に含まれる反応式である。9 is a reaction formula included in Example 4. FIG.

【図１０】実施例５に含まれる反応式である。FIG. 10 is a reaction formula included in Example 5.

【図１１】実施例５に含まれる反応式である。11 is a reaction formula included in Example 5. FIG.

【図１２】実施例６に含まれる反応式である。12 is a reaction formula included in Example 6. FIG.

【図１３】実施例６に含まれる反応式である。13 is a reaction formula included in Example 6. FIG.

【図１４】実施例７に含まれる反応式である。FIG. 14 is a reaction formula included in Example 7.

【図１５】実施例８に含まれる反応式である。15 is a reaction formula included in Example 8. FIG.

【図１６】実施例９に含まれる反応式である。16 is a reaction formula contained in Example 9. FIG.

【図１７】実施例１０に含まれる反応式である。FIG. 17 is a reaction formula contained in Example 10.

【図１８】実施例１１に含まれる反応式である。18 is a reaction formula included in Example 11. FIG.

【図１９】実施例１２に含まれる反応式である。FIG. 19 is a reaction formula contained in Example 12.

【図２０】実施例１２に含まれる反応式である。FIG. 20 is a reaction formula contained in Example 12.

【図２１】試験例１における血漿中濃度の経時的変化を
表すグラフである。FIG. 21 is a graph showing changes over time in plasma concentration in Test Example 1.

【図２２】試験例１における臓器毎のKp値を示す棒グラ
フである。22 is a bar graph showing Kp values for each organ in Test Example 1. FIG.

─────────────────────────────────────────────────────
─────────────────────────────────────────────────── ───

【手続補正書】[Procedure amendment]

【提出日】平成５年１月２９日[Submission date] January 29, 1993

【手続補正１】[Procedure Amendment 1]

【補正対象書類名】明細書[Document name to be amended] Statement

【補正対象項目名】図面の簡単な説明[Name of item to be corrected] Brief description of the drawing

【補正方法】変更[Correction method] Change

【補正内容】[Correction content]

【図面の簡単な説明】[Brief description of drawings]

【図１Ａ】実施例１に含まれる反応式である。1A is a reaction formula included in Example 1. FIG.

【図１Ｂ】実施例１に含まれる反応式である。1B is a reaction formula included in Example 1. FIG.

【図２Ａ】実施例２に含まれる反応式である。2A is a reaction formula included in Example 2. FIG.

【図２Ｂ】実施例２に含まれる反応式である。2B is a reaction formula included in Example 2. FIG.

【図３Ａ】実施例３に含まれる反応式である。3A is a reaction formula included in Example 3. FIG.

【図３Ｂ】実施例３に含まれる反応式である。3B is a reaction formula included in Example 3. FIG.

【図３Ｃ】実施例３に含まれる反応式である。3C is a reaction formula included in Example 3. FIG.

【図４Ａ】実施例４に含まれる反応式である。4A is a reaction formula included in Example 4. FIG.

【図４Ｂ】実施例４に含まれる反応式である。4B is a reaction formula included in Example 4. FIG.

【図５Ａ】実施例５に含まれる反応式である。5A is a reaction formula included in Example 5. FIG.

【図５Ｂ】実施例５に含まれる反応式である。5B is a reaction formula included in Example 5. FIG.

【図６Ａ】実施例６に含まれる反応式である。6A is a reaction formula included in Example 6. FIG.

【図６Ｂ】実施例６に含まれる反応式である。6B is a reaction formula included in Example 6. FIG.

【図７】実施例７に含まれる反応式である。7 is a reaction formula included in Example 7. FIG.

【図８】実施例８に含まれる反応式である。8 is a reaction formula included in Example 8. FIG.

【図９】実施例９に含まれる反応式である。9 is a reaction formula included in Example 9. FIG.

【図１０】実施例１０に含まれる反応式である。FIG. 10 is a reaction formula contained in Example 10.

【図１１】実施例１１に含まれる反応式である。11 is a reaction formula included in Example 11. FIG.

【図１２Ａ】実施例１２に含まれる反応式である。12A is a reaction formula included in Example 12. FIG.

【図１２Ｂ】実施例１２に含まれる反応式である。12B is a reaction formula contained in Example 12. FIG.

【図１３】試験例１における血漿中濃度の経時的変化を
表すグラフである。FIG. 13 is a graph showing changes over time in plasma concentration in Test Example 1.

【図１４】試験例１における臓器毎のＫｐ値を示す棒グ
ラフである。FIG. 14 is a bar graph showing Kp values for each organ in Test Example 1.

【手続補正２】[Procedure Amendment 2]

【補正対象書類名】図面[Document name to be corrected] Drawing

【補正対象項目名】全図[Correction target item name] All drawings

【補正方法】変更[Correction method] Change

【補正内容】[Correction content]

【図１Ａ】 FIG. 1A

【図２Ｂ】 FIG. 2B

【図１Ｂ】 FIG. 1B

【図１２Ｂ】 FIG. 12B

【図２Ａ】 [FIG. 2A]

【図１０】 [Figure 10]

【図１１】 FIG. 11

【図３Ａ】 FIG. 3A

【図３Ｂ】 FIG. 3B

【図３Ｃ】 [Fig. 3C]

【図４Ｂ】 FIG. 4B

【図７】 [Figure 7]

【図４Ａ】 FIG. 4A

【図１４】 FIG. 14

【図５Ａ】 FIG. 5A

【図５Ｂ】 FIG. 5B

【図８】 [Figure 8]

【図９】 [Figure 9]

【図６Ａ】 FIG. 6A

【図６Ｂ】 FIG. 6B

【図１２Ａ】 FIG. 12A

【図１３】 [Fig. 13]

Claims (4)

【特許請求の範囲】[Claims] 【請求項１】 下記式（Ｉ）によって表されるシアル酸
オリゴ糖誘導体。 【化１】 式（Ｉ）において、ＸはＯ又はＳを表し、Ｗは下記式(I
I)〜(VII) のいずれかを表し、ｍは１〜８の整数を表
し、Ｒ0 はＮ3 、ＮＨ2 又はＮＨＲ（ここに、Ｒは、直
鎖又は分枝鎖のアシル基、ベンジルオキシカルボニル
基、ｔ−ブトキシカルボニル基又はトリメチルシリル基
を表す）を表し、Ｒ1 はＨ、低級アルキル基又はアルカ
リ金属を表し、Ｒ2 〜Ｒ4 は同一又は異なっていてもよ
く、それぞれＨ又は水酸基の保護基を表し、Ｒ5 はＯ
Ｈ、ＯＡｃ又はＨを表す。 【化２】 【化３】 式（II）〜(VII) において、Ｒ6 はＨ、低級アルキル基
又はアルカリ金属を表し、Ｒ7 〜Ｒ9 及びＲ11〜Ｒ15は
同一又は異なっていてもよく、それぞれＨ又は水酸基の
保護基を表し、Ｒ10はＯＨ、ＯＡｃ、ＮＨ2 又はＮＨＡ
ｃを表す。1. A sialic acid oligosaccharide derivative represented by the following formula (I): [Chemical 1] In formula (I), X represents O or S, and W represents the following formula (I
I) to (VII), m represents an integer of 1 to 8, R 0 represents N 3 , NH 2 or NHR (wherein R represents a linear or branched acyl group, benzyl). An oxycarbonyl group, a t-butoxycarbonyl group or a trimethylsilyl group), R 1 represents H, a lower alkyl group or an alkali metal, and R 2 to R 4 may be the same or different and each represents H or a hydroxyl group. And R 5 is O.
Represents H, OAc or H. [Chemical 2] [Chemical 3] In formulas (II) to (VII), R 6 represents H, a lower alkyl group or an alkali metal, and R 7 to R 9 and R 11 to R 15 may be the same or different, and each of them is protected by H or a hydroxyl group. Represents a group, R 10 is OH, OAc, NH 2 or NHA
represents c. 【請求項２】 ｍが２である請求項１記載のシアル酸オ
リゴ糖誘導体。2. The sialic acid oligosaccharide derivative according to claim 1, wherein m is 2. 【請求項３】 Ｒがパミルトイル基である請求項１又は
２記載のシアル酸オリゴ糖誘導体。3. The sialic acid oligosaccharide derivative according to claim 1, wherein R is a pamiltoyl group. 【請求項４】 請求項１〜３のいずれかに記載のシアル
酸オリゴ糖誘導体を構成成分として含有する微粒子キャ
リヤー。4. A fine particle carrier containing the sialic acid oligosaccharide derivative according to any one of claims 1 to 3 as a constituent.
JP4005955A 1992-01-16 1992-01-16 Sialic acid oligosaccharide derivative and fine particle carrier Expired - Lifetime JPH0826057B2 (en)

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