JP2000001541A - Amino group-containing polyoxyalkylene compound - Google Patents
Amino group-containing polyoxyalkylene compoundInfo
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- JP2000001541A JP2000001541A JP16692898A JP16692898A JP2000001541A JP 2000001541 A JP2000001541 A JP 2000001541A JP 16692898 A JP16692898 A JP 16692898A JP 16692898 A JP16692898 A JP 16692898A JP 2000001541 A JP2000001541 A JP 2000001541A
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明はグリセリンのα、β
位にポリオキシアルキレン鎖を持ち、γ位にアミノ基を
有するポリオキシアルキレン化合物に関する。さらに詳
しくは、ポリペプチド、生理活性蛋白質、酵素などへの
ポリオキシアルキレン修飾や脂肪乳剤、リポソームなど
の薬物送達システム（以下ドラッグデリバリーシステム
という。）におけるポリオキシアルキレン基の修飾など
主として医薬用途に用いられる末端アミノ基を有するポ
リオキシアルキレン化合物に関する。The present invention relates to glycerin having α, β
A polyoxyalkylene compound having a polyoxyalkylene chain at the γ-position and an amino group at the γ-position. More specifically, it is mainly used for pharmaceutical applications, such as modification of polyoxyalkylene to polypeptides, bioactive proteins, enzymes, etc., and modification of polyoxyalkylene groups in drug delivery systems (hereinafter referred to as drug delivery systems) such as fat emulsions and liposomes. To a polyoxyalkylene compound having a terminal amino group.
【０００２】[0002]
【従来の技術】これまでポリオキシアルキレングリコー
ルの末端水酸基をアミノ基に置換した化合物は潤滑油
（特公昭５４−７４５８５４号公報）あるいは合成樹脂
添加剤（特開昭５７−３６１１５号公報）が記載されて
おり、幅広く利用されている。また、近年になり、ポリ
オキシアルキレン化合物がドラッグデリバリーシステム
の重要な担体として注目を集めるようになり、ポリオキ
シアルキレン化合物にアミノ基やカルボキシル基を導入
した化合物についても研究が盛んに行われるようになっ
ている。なかでも、２本のポリオキシアルキレン鎖を持
つ化合物は特開平３−７２４６９号公報に示されている
トリアジン環を介した２，４−ビス（Ｏ−メトキシポリ
エチレングリコール）−６−クロロ−Ｓ−トリアジン
（以下「活性化ＰＥＧ２」という）が知られている。ま
た、ポリオキシアルキレン基の側鎖に多数のアミノ基を
持つポリオキシアルキレン化合物も知られている。（特
開平８−４８７６４号公報）2. Description of the Related Art Heretofore, compounds in which terminal hydroxyl groups of polyoxyalkylene glycol have been substituted with amino groups are described in lubricating oils (JP-B-54-745854) or synthetic resin additives (JP-A-57-36115). It has been widely used. In recent years, polyoxyalkylene compounds have attracted attention as important carriers of drug delivery systems, and research has been actively conducted on compounds in which an amino group or a carboxyl group is introduced into a polyoxyalkylene compound. Has become. Among them, a compound having two polyoxyalkylene chains is disclosed in JP-A-3-72469, in which 2,4-bis (O-methoxypolyethyleneglycol) -6-chloro-S- is bonded via a triazine ring. Triazines (hereinafter "activated PEG2") are known. Further, polyoxyalkylene compounds having a large number of amino groups in the side chains of the polyoxyalkylene groups are also known. (JP-A-8-48764)
【０００３】[0003]
【発明が解決しようとする課題】特に、ポリオキシアル
キレン化合物で修飾したリン脂質を用いた脂肪乳剤、リ
ポソームにおいては抗原性（免疫反応性）の低減、内包
した薬剤の安定性のみならず、体内滞留時間の延長効果
が得られるとされている。ところが、これら従来のアミ
ノ基含有ポリオキシアルキレン化合物は、例えば一本鎖
の末端アミノ基含有ポリオキシアルキレン化合物の場
合、これを用いて対象物質を修飾すると、一本鎖である
が故にポリオキシアルキレンの持つ体内滞留時間の延長
効果が十分に発揮できないケースが多々ある。また、前
述した活性化ＰＥＧ２はトリアジン環を持つため、医薬
品として体内に投与した場合、毒性が生じる可能性があ
る。さらに、ポリオキシアルキレン骨格の側鎖に多数の
アミノ基を持つものは、反応点がたくさんあるため、修
飾反応を制御するのが難しく、単一の化合物を得ること
が困難である。In particular, in lipid emulsions and liposomes using phospholipids modified with polyoxyalkylene compounds, not only are the antigenicity (immunoreactivity) reduced, the stability of the encapsulated drug is reduced, but also It is said that the effect of extending the residence time can be obtained. However, these conventional amino group-containing polyoxyalkylene compounds are, for example, a single-chain terminal amino group-containing polyoxyalkylene compound. In many cases, the effect of prolonging the residence time in the body cannot be fully exhibited. In addition, since the above-mentioned activated PEG2 has a triazine ring, it may cause toxicity when administered to the body as a pharmaceutical. Further, those having a large number of amino groups in the side chain of the polyoxyalkylene skeleton have many reaction points, so that it is difficult to control the modification reaction, and it is difficult to obtain a single compound.
【０００４】本発明の目的は、化合物ないしは薬剤の抗
原性の低減および安定化のみならず、体内滞留時間の延
長などの目的をもって、リン脂質を修飾するために使用
され、しかも修飾されたリン脂質を用いた脂肪乳剤、リ
ポソームの毒性が少なく、さらに副生物の生成が少ない
アミノ基含有ポリオキシアルキレン化合物を提供するこ
とである。[0004] It is an object of the present invention to use a modified phospholipid for modifying a phospholipid for the purpose of not only reducing and stabilizing the antigenicity of the compound or drug, but also extending the residence time in the body. It is an object of the present invention to provide an amino group-containing polyoxyalkylene compound which is less toxic to fat emulsions and liposomes and further produces less by-products.
【０００５】[0005]
【課題を解決するための手段】本発明者らは上記の課題
を解決すべく鋭意研究を重ねた結果、グリセリンのα、
β位にポリオキシアルキレン鎖を持ち、γ位にアミノ基
を有するポリオキシアルキレン化合物が、上記した目的
を達成できることを見出し、本発明に到達した。すなわ
ち、本発明は式（１）で示されるアミノ基を含有するポ
リオキシアルキレン化合物である。Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that glycerin α,
The present inventors have found that a polyoxyalkylene compound having a polyoxyalkylene chain at the β-position and having an amino group at the γ-position can achieve the above object, and arrived at the present invention. That is, the present invention is a polyoxyalkylene compound containing an amino group represented by the formula (1).
【０００６】[0006]
【化２】 Embedded image
【０００７】（ただし、Ｒ1は水素原子、炭素数１〜２
４の炭化水素基または炭素数１〜２４のアシル基、Ｒ2
は炭素数３〜４の炭化水素基、Ｒ3は炭素数１〜１０の
炭化水素基、ＡＯは炭素数３〜４のオキシアルキレン
基、ｎはオキシエチレン基の平均付加モル数で１〜１０
００、ｍは炭素数３〜４のオキシアルキレン基の平均付
加モル数、ｎ／（ｎ＋ｍ）は０．８以上、オキシエチレ
ン基と炭素数３〜４のオキシアルキレン基の付加状態は
ブロック状またはランダム状でもよい。）(However, R 1 is a hydrogen atom and has 1 to 2 carbon atoms.)
A hydrocarbon group of 4 or an acyl group having 1 to 24 carbon atoms, R 2
Is a hydrocarbon group having 3 to 4 carbon atoms, R 3 is a hydrocarbon group having 1 to 10 carbon atoms, AO is an oxyalkylene group having 3 to 4 carbon atoms, and n is an average addition mole number of 1 to 10 oxyethylene groups.
00, m is the average number of moles of the added oxyalkylene group having 3 to 4 carbon atoms, n / (n + m) is 0.8 or more, and the addition state of the oxyethylene group and the oxyalkylene group having 3 to 4 carbon atoms is block-like or It may be random. )
【０００８】[0008]
【発明の実施の形態】式（１）においてＲ1で示される
炭素数１〜２４の炭化水素基としては、脂肪族炭化水素
基として、メチル基、エチル基、プロピル基、イソプロ
ピル基、ブチル基、イソブチル基、第三ブチル基、ペン
チル基、イソペンチル基、ヘキシル基、イソヘプチル
基、２−エチルヘキシル基、オクチル基、イソノニル
基、デシル基、ドデシル基、イソトリデシル基、テトラ
デシル基、ヘキサデシル基、イソセチル基、オクタデシ
ル基、イソステアリル基、オクチルドデシル基、ドコシ
ル基、デシルテトラデシル基などの直鎖または分岐状の
アルキル基；芳香族炭化水素基として、ブチルフェニル
基、ジブチルフェニル基、オクチルフェニル基、ジノニ
ルフェニル基、α−メチルベンジルフェニル基などのア
リール基、ベンジル基などのアラルキル基およびクレジ
ル基が挙げられる。BEST MODE FOR CARRYING OUT THE INVENTION In the formula (1), as the hydrocarbon group having 1 to 24 carbon atoms represented by R 1 , as an aliphatic hydrocarbon group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group , Isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isoheptyl, 2-ethylhexyl, octyl, isononyl, decyl, dodecyl, isotridecyl, tetradecyl, hexadecyl, isocetyl, Linear or branched alkyl group such as octadecyl group, isostearyl group, octyldodecyl group, docosyl group, decyltetradecyl group; aromatic hydrocarbon groups such as butylphenyl group, dibutylphenyl group, octylphenyl group, dinonyl Phenyl group, aryl group such as α-methylbenzylphenyl group, benzyl group, etc. Any aralkyl and cresyl groups are included.
【０００９】また、炭素数１〜２４のアシル基として
は、酢酸、プロピオン酸、酪酸、イソ酪酸、カプリル
酸、２−エチルヘキサン酸、イソノナン酸、カプリン
酸、ラウリン酸、ミリスチン酸、パルミチン酸、イソパ
ルミチン酸、ステアリン酸、イソステアリン酸、アラキ
ン酸、ベヘン酸、パルミトレイン酸、安息香酸、ヒドロ
キシ安息香酸、桂皮酸、没食子酸などに由来するアシル
基が挙げられる。これらのなかでも、Ｒ1としては、水
素原子および炭素数１〜４の直鎖のアルキル基が好まし
い。なお、式（１）中にはＲ1が２つ存在するが、これ
らは同一または異なっていてもよい。The acyl groups having 1 to 24 carbon atoms include acetic acid, propionic acid, butyric acid, isobutyric acid, caprylic acid, 2-ethylhexanoic acid, isononanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, Examples include acyl groups derived from isopalmitic acid, stearic acid, isostearic acid, arachiic acid, behenic acid, palmitoleic acid, benzoic acid, hydroxybenzoic acid, cinnamic acid, gallic acid, and the like. Among them, R 1 is preferably a hydrogen atom and a linear alkyl group having 1 to 4 carbon atoms. In addition, although two R < 1 > exist in Formula (1), these may be same or different.
【００１０】Ｒ2で示される炭素数３〜４の炭化水素基
としては、重合性不飽和基をもつ炭化水素基に由来する
基、好ましくはアリル基、メタリル基など二重結合をも
つ炭化水素基に由来するトリメチレン基、イソブチレン
基などの直鎖または分岐状のアルキレン基などが挙げら
れる。The hydrocarbon group having 3 to 4 carbon atoms represented by R 2 is a group derived from a hydrocarbon group having a polymerizable unsaturated group, preferably a hydrocarbon having a double bond such as an allyl group or a methallyl group. Examples thereof include a linear or branched alkylene group such as a trimethylene group and an isobutylene group derived from the group.
【００１１】Ｒ3で示される炭素数１〜１０の炭化水素
基としては、メチレン基、エチレン基、プロピレン基、
トリメチレン基などの直鎖または分岐状のアルキレン
基、フェニレン基、ベンジル基などの２価の芳香族炭化
水素基が挙げられる。なかでも、メチレン基およびエチ
レン基が好ましい。The hydrocarbon group having 1 to 10 carbon atoms represented by R 3 includes a methylene group, an ethylene group, a propylene group,
Examples thereof include a linear or branched alkylene group such as a trimethylene group, and a divalent aromatic hydrocarbon group such as a phenylene group and a benzyl group. Among them, a methylene group and an ethylene group are preferred.
【００１２】ＡＯで示される炭素数３〜４のオキシアル
キレン基のアルキレン部位は、直鎖または分岐状のいず
れでもよく、このようなオキシアルキレン基として、た
とえば、オキシプロピレン基、オキシトリメチレン基、
オキシブチレン基、オキシテトラメチレン基などが挙げ
られる。The alkylene moiety of the oxyalkylene group having 3 to 4 carbon atoms represented by AO may be linear or branched. Examples of such an oxyalkylene group include an oxypropylene group, an oxytrimethylene group,
Oxybutylene group, oxytetramethylene group and the like can be mentioned.
【００１３】ｎはオキシアルキレン基の平均付加モル数
で１〜１０００であり、ｍは炭素数３〜４のオキシアル
キレン基の平均付加モル数であって、ｎ／（ｎ＋ｍ）は
０．８以上、好ましくは０．９以上、より好ましくは
１．０である。ｎ／（ｎ＋ｍ）が１．０未満の場合、オ
キシエチレン基と炭素数３〜４のオキシアルキレン基の
付加状態はブロック状でもランダム状でもよい。N is the average number of added moles of the oxyalkylene group of 1 to 1000, m is the average number of added moles of the oxyalkylene group having 3 to 4 carbon atoms, and n / (n + m) is 0.8 or more. , Preferably 0.9 or more, more preferably 1.0. When n / (n + m) is less than 1.0, the addition state of the oxyethylene group and the oxyalkylene group having 3 to 4 carbon atoms may be block-like or random.
【００１４】式（１）で表される本発明のアミノ基含有
ポリオキシアルキレン化合物は、例えば、以下のように
して製造することができる。まず式（２）The amino group-containing polyoxyalkylene compound of the present invention represented by the formula (1) can be produced, for example, as follows. First, equation (2)
【００１５】[0015]
【化３】 Embedded image
【００１６】（式中、Ｒ2'は重合性不飽和基をもつ炭化
水素基、好ましくはアリル基あるいはメタリル基などの
炭素数３〜４の二重結合含有炭化水素基を示す。）で表
される化合物に、エチレンオキシド単独あるいはエチレ
ンオキシドおよび炭素数３〜４のアルキレンオキシドを
付加させる。この際、化合物（２）にエチレンオキシド
を付加させた後、炭素数３〜４のアルキレンオキシドを
付加させてもよいし、エチレンオキシドと炭素数３〜４
のアルキレンオキシドを混合して一度に付加反応を行っ
てもよい。エチレンオキシドと炭素数３〜４のアルキレ
ンオキシドの付加モル数の比率は、全体のオキシアルキ
レン鎖の親水性を保つため、オキシエチレン基が８０％
以上になるようにする。(In the formula, R 2 ′ represents a hydrocarbon group having a polymerizable unsaturated group, preferably a hydrocarbon group having a double bond having 3 to 4 carbon atoms such as an allyl group or a methallyl group.) Ethylene oxide alone or ethylene oxide and an alkylene oxide having 3 to 4 carbon atoms are added to the resulting compound. At this time, after adding ethylene oxide to the compound (2), an alkylene oxide having 3 to 4 carbon atoms may be added, or ethylene oxide and 3 to 4 carbon atoms may be added.
And the addition reaction may be performed at once by mixing the alkylene oxides. The ratio of the number of moles of ethylene oxide added to the alkylene oxide having 3 to 4 carbon atoms is 80% in order to maintain the hydrophilicity of the entire oxyalkylene chain.
So that
【００１７】具体的には、まず化合物（２）を反応釜に
仕込み、窒素置換を行い、１００〜１４０℃でアルキレ
ンオキシド（エチレンオキシド単独、あるいはエチレン
オキシドと炭素数３〜４のアルキレンオキシドとの混合
物）を圧入し、反応させる。反応終了後、減圧下で未反
応アルキレンオキシドを除去し、８０℃に冷却し、リン
酸、塩酸などの酸を加えて中和し、脱水およびろ過を行
い、式（３'）Specifically, first, compound (2) is charged into a reaction vessel, and the atmosphere is replaced with nitrogen. Then, at 100 to 140 ° C., alkylene oxide (ethylene oxide alone or a mixture of ethylene oxide and alkylene oxide having 3 to 4 carbon atoms) is used. And let it react. After completion of the reaction, unreacted alkylene oxide is removed under reduced pressure, cooled to 80 ° C., neutralized by adding an acid such as phosphoric acid or hydrochloric acid, dehydrated and filtered, and subjected to the formula (3 ′)
【００１８】[0018]
【化４】 Embedded image
【００１９】（式中の記号は前記と同様）で表される化
合物を得る。必要に応じて末端水酸基をアルキル化ある
はアシル化するなど、炭化水素基の導入を行って式
（３''）(The symbols in the formula are as defined above.) If necessary, a hydrocarbon group may be introduced by alkylating or acylating the terminal hydroxyl group to obtain a compound of the formula (3 ″)
【００２０】[0020]
【化５】 Embedded image
【００２１】（式中、Ｒ1'は炭素数１〜２４の炭化水素
基または炭素数１〜２４のアシル基を示し、その他の記
号は前記と同様）で表される化合物となる。例えば、ア
ルキル化反応は、Ｒ1で示される炭化水素基を有するア
ルキルハライド（ハロゲン化アルキル）、アルケニルハ
ライドなどのアルキル化剤を、化合物（３'）の水酸基
に対して１．１〜３．０倍モル加え、９０〜１２０℃で
２〜５時間反応を行い、水洗し、未反応物を除去し、中
和、脱水およびろ過を行う。(Wherein, R 1 ′ represents a hydrocarbon group having 1 to 24 carbon atoms or an acyl group having 1 to 24 carbon atoms, and other symbols are the same as those described above). For example, in the alkylation reaction, an alkylating agent such as an alkyl halide (alkyl halide) or an alkenyl halide having a hydrocarbon group represented by R 1 is used in an amount of from 1.1 to 3.1 with respect to the hydroxyl group of compound (3 ′). The reaction is carried out at 90 to 120 ° C. for 2 to 5 hours, washed with water to remove unreacted substances, and neutralized, dehydrated and filtered.
【００２２】アシル化の反応は、Ｒ1で示されるアシル
基を有するハロゲン化アシルやカルボン酸無水物などの
アシル化剤を化合物（３'）の水酸基に対して１．１〜
２．０倍モル加え、ｐ−トルエンスルホン酸の存在下、
１１０〜１４０℃で９時間、脱水縮合反応を行い、吸着
剤処理し、脱水およびろ過を行う。上記したハロゲン化
物やカルボン酸無水物中のＲ1が芳香族炭化水素基であ
る化合物を用いた場合、芳香族炭化水素基が導入され
る。この場合の反応条件も上記したアルキル化およびア
シル化に準じる。このようにして得た式（４）In the acylation reaction, an acylating agent such as an acyl halide having an acyl group represented by R 1 or a carboxylic acid anhydride is reacted with the hydroxyl group of the compound (3 ′) in an amount of 1.1 to 1.0.
2.0-fold molar addition, in the presence of p-toluenesulfonic acid,
A dehydration condensation reaction is performed at 110 to 140 ° C. for 9 hours, treated with an adsorbent, and dehydration and filtration are performed. When a compound in which R 1 in the above-mentioned halide or carboxylic acid anhydride is an aromatic hydrocarbon group is used, an aromatic hydrocarbon group is introduced. The reaction conditions in this case also conform to the above-described alkylation and acylation. Equation (4) obtained in this way
【００２３】[0023]
【化６】 Embedded image
【００２４】（式中の各記号は前記と同様）で表される
化合物に、式（５） ＨＳ−Ｒ3−ＮＨ2・ＨＣｌ （５） （式中、Ｒ3は前記と同様）で表される化合物（４）中
のアリル基またはメタリル基に対して１．５〜１０倍モ
ル加え、例えばメタノール、エタノールなどのアルコー
ル中で３０〜４０℃で３〜７時間反応させ、アミノ基の
導入を行う。反応終了後、１ＮＮａＯＨ水溶液でｐＨを
９に調整した後、アルコールを留去し、反応混合物をク
ロロホルムやジクロロメタンなどの溶媒に溶解し、その
後水洗して未反応の化合物（５）を除去する。ついで溶
媒を留去したのちろ過を行い、式（１）の化合物を得
る。A compound represented by the formula (5) HS-R 3 —NH 2 .HCl (5) (where R 3 is the same as described above) is added to a compound represented by the formula (wherein each symbol is the same as described above). 1.5 to 10 times the molar amount of the allyl group or methallyl group in the compound (4) to be prepared, and reacted in an alcohol such as methanol or ethanol at 30 to 40 ° C. for 3 to 7 hours to introduce an amino group. I do. After completion of the reaction, the pH is adjusted to 9 with a 1N aqueous solution of NaOH, the alcohol is distilled off, and the reaction mixture is dissolved in a solvent such as chloroform or dichloromethane, and then washed with water to remove the unreacted compound (5). Then, the solvent is distilled off, followed by filtration to obtain a compound of the formula (1).
【００２５】本発明のアミノ基含有ポリオキシアルキレ
ン化合物は、主にアドレアマイシン、シスプラチンなど
の抗癌剤を内包するドラッグデリバリーシステムの一種
である脂肪乳剤、リポソームの基材であるリン脂質への
化学修飾が考えられる。ポリオキシアルキレン基で修飾
されることにより、脂肪乳剤およびリポソーム自身の安
定性を高めるだけでなく、血中滞留時間の延長効果が期
待される。The amino group-containing polyoxyalkylene compound of the present invention is obtained by chemically modifying a lipid emulsion which is a kind of a drug delivery system containing an anticancer agent such as adreamycin and cisplatin, and a phospholipid which is a base of liposome. Conceivable. Modification with a polyoxyalkylene group is expected not only to enhance the stability of the fat emulsion and liposome itself, but also to prolong the residence time in blood.
【００２６】[0026]
【実施例】以下、本発明を実施例により更に詳細に説明
する。 製造例１ グリセリンモノアリルエーテル６６ｇ（０．５モル）と
水酸化カリウム１ｇを５リットル容オートクレーブに仕
込み、系内を窒素ガスに置換した後、１２０℃に昇温し
た。次いでエチレンオキシド２４４０ｇ（５５モル）を
圧入後、１３０±５℃で１時間反応を行った。次いで、
窒素ガスを通じながら減圧下（２００ｍｍＨｇ、０．５
時間）、未反応のエチレンオキシドを除去し８０℃まで
冷却した。その後、１０重量％塩酸水溶液でｐＨを７．
０に調整し、１００±５℃で１００ｍｍＨｇ、１時間脱
水を行った。次いで反応混合物を８０℃に冷却し、析出
した塩を濾別して化合物２３８０ｇを得た。得られた化
合物の水酸基価は２２．４（計算値は２３．０）、不飽
和度は０．１９（計算値は０．２）であった。なお、水
酸基価はＪＩＳ Ｋ−１５５７ ６．４（１９７０）の
方法に準じて、不飽和度はＪＩＳ Ｋ−１５５７ ６．
７（１９７０）の方法に準じて測定した。化合物の赤外
線吸収スペクトルを図１に示す。ゲルパーミエーション
クロマトグラフィー（以下ＧＰＣという。）の分析結果
を図２および表１に示す。ＧＰＣの分析条件は以下の通
りである。 ＧＰＣシステム：ＳＹＳＴＥＭ−１１（昭和電工株式会
社製） ＧＰＣカラム：ＳＨＯＤＥＸ ＫＦ−８０４Ｌ ×３ 展開液：ＴＨＦ 流速：１ｍｌ／ｍｉｎ サンプル濃度：０．１５ｗｔ％ カラムオーブン温度：４０℃The present invention will be described in more detail with reference to the following examples. Production Example 1 66 g (0.5 mol) of glycerin monoallyl ether and 1 g of potassium hydroxide were charged into a 5-liter autoclave, and the inside of the system was replaced with nitrogen gas. Then, after injection of 2440 g (55 mol) of ethylene oxide, the mixture was reacted at 130 ± 5 ° C. for 1 hour. Then
Under a reduced pressure (200 mmHg, 0.5
Hour), unreacted ethylene oxide was removed, and the mixture was cooled to 80 ° C. Thereafter, the pH was adjusted to 7 with a 10% by weight aqueous hydrochloric acid solution.
The temperature was adjusted to 0, and dehydration was performed at 100 ± 5 ° C and 100 mmHg for 1 hour. Next, the reaction mixture was cooled to 80 ° C., and the precipitated salt was separated by filtration to obtain 2380 g of a compound. The hydroxyl value of the obtained compound was 22.4 (calculated value: 23.0), and the degree of unsaturation was 0.19 (calculated value: 0.2). In addition, the hydroxyl value is based on the method of JIS K-1557 6.4 (1970), and the degree of unsaturation is JIS K-1557 6.
7 (1970). FIG. 1 shows the infrared absorption spectrum of the compound. The analysis results of gel permeation chromatography (hereinafter, referred to as GPC) are shown in FIG. GPC analysis conditions are as follows. GPC system: SYSTEM-11 (manufactured by Showa Denko KK) GPC column: SHOdex KF-804L x 3 Developing solution: THF Flow rate: 1 ml / min Sample concentration: 0.15 wt% Column oven temperature: 40 ° C
【００２７】[0027]
【表１】 [Table 1]
【００２８】1Ｈ−ＮＭＲスペクトルの結果は以下の通
りである。1 Ｈ−ＮＭＲ（δ（ｐｐｍ）、ＣＤＣｌ／ＴＭＳ） δ＝５．２ｐｐｍ （Ｃ＝ＣＨ2 ） δ＝５．９ｐｐｍ （−ＣＨ＝） 出発原料、反応条件および分析値より、得られた化合物
は式（６）The results of the 1 H-NMR spectrum are as follows. 1 H-NMR (δ (ppm ), CDCl / TMS) δ = 5.2ppm (C = C H 2) δ = 5.9ppm (-C H =) starting materials, from the reaction conditions and analytical values, resulting The compound has the formula (6)
【００２９】[0029]
【化７】 Embedded image
【００３０】で表される化合物（分子量：５００９）と
推定した。(Molecular weight: 5009).
【００３１】製造例２ グリセリンモノアリルエーテル６６ｇ（０．５モル）と
水酸化カリウム０．６ｇを５リットル容オートクレーブ
に仕込み、系内を窒素ガスに置換した後、１００℃に昇
温した。次いでエチレンオキシド１３４０ｇ（３０モ
ル）、プロピレンオキシド１１０ｇ（２モル）を計量槽
に計り取り、均一になるまで混合した。１１０±５℃、
１０ｋｇ／ｃｍ2以下の条件で計量槽よりエチレンオキ
シドとプロピレンオキシド混合物を８時間かけて圧入し
た。圧入後、一時間反応を行い、次いで、窒素ガスを通
じながら２００ｍｍＨｇの減圧下、３０分間で未反応の
エチレンオキシドとプロピレンオキシドを除去した後、
８０℃まで冷却した。その後、１０重量％塩酸水溶液で
ｐＨを７．０に調整し、１００±５℃、１００ｍｍＨｇ
の条件で１時間脱水を行った。次に８０℃に冷却して、
析出した塩を濾別して化合物１４４０ｇを得た。Production Example 2 A 5-liter autoclave was charged with 66 g (0.5 mol) of glycerin monoallyl ether and 0.6 g of potassium hydroxide. After the inside of the system was replaced with nitrogen gas, the temperature was raised to 100 ° C. Next, 1340 g (30 mol) of ethylene oxide and 110 g (2 mol) of propylene oxide were measured in a measuring tank and mixed until uniform. 110 ± 5 ° C,
Under a condition of 10 kg / cm 2 or less, a mixture of ethylene oxide and propylene oxide was injected from the measuring tank over 8 hours. After the injection, the reaction was carried out for one hour, and then the unreacted ethylene oxide and propylene oxide were removed under a reduced pressure of 200 mmHg for 30 minutes while passing nitrogen gas.
Cooled to 80 ° C. Thereafter, the pH was adjusted to 7.0 with a 10% by weight aqueous hydrochloric acid solution, and 100 ± 5 ° C., 100 mmHg
Dehydration was performed for 1 hour under the conditions described above. Then cool to 80 ° C,
The precipitated salt was separated by filtration to obtain 1440 g of a compound.
【００３２】得られた化合物の水酸基価は３６．４（計
算値は３６．２）、不飽和度は０．３０（計算値は０．
３２）であった。なお、水酸基価および不飽和度は、製
造例１と同様にして測定した。ＧＰＣの分析結果を図３
および表２に示す。ＧＰＣの分析条件は製造例１とし
た。The resulting compound has a hydroxyl value of 36.4 (calculated value of 36.2) and an unsaturation of 0.30 (calculated value of 0.3).
32). The hydroxyl value and the degree of unsaturation were measured in the same manner as in Production Example 1. Figure 3 shows the GPC analysis results.
And Table 2. The analysis conditions for GPC were Production Example 1.
【００３３】[0033]
【表２】 [Table 2]
【００３４】出発原料、反応条件および上記の分析値よ
り得られた化合物は式（７）The starting material, the reaction conditions and the compound obtained from the above analytical values are of the formula (7)
【００３５】[0035]
【化８】 Embedded image
【００３６】で表される化合物（分子量：３０８２）と
推定した。(Molecular weight: 3082).
【００３７】製造例３ 製造例２で得られた式（６）の化合物１０００ｇ（０．
３２モル）と水酸化カリウム１５０ｇを５リットル容オ
ートクレーブに仕込み、系内を窒素ガスに置換した後、
１００℃に昇温した。次いでメチルクロリド４３．５ｇ
（０．８４モル）を１００±５℃の条件下で仕込んだ。
４時間反応後、８０℃に冷却し、窒素ガスを通じながら
減圧下（２００ｍｍＨｇ以下）で０．５時間、未反応の
メチルクロリドを除去した。次いで５００ｇの水を系中
に加え撹拌を行った後、静置して分層を行い下層の過剰
のアルカリ分を取り除いた。その後、１０重量％塩酸水
溶液でｐＨを７．０に調整し、１００±５℃、１００ｍ
ｍＨｇの条件で１時間脱水を行った。次に８０℃に冷却
し、析出した塩を濾別して化合物９５５ｇを得た。得ら
れた化合物の水酸基価は０．０４（計算値は０）、不飽
和度は０．２９（計算値は０．３２）であった。なお、
水酸基価および不飽和度は製造例１と同様にして測定し
た。ＧＰＣの分析結果を図４および表３に示す。ＧＰＣ
の分析条件は製造例１と同じとした。Preparation Example 3 1000 g of the compound of the formula (6) obtained in Preparation Example 2 (0.
32 mol) and 150 g of potassium hydroxide were charged into a 5-liter autoclave, and the inside of the system was replaced with nitrogen gas.
The temperature was raised to 100 ° C. Then 43.5 g of methyl chloride
(0.84 mol) was charged at 100 ± 5 ° C.
After reacting for 4 hours, the mixture was cooled to 80 ° C., and unreacted methyl chloride was removed under a reduced pressure (200 mmHg or less) for 0.5 hour while passing nitrogen gas. Next, 500 g of water was added to the system, and the mixture was stirred, and then allowed to stand, followed by separation to remove excess alkali in the lower layer. Thereafter, the pH was adjusted to 7.0 with a 10% by weight aqueous hydrochloric acid solution, and the temperature was adjusted to 100 ± 5 ° C. and 100 m
Dehydration was performed for 1 hour under the condition of mHg. Next, the mixture was cooled to 80 ° C., and the precipitated salt was separated by filtration to obtain 955 g of a compound. The hydroxyl value of the obtained compound was 0.04 (calculated value: 0), and the degree of unsaturation was 0.29 (calculated value: 0.32). In addition,
The hydroxyl value and the degree of unsaturation were measured in the same manner as in Production Example 1. The GPC analysis results are shown in FIG. GPC
Are the same as those in Production Example 1.
【００３８】[0038]
【表３】 [Table 3]
【００３９】出発原料、反応条件および上記の分析値よ
り、得られた化合物は式（８）From the starting materials, reaction conditions and the above analytical values, the obtained compound was represented by the formula (8)
【００４０】[0040]
【化９】 Embedded image
【００４１】で表される化合物（分子量：３１１０）と
推定した。(Molecular weight: 3110).
【００４２】実施例１ 四つ口フラスコに式（５）の化合物としてアミノエタン
チオール（ＨＳＣＨ2ＣＨ2ＮＨ2・ＨＣｌ）４５．４ｇ
（０．４モル）を入れ、かき混ぜながら温度を３５±５
℃に保持した。次いで製造例１で合成した式（６）の化
合物５００ｇ（０．１モル）をメタノール５００ｇに溶
解させ、滴下ロートにより四つ口フラスコに５時間かけ
て滴下した。全量滴下終了後、さらに４０±５℃で５時
間保持して反応を続けた。反応後、１ＮＮａＯＨ水溶液
でｐＨを９に調整した。次に６０±１０℃、２００ｍｍ
Ｈｇ以下の減圧下でメタノールを留去したのち、反応混
合物をクロロホルム１０００ｇに再び溶解させた。次に
全量を分液ロートに移し、飽和食塩水１リットルで３回
水洗し、未反応のアミノエタンチオールを除去した。次
いで１１０±１０℃、窒素雰囲気下、５０ｍｍＨｇ以下
の減圧下でクロロホルムおよび水を留去し、析出した食
塩をろ過により除去し、化合物（分子量５０８６）４７
２ｇを得た。得られた化合物の一級アミン価は１１．３
（計算値は１１．０）、不飽和度０．０１（計算値は
０）であった。Example 1 45.4 g of aminoethanethiol (HSCH 2 CH 2 NH 2 .HCl) as a compound of the formula (5) was placed in a four-necked flask.
(0.4 mol), and stir the temperature to 35 ± 5.
C. was maintained. Next, 500 g (0.1 mol) of the compound of the formula (6) synthesized in Production Example 1 was dissolved in 500 g of methanol, and added dropwise to the four-necked flask with a dropping funnel over 5 hours. After the completion of the dropwise addition, the reaction was further continued at 40 ± 5 ° C. for 5 hours. After the reaction, the pH was adjusted to 9 with a 1N aqueous NaOH solution. Next, 60 ± 10 ° C, 200mm
After the methanol was distilled off under reduced pressure of Hg or less, the reaction mixture was dissolved again in 1000 g of chloroform. Next, the whole amount was transferred to a separating funnel, and washed three times with 1 liter of saturated saline to remove unreacted aminoethanethiol. Then, chloroform and water were distilled off at 110 ± 10 ° C. under a nitrogen atmosphere under a reduced pressure of 50 mmHg or less, and the precipitated salt was removed by filtration to give Compound 47 (molecular weight: 5086).
2 g were obtained. The primary amine value of the obtained compound was 11.3.
(The calculated value was 11.0) and the degree of unsaturation was 0.01 (the calculated value was 0).
【００４３】なお、一級アミン価は塩酸滴定により求め
た全アミン価の値より、サリチルアルデヒドとサンプル
を反応させた後、塩酸滴定より求めた二級アミン価と三
級アミン価の値を差し引いた値である。酸価の測定はＪ
ＩＳ Ｋ−１５５７，６．６（１９７０）の方法に準じ
て行った。不飽和度は製造例１と同様にして測定した。
赤外線吸収スペクトルを図５に示す。1Ｈ−ＮＭＲスペ
クトルの結果は以下の通りである。1 Ｈ−ＮＭＲ（δ（ｐｐｍ），ＣＤＣｌ／ＴＭＳ） δ＝１．８５ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2 ＣＨ2−Ｓ−
ＣＨ2ＣＨ2−ＮＨ2） δ＝２．７５ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2ＣＨ2 −Ｓ−
ＣＨ2ＣＨ2−ＮＨ2） δ＝２．６５ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2ＣＨ2−Ｓ−
ＣＨ2 ＣＨ2−ＮＨ2） δ＝３．４０ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2ＣＨ2−Ｓ−
ＣＨ2ＣＨ2 −ＮＨ2） 出発原料、反応条件および上記の分析値より、得られた
化合物は式（９）The primary amine value was obtained by subtracting the secondary amine value and the tertiary amine value obtained by reacting salicylaldehyde with a sample and then hydrochloric acid titration from the total amine value determined by hydrochloric acid titration. Value. Measurement of acid value is J
It carried out according to the method of ISK-1557,6.6 (1970). The degree of unsaturation was measured in the same manner as in Production Example 1.
FIG. 5 shows the infrared absorption spectrum. The results of the 1 H-NMR spectrum are as follows. 1 H-NMR (δ (ppm ), CDCl / TMS) δ = 1.85ppm (-O-CH 2 C H 2 CH 2 -S-
CH 2 CH 2 —NH 2 ) δ = 2.75 ppm (—O—CH 2 CH 2 CH 2 —S—
CH 2 CH 2 —NH 2 ) δ = 2.65 ppm (—O—CH 2 CH 2 CH 2 —S—
C H 2 CH 2 -NH 2) δ = 3.40ppm (-O-CH 2 CH 2 CH 2 -S-
CH 2 C H 2 -NH 2) starting material, from the analysis of the reaction conditions and above, the resulting compound (9)
【００４４】[0044]
【化１０】 Embedded image
【００４５】の化合物（分子量：５０８６）と推定し
た。The compound (molecular weight: 5086) was estimated.
【００４６】実施例２ 四つ口フラスコに式（５）の化合物としてアミノメタン
チオール（ＨＳＣＨ2ＮＨ2・ＨＣｌ）４０．０ｇ（０．
４モル）を入れ、かき混ぜながら温度を３５±５℃に保
持した。次いで製造例１で合成した式（６）の化合物５
００ｇ（０．１モル）をメタノール５００ｇに溶解さ
せ、滴下ロートにより四つ口フラスコに５時間かけて滴
下した。全量滴下終了後、さらに４０±５℃で５時間保
持して反応を続けた。反応後、１ＮＮａＯＨ水溶液でｐ
Ｈを９に調整した。次に６０±１０℃、２００ｍｍＨｇ
以下の減圧下でメタノールを留去したのち、反応混合物
をクロロホルム１０００ｇに再び溶解させた。次に全量
を分液ロートに移し、飽和食塩水１リットルで３回水洗
し、未反応のアミノエタンチオールを除去した。次いで
１１０±１０℃、窒素雰囲気下、５０ｍｍＨｇ以下の減
圧下でクロロホルムおよび水を留去し、析出した食塩を
ろ過により除去し、化合物（分子量５０７４）４７２ｇ
を得た。得られた化合物の一級アミン価は１１．４（計
算値は１１．０）、不飽和度０．０１（計算値は０）で
あった。なお、一級アミン価および不飽和度は実施例１
と同様にして測定した。1Ｈ−ＮＭＲスペクトルの結果
は以下の通りである。1 Ｈ−ＮＭＲ（δ（ｐｐｍ），ＣＤＣｌ／ＴＭＳ） δ＝１．８５ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2 ＣＨ2−Ｓ−
ＣＨ2−ＮＨ2） δ＝２．７５ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2ＣＨ2 −Ｓ−
ＣＨ2−ＮＨ2） δ＝３．７４ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2ＣＨ2−Ｓ−
ＣＨ2 −ＮＨ2） 出発原料、反応条件および上記の分析値より、得られた
化合物は式（１０）Example 2 In a four-necked flask, 40.0 g of aminomethanethiol (HSCH 2 NH 2 .HCl) as a compound of the formula (5) (0.
4 mol), and the temperature was maintained at 35 ± 5 ° C. while stirring. Next, compound 5 of formula (6) synthesized in Production Example 1
00 g (0.1 mol) was dissolved in 500 g of methanol, and added dropwise to the four-necked flask over a period of 5 hours using a dropping funnel. After the completion of the dropwise addition, the reaction was further continued at 40 ± 5 ° C. for 5 hours. After the reaction, p with 1N NaOH aqueous solution
H was adjusted to 9. Next, at 60 ± 10 ° C, 200mmHg
After methanol was distilled off under the following reduced pressure, the reaction mixture was dissolved again in 1000 g of chloroform. Next, the whole amount was transferred to a separating funnel, and washed three times with 1 liter of saturated saline to remove unreacted aminoethanethiol. Then, chloroform and water were distilled off under a reduced pressure of 50 mmHg or less under a nitrogen atmosphere at 110 ± 10 ° C., and the precipitated salt was removed by filtration to obtain 472 g of a compound (molecular weight: 5074).
I got The primary amine value of the obtained compound was 11.4 (calculated value: 11.0), and the degree of unsaturation was 0.01 (calculated value: 0). The primary amine value and the degree of unsaturation were determined in Example 1.
The measurement was performed in the same manner as described above. The results of the 1 H-NMR spectrum are as follows. 1 H-NMR (δ (ppm ), CDCl / TMS) δ = 1.85ppm (-O-CH 2 C H 2 CH 2 -S-
CH 2 —NH 2 ) δ = 2.75 ppm (—O—CH 2 CH 2 CH 2 —S—
CH 2 —NH 2 ) δ = 3.74 ppm (—O—CH 2 CH 2 CH 2 —S—
C H 2 —NH 2 ) From the starting materials, reaction conditions and the above analytical values, the obtained compound is represented by the formula (10)
【００４７】[0047]
【化１１】 Embedded image
【００４８】の化合物（分子量：５０７４）と推定し
た。The compound (molecular weight: 5074) was estimated.
【００４９】実施例３ 四つ口フラスコに式（５）の化合物としてアミノエタン
チオール（ＨＳＣＨ2ＣＨ2ＮＨ2・ＨＣｌ）７２．６ｇ
（０．６４モル）を入れ、かき混ぜながら温度を３５±
５℃に保持した。次いで製造例２で合成した式（７）の
化合物５００ｇ（０．１６モル）をメタノール５００ｇ
に溶解させ、滴下ロートにより四つ口フラスコに５時間
かけて滴下した。全量滴下終了後、さらに４０±５℃で
５時間保持して反応を続けた。反応後、１ＮＮａＯＨ水
溶液でｐＨを９に調整した。次に６０±１０℃、２００
ｍｍＨｇ以下の減圧下でメタノールを留去したのち、反
応混合物をクロロホルム１０００ｇに再び溶解させた。
次に全量を分液ロートに移し、飽和食塩水１リットルで
３回水洗し、未反応のアミノエタンチオールを除去し
た。次いで１１０±１０℃、窒素雰囲気下、５０ｍｍＨ
ｇ以下の減圧下でクロロホルムおよび水を留去し、析出
した食塩をろ過により除去し、化合物（分子量３１５
９）４７０ｇを得た。得られた化合物の一級アミン価は
１７．９（計算値は１７．８）、不飽和度０．０２（計
算値は０）であった。なお、一級アミン価および不飽和
度は実施例１と同様にして測定した。1Ｈ−ＮＭＲスペ
クトルの結果は以下の通りである。1 Ｈ−ＮＭＲ（δ（ｐｐｍ），ＣＤＣｌ／ＴＭＳ） δ＝１．８５ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2 ＣＨ2−Ｓ−
ＣＨ2ＣＨ2−ＮＨ2） δ＝２．７５ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2ＣＨ2 −Ｓ−
ＣＨ2ＣＨ2−ＮＨ2） δ＝２．６５ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2ＣＨ2−Ｓ−
ＣＨ2 ＣＨ2−ＮＨ2） δ＝３．４０ｐｐｍ （−Ｏ−ＣＨ2ＣＨ2ＣＨ2−Ｓ−
ＣＨ2ＣＨ2 −ＮＨ2） 出発原料、反応条件および上記の分析値より、得られた
化合物は式（１１）Example 3 72.6 g of aminoethanethiol (HSCH 2 CH 2 NH 2 .HCl) as a compound of the formula (5) was placed in a four-necked flask.
(0.64 mol), and stir the temperature to 35 ±
It was kept at 5 ° C. Next, 500 g (0.16 mol) of the compound of the formula (7) synthesized in Production Example 2 was added to 500 g of methanol.
And the mixture was added dropwise to the four-necked flask over 5 hours using a dropping funnel. After the completion of the dropwise addition, the reaction was further continued at 40 ± 5 ° C. for 5 hours. After the reaction, the pH was adjusted to 9 with a 1N aqueous NaOH solution. Next, at 60 ± 10 ° C, 200
After methanol was distilled off under reduced pressure of not more than mmHg, the reaction mixture was dissolved again in 1000 g of chloroform.
Next, the whole amount was transferred to a separating funnel, and washed three times with 1 liter of saturated saline to remove unreacted aminoethanethiol. Then, at 110 ± 10 ° C. under a nitrogen atmosphere, 50 mmH
Chloroform and water were distilled off under reduced pressure of not more than g, and the precipitated salt was removed by filtration to give a compound (molecular weight: 315).
9) 470 g were obtained. The primary amine value of the obtained compound was 17.9 (calculated value: 17.8), and the degree of unsaturation was 0.02 (calculated value: 0). The primary amine value and the degree of unsaturation were measured in the same manner as in Example 1. The results of the 1 H-NMR spectrum are as follows. 1 H-NMR (δ (ppm ), CDCl / TMS) δ = 1.85ppm (-O-CH 2 C H 2 CH 2 -S-
CH 2 CH 2 —NH 2 ) δ = 2.75 ppm (—O—CH 2 CH 2 CH 2 —S—
CH 2 CH 2 —NH 2 ) δ = 2.65 ppm (—O—CH 2 CH 2 CH 2 —S—
C H 2 CH 2 -NH 2) δ = 3.40ppm (-O-CH 2 CH 2 CH 2 -S-
CH 2 C H 2 -NH 2) starting material, from the analysis of the reaction conditions and above, the obtained compound formula (11)
【００５０】[0050]
【化１２】 Embedded image
【００５１】の化合物（分子量：３１５９）と推定し
た。The compound (molecular weight: 3159) was estimated.
【００５２】試験例１ 油成分として、精製大豆油２００ｇ、薬物としてデキサ
メタゾンパルミテート（以下ＤＰＡＬという。）４ｇ、
実施例１で得られた式（９）の化合物でＰＥＧ修飾を行
った式（１２）で示されるジステアロイルホスファチジ
ルエタノールアミン（以下ＰＥＧ２−ＤＳＰＥとい
う。）５ｇ、および卵黄レシチン（以下ＹＰＬとい
う。）７ｇを混合して調整した脂肪乳剤を用い、この脂
肪乳剤をラット静脈内に投与し（２００ｍｇＴＧ／ｋｇ
体重）、血しょう中のＤＰＡＬレベルを液体クロマトグ
ラフィーにより測定した。その結果を図６に示す。Test Example 1 200 g of refined soybean oil as an oil component, 4 g of dexamethasone palmitate (hereinafter referred to as DPAL) as a drug,
5 g of distearoylphosphatidylethanolamine (hereinafter, referred to as PEG2-DSPE) represented by the formula (12) obtained by performing PEG modification with the compound of the formula (9) obtained in Example 1, and egg yolk lecithin (hereinafter, referred to as YPL). This fat emulsion was administered intravenously to rats using a fat emulsion prepared by mixing 7 g of the fat emulsion (200 mg TG / kg).
Body weight) and plasma DPAL levels were measured by liquid chromatography. FIG. 6 shows the result.
【００５３】[0053]
【化１３】 Embedded image
【００５４】比較試験例１ 試験例１で使用した化合物（１２）の代わりに一本鎖の
ポリエチレングリコールで修飾を行った式（１３）で示
されるジステアロイルホスファチジルエタノールアミン
（以下、ＰＥＧ１−ＤＳＰＥという。）５ｇを用いたこ
と以外は試験例１と同様に行った。その結果を図６に示
す。Comparative Test Example 1 Distearoyl phosphatidylethanolamine (hereinafter referred to as PEG1-DSPE) of the formula (13) modified with a single-chain polyethylene glycol in place of the compound (12) used in the test example 1 )), Except that 5 g was used. FIG. 6 shows the result.
【００５５】[0055]
【化１４】 Embedded image
【００５６】比較試験例２ 試験例１で調整された薬物含有脂肪乳剤とＰＥＧ２−Ｄ
ＳＰＥを用いず、卵黄レシチン（ＹＰＬ）１２ｇを用い
たこと以外は試験例１と同様に行った。その結果を図６
に示す。図６よりＤＰＡＬの血しょう中レベルは、ＰＥ
Ｇ２−ＤＳＰＥ＞ＰＥＧ１−ＤＳＰＥ＞ＹＰＬの順に高
い値を維持する結果が得られた。Comparative Test Example 2 The drug-containing fat emulsion prepared in Test Example 1 and PEG2-D
The test was performed in the same manner as in Test Example 1 except that 12 g of yolk lecithin (YPL) was used without using SPE. The result is shown in FIG.
Shown in According to FIG. 6, the plasma level of DPAL is PE
The result of maintaining a high value in the order of G2-DSPE>PEG1-DSPE> YPL was obtained.
【００５７】[0057]
【発明の効果】本発明の化合物はグリセリンのα、β位
にポリオキシアルキレン鎖を持ち、γ位にアミノ基を持
つ化合物であり、末端にアミノ基を有することにより、
ドラッグデリバリーシステムの一環を担う、脂肪乳剤お
よびリポソームの成分であるリン脂質と容易に反応する
ことができる。また、本発明の化合物はリン脂質に修飾
を行うことにより、内包したアドレアマイシン、シスプ
ラチンなど制癌剤の免疫原生の向上、安定化のみなら
ず、血中滞留時間の延長効果が発揮でき、毒性も少な
く、さらに副生物の生成が少ない。The compound of the present invention has a polyoxyalkylene chain at the α and β positions of glycerin and has an amino group at the γ position, and has a terminal amino group.
It can easily react with phospholipids, which are components of fat emulsions and liposomes, which are part of the drug delivery system. In addition, the compound of the present invention, by modifying the phospholipid, can improve the immunogenicity of anticancer drugs such as adreamycin and cisplatin, and stabilize the drug. And the generation of by-products is low.
【図１】製造例１で得た化合物の赤外吸収スペクトルを
示す。FIG. 1 shows an infrared absorption spectrum of the compound obtained in Production Example 1.
【図２】製造例１で得た化合物のＧＰＣの微分積分分子
量分布曲線を示す。2 shows a GPC differential integral molecular weight distribution curve of the compound obtained in Production Example 1. FIG.
【図３】製造例２で得た化合物のＧＰＣの微分積分分子
量分布曲線を示す。FIG. 3 shows a GPC differential integral molecular weight distribution curve of the compound obtained in Production Example 2.
【図４】製造例３で得た化合物のＧＰＣの微分積分分子
量分布曲線を示す。FIG. 4 shows a GPC differential integral molecular weight distribution curve of the compound obtained in Production Example 3.
【図５】実施例１で得た化合物の赤外吸収スペクトルを
示す。FIG. 5 shows an infrared absorption spectrum of the compound obtained in Example 1.
【図６】試験例１、比較試験例１および２で得た血しょ
う中のＤＰＡＬレベルの評価結果を示す。FIG. 6 shows the evaluation results of DPAL levels in plasma obtained in Test Example 1 and Comparative Test Examples 1 and 2.
Claims (1)
シアルキレン化合物。 【化１】 （ただし、Ｒ1は水素原子、炭素数１〜２４の炭化水素
基または炭素数１〜２４のアシル基、Ｒ2は炭素数３〜
４の炭化水素基、Ｒ3は炭素数１〜１０の炭化水素基、
ＡＯは炭素数３〜４のオキシアルキレン基、ｎはオキシ
エチレン基の平均付加モル数で１〜１０００、ｍは炭素
数３〜４のオキシアルキレン基の平均付加モル数、ｎ／
（ｎ＋ｍ）は０．８以上、オキシエチレン基と炭素数３
〜４のオキシアルキレン基の付加状態はブロック状また
はランダム状でもよい。）1. An amino group-containing polyoxyalkylene compound represented by the formula (1). Embedded image (However, R 1 is a hydrogen atom, a hydrocarbon group having 1 to 24 carbon atoms or an acyl group having 1 to 24 carbon atoms, and R 2 is a carbon atom having 3 to 24 carbon atoms.
A hydrocarbon group of 4, R 3 is a hydrocarbon group having 1 to 10 carbon atoms,
AO is an oxyalkylene group having 3 to 4 carbon atoms, n is an average addition mole number of the oxyethylene group of 1 to 1000, m is an average addition mole number of the oxyalkylene group having 3 to 4 carbon atoms, n /
(N + m) is 0.8 or more, oxyethylene group and carbon number 3
The addition state of the oxyalkylene groups of Nos. To 4 may be block-like or random. )
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|---|---|---|---|
| JP16692898A JP4055250B2 (en) | 1998-06-15 | 1998-06-15 | Amino group-containing polyoxyalkylene compounds |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16692898A JP4055250B2 (en) | 1998-06-15 | 1998-06-15 | Amino group-containing polyoxyalkylene compounds |
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| Publication Number | Publication Date |
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| JP2000001541A true JP2000001541A (en) | 2000-01-07 |
| JP4055250B2 JP4055250B2 (en) | 2008-03-05 |
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ID=15840266
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| JP16692898A Expired - Lifetime JP4055250B2 (en) | 1998-06-15 | 1998-06-15 | Amino group-containing polyoxyalkylene compounds |
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