JPH05117385A - Production of block copolymer, block copolymer and water-soluble polymeric carcinostatic agent - Google Patents
Production of block copolymer, block copolymer and water-soluble polymeric carcinostatic agentInfo
- Publication number
- JPH05117385A JPH05117385A JP3313807A JP31380791A JPH05117385A JP H05117385 A JPH05117385 A JP H05117385A JP 3313807 A JP3313807 A JP 3313807A JP 31380791 A JP31380791 A JP 31380791A JP H05117385 A JPH05117385 A JP H05117385A
- Authority
- JP
- Japan
- Prior art keywords
- block copolymer
- group
- poly
- water
- acid
- 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.)
- Pending
Links
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
Description
【０００１】[0001]
【産業上の利用分野】本発明は、ブロック共重合体の製
造法、ブロック共重合体及び水溶性高分子抗癌剤に関す
る。TECHNICAL FIELD The present invention relates to a method for producing a block copolymer, a block copolymer and a water-soluble polymer anticancer agent.
【０００２】[0002]
【従来の技術】親水性高分子構造部分とポリ−α−アミ
ノ酸構造部分を有するブロック共重合体及びこれに抗癌
性物質を結合せしめた水溶性高分子抗癌剤は、特開平２
−３００１３３号公報に記載されている。2. Description of the Related Art A block copolymer having a hydrophilic polymer structure portion and a poly-.alpha.-amino acid structure portion and a water-soluble polymer anticancer agent in which an anticancer substance is bound to the block copolymer are disclosed in Japanese Patent Application Laid-Open No. HEI 2-596.
No. 3001333.
【０００３】[0003]
【発明が解決しようとする課題】特開平２−３００１３
３号公報の実施例に記載された方法により得られるポリ
エチレングリコール−ポリアスパラギン酸ブロック共重
合体を用いて得られる水溶性高分子抗癌剤は、優れた抗
癌活性を示すが、より一層の抗癌活性の向上が望まれ
る。DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The water-soluble polymer anticancer agent obtained by using the polyethylene glycol-polyaspartic acid block copolymer obtained by the method described in the Example of JP-A No. 3 shows excellent anticancer activity, but further anticancer activity. Improvement of activity is desired.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、前記水溶
性高分子抗癌剤の抗癌活性を改良するためにその製造法
及び構造について鋭意検討した結果本発明を完成した。
即ち、本発明は、（１）親水性高分子構造部分と、カル
ボキシル基が保護基で保護されている光学活性なポリ−
α−アミノ酸構造部分とを有するブロック共重合体か
ら、保護基を酸を用いて除去することを特徴とする、親
水性高分子構造部分と、光学活性なポリ−α−アミノ酸
構造部分とを有するブロック共重合体の製造法，（２）
親水性高分子構造部分がポリエチレングリコール構造を
有する、上記（１）記載のブロック共重合体の製造法，
（３）ポリ−α−アミノ酸がポリ−α−アスパラギン酸
又はポリ−α−グルタミン酸である、上記（１）又は
（２）記載のブロック共重合体の製造法，（４）エステ
ル構造の形でカルボキシル基が保護基で保護されてい
る、上記（１），（２）又は（３）記載のブロック共重
合体の製造法，（５）親水性高分子構造部分と、光学活
性なポリ−α−アスパラギン酸構造部分とを有するブロ
ック共重合体，（６）式（１）で表される上記（５）記
載のブロック共重合体，[Means for Solving the Problems] The present inventors have completed the present invention as a result of extensive studies on the production method and structure of the water-soluble polymer anticancer agent in order to improve its anticancer activity.
That is, the present invention provides (1) an optically active poly-polymer having a hydrophilic polymer structural portion and a carboxyl group protected by a protective group.
A hydrophilic polymer structural part and an optically active poly-α-amino acid structural part, characterized in that a protecting group is removed from the block copolymer having an α-amino acid structural part with an acid. Process for producing block copolymer, (2)
The method for producing a block copolymer as described in (1) above, wherein the hydrophilic polymer structure portion has a polyethylene glycol structure,
(3) The method for producing a block copolymer according to (1) or (2) above, wherein the poly-α-amino acid is poly-α-aspartic acid or poly-α-glutamic acid, and (4) in the form of an ester structure. The method for producing a block copolymer according to the above (1), (2) or (3), wherein the carboxyl group is protected by a protective group, (5) a hydrophilic polymer structural portion, and an optically active poly-α. A block copolymer having an aspartic acid structure moiety, (6) the block copolymer according to the above (5) represented by the formula (1),
【０００５】[0005]
【化２】 （式中、Ｒ1 は低級アルキル基を表し、Ｒ2 は結合基を
表し、ｎは５〜１，０００、ｍは１〜３００の整数を示
す。） （７）Ｒ1 がメチル基である上記（６）記載のブロック
共重合体，（８）Ｒ2 が炭素数２〜４のアルキレン基で
ある上記（６）又は（７）記載のブロック共重合体，
（９）上記（５），（６），（７）又は（８）のブロッ
ク共重合体のポリ−α−アスパラギン酸構造部分の側鎖
に抗癌性物質を結合せしめた水溶性高分子抗癌剤，（１
０）抗癌性物質がアドリアマイシンである上記（９）の
水溶性高分子抗癌剤，（１１）抗癌性物質を結合せしめ
た光学活性なポリ−α−アスパラギン酸構造部分を内側
に、親水性高分子構造部分を外側とするミセルを形成す
るものである 上記（９）又は（１０）に記載の水溶性高分子抗癌剤，
に関する。[Chemical 2] (In the formula, R 1 represents a lower alkyl group, R 2 represents a bonding group, n represents an integer of 5 to 1,000, and m represents an integer of 1 to 300.) (7) R 1 is a methyl group The block copolymer according to (6) above, (8) the block copolymer according to (6) or (7) above, wherein R 2 is an alkylene group having 2 to 4 carbon atoms,
(9) A water-soluble polymer anticancer agent in which an anticancer substance is bound to the side chain of the poly-α-aspartic acid structural portion of the block copolymer of (5), (6), (7) or (8) above. , (1
0) The water-soluble polymer anticancer agent according to the above (9), wherein the anticancer substance is adriamycin, and (11) the optically active poly-α-aspartic acid structure part to which the anticancer substance is bound, the inside of which is highly hydrophilic. A water-soluble polymer anticancer agent according to the above (9) or (10), which forms a micelle having a molecular structure portion on the outside.
Regarding
【０００６】本発明によれば、特開平２−３００１３３
号公報の実施例に記載された方法により得られるポリエ
チレングリコール−ポリアスパラギン酸ブロック共重合
体に比べ、共重合体主鎖のβ−転位がなく、化学構造的
に均一なα−構造を持つ共重合体が得られ、これに抗癌
性物質を結合させた水溶性高分子抗癌剤は、特開平２−
３００１３３号公報の実施例のものより抗癌活性が優れ
ている。According to the present invention, Japanese Patent Laid-Open No. 2-310033
Compared with the polyethylene glycol-polyaspartic acid block copolymer obtained by the method described in the Examples of the publication, a copolymer having a β-rearrangement in the main chain of the copolymer and a chemically structurally uniform α-structure is obtained. A water-soluble polymer anticancer agent obtained by obtaining a polymer and binding an anticancer substance thereto is disclosed in JP-A-2-
The anticancer activity is superior to that of the example of 300133.
【０００７】以下、本発明について詳細に説明する。The present invention will be described in detail below.
【０００８】親水性高分子構造部分の構造としては、例
えばポリエチレングリコール、ポリサッカライド、ポリ
アクリルアミド、ポリメタクリルアミド、ポリアミノ
酸、ポリアクリル酸、ポリメタクリル酸、ポリビニルア
ルコール、ポリビニルピロリドン、キトサン等の構造が
挙げられるが、親水性高分子構造であれば特に限定され
ない。特に好ましい構造は、ポリエチレングリコール構
造である。Examples of the structure of the hydrophilic polymer structural part include structures such as polyethylene glycol, polysaccharide, polyacrylamide, polymethacrylamide, polyamino acid, polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone and chitosan. However, it is not particularly limited as long as it has a hydrophilic polymer structure. A particularly preferred structure is a polyethylene glycol structure.
【０００９】ポリ−α−アミノ酸構造部分の構造として
は特に限定されず、例えばポリ−α−アスパラギン酸、
ポリ−α−グルタミン酸等の構造が挙げられる。The structure of the poly-α-amino acid structural portion is not particularly limited. For example, poly-α-aspartic acid,
Examples thereof include structures such as poly-α-glutamic acid.
【００１０】ポリ−α−アミノ酸構造部分のカルボキシ
ル基の保護基としては特に限定されないが、通常、該カ
ルボキシル基が保護基で保護されたことにより−ＣＯＯ
Ｒ3 （Ｒ3 ：保護基）で示されるエステル構造をとるよ
うな保護基が挙げられ、この保護基（Ｒ3 ）としては、
例えば、メチル基、エチル基、第３ブチル基、フェナシ
ル基、トリクロロエチル基、ベンジル基、ｐ−ニトロベ
ンジル基やｐ−メトキシベンジル基等の置換ベンジル
基、ジフェニルメチル基、ベンズヒドリル基、シクロヘ
キシル基等、種々のものが挙げられる。好ましくは第３
ブチル基、ベンジル基、ｐ−メトキシベンジル基等であ
る。The protecting group for the carboxyl group of the poly-α-amino acid structural portion is not particularly limited, but usually, -COO is obtained by protecting the carboxyl group with a protecting group.
Examples of the protecting group having an ester structure represented by R 3 (R 3 : protecting group) include the protecting group (R 3 ).
For example, methyl group, ethyl group, tert-butyl group, phenacyl group, trichloroethyl group, benzyl group, substituted benzyl group such as p-nitrobenzyl group and p-methoxybenzyl group, diphenylmethyl group, benzhydryl group, cyclohexyl group, etc. , Various things are mentioned. Preferably third
A butyl group, a benzyl group, a p-methoxybenzyl group and the like.
【００１１】保護基を有するブロック共重合体は、無溶
媒で、又は例えばジオキサン等の通常の有機溶媒に溶解
し、これに酸を加えて反応させることにより、保護基を
除去する。The block copolymer having a protecting group is removed without a solvent or by dissolving it in an ordinary organic solvent such as dioxane, and adding an acid to the solution to react it.
【００１２】酸としては、トリフルオロメタンスルホン
酸、メタンスルホン酸、トリフルオロ酢酸、酢酸、ギ
酸、フッ化水素酸、臭化水素酸、塩化水素酸等の通常の
酸性物質を用いることができる。酸は、保護基を有する
ブロック共重合体に対して、０．１〜１００重量倍用い
るのが好ましく、特に０．５〜１０重量倍用いるのが好
ましい。As the acid, a usual acidic substance such as trifluoromethane sulfonic acid, methane sulfonic acid, trifluoroacetic acid, acetic acid, formic acid, hydrofluoric acid, hydrobromic acid, and hydrochloric acid can be used. The acid is preferably used in an amount of 0.1 to 100 times by weight, and particularly preferably 0.5 to 10 times by weight, of the block copolymer having a protective group.
【００１３】また、副反応を防止するため、アニソー
ル、チオアニソール、ｍ−クレゾール、ｏ−クレゾール
等を、使用する酸に対し、好ましくは０．１〜１０モル
％加えることもできる。In order to prevent side reactions, anisole, thioanisole, m-cresol, o-cresol and the like can be added to the acid used, preferably in an amount of 0.1 to 10 mol%.
【００１４】保護基を酸を用いて除去する際の反応温度
は、好ましくは−２０〜５０℃であり、特に好ましくは
０〜２０℃である。また、反応は０．５〜４時間行えば
充分である。The reaction temperature for removing the protecting group with an acid is preferably -20 to 50 ° C, particularly preferably 0 to 20 ° C. Further, it is sufficient to carry out the reaction for 0.5 to 4 hours.
【００１５】このようにして保護基を除去して得られ
た、親水性高分子構造部分と光学活性なポリ−α−アミ
ノ酸構造部分とを有するブロック共重合体において、親
水性高分子構造部分と光学活性なポリ−α−アミノ酸構
造部分の割合は、好ましくは１：０．１〜１０（重量
比）、特に好ましくは１：０．２〜５（重量比）であ
る。また、ブロック共重合体の好ましい平均分子量は
５，０００〜５０，０００であり、このブロック共重合
体は薬物担持用担体として用いることができ、この薬物
担持用担体に、抗癌性物質を反応させて結合することに
より水溶性高分子抗癌剤が得られる。In the block copolymer having the hydrophilic polymer structural portion and the optically active poly-α-amino acid structural portion obtained by removing the protective group in this manner, the hydrophilic polymer structural portion The ratio of the optically active poly-α-amino acid structural portion is preferably 1: 0.1 to 10 (weight ratio), particularly preferably 1: 0.2 to 5 (weight ratio). The block copolymer preferably has an average molecular weight of 5,000 to 50,000, and the block copolymer can be used as a carrier for supporting a drug. An anticancer substance is reacted with the carrier for supporting a drug. A water-soluble polymer anti-cancer agent can be obtained by binding them.
【００１６】なお、本発明の方法で原料として用いる保
護基を有するブロック共重合体は、公知の方法により得
ることができる。例えば、親水性高分子構造部分を構成
することになる化合物（例えば、ポリエチレングリコー
ル、ポリサッカライド、ポリアクリルアミド、ポリメタ
クリルアミド、ポリアミノ酸、ポリアクリル酸、ポリメ
タクリル酸、ポリビニルアルコール、ポリビニルピロリ
ドン、キトサンあるいはこれらの誘導体）もしくはその
末端を変性したものに、光学活性なポリ−α−アミノ酸
のカルボキシル基が保護基で保護されているアミノ酸誘
導体を反応させるか、又は親水性高分子構造部分を構成
することになる化合物もしくはその末端を変性したもの
と光学活性なα−アミノ酸の一方のカルボキシル基を保
護基で保護したモノマーを反応させることにより得られ
る。The block copolymer having a protective group used as a raw material in the method of the present invention can be obtained by a known method. For example, a compound (for example, polyethylene glycol, polysaccharide, polyacrylamide, polymethacrylamide, polyamino acid, polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polyvinylpyrrolidone, chitosan, or the like which constitutes the hydrophilic polymer structural portion. These derivatives) or those with modified ends thereof are reacted with an amino acid derivative in which the carboxyl group of the optically active poly-α-amino acid is protected by a protecting group, or a hydrophilic polymer structural part is constituted. Can be obtained by reacting a compound having a carboxyl group of one of the optically active α-amino acids with a protecting group, or a compound having the terminal modified.
【００１７】親水性高分子構造部分を構成することにな
る化合物の末端の変性は公知の方法によって行うことが
でき、例えば、水酸基をアミノ基に変換する方法として
エチレンイミン等を反応させる方法、アクリロニトリル
やメタクリロニトリル等にマイケル付加後ニトリル基を
還元しアミノ基に変換する方法、水酸基をハロゲン基に
置換した後エタノールアミン等のアルコールアミンを反
応する方法、水酸基を直接ニトリル基に変換後還元しア
ミノ基に変換する方法等で行うことができる。前記
（５）〜（８）に記載のブロック共重合体は、α−アミ
ノ酸としてアスパラギン酸を用い、前記の方法に従って
反応を行うことにより得ることができる。前記式（１）
において、Ｒ2 は、本発明の水溶性高分子抗癌剤の水溶
性を損なわない限り（好ましくは、更に本発明の水溶性
高分子抗癌剤のミセル形成能を損なわない限り）、特に
限定されず、親水性高分子構造部分の末端にポリ−α−
アスパラギン酸構造部分を形成させる際、親水性高分子
構造部分を構成することになる化合物の末端を該形成に
適した構造に変換させるために使用した方法及び化合物
に対応した構造をとり、例えばエチレン基（−ＣＨ2Ｃ
Ｈ2 −）、プロピレン基（−ＣＨ（ＣＨ3 ）ＣＨ
2 −）、トリメチレン基（−ＣＨ2 ＣＨ2 ＣＨ2 −）、
ブチレン基（−ＣＨ2 ＣＨ（ＣＨ3 ）ＣＨ2 −等）等の
炭素数２〜８、好ましくは炭素数２〜４のアルキレン基
等が挙げられるが特に限定されない。The modification of the terminal of the compound that constitutes the hydrophilic polymer structural portion can be carried out by a known method. For example, as a method of converting a hydroxyl group into an amino group, a method of reacting ethyleneimine or the like, acrylonitrile. Method of converting nitrile group to amino group after Michael addition to or methacrylonitrile, etc., method of reacting alcohol amine such as ethanolamine after replacing hydroxyl group with halogen group, directly converting hydroxyl group to nitrile group and reducing It can be performed by a method of converting to an amino group. The block copolymers described in (5) to (8) above can be obtained by using aspartic acid as an α-amino acid and performing a reaction according to the above method. Formula (1)
In the above, R 2 is not particularly limited as long as it does not impair the water solubility of the water-soluble polymeric anti-cancer agent of the present invention (preferably, unless it further impairs the micelle forming ability of the water-soluble polymeric anti-cancer agent of the present invention). Of poly-α-
When forming the aspartic acid structural portion, the method used for converting the terminal of the compound that will constitute the hydrophilic polymer structural portion into a structure suitable for the formation and the structure corresponding to the compound are taken, and, for example, ethylene based on (-CH 2 C
H 2 -), propylene group (-CH (CH 3) CH
2 -), trimethylene (-CH 2 CH 2 CH 2 -),
Butylene (-CH 2 CH (CH 3) CH 2 - , etc.) carbon atoms, such as 2-8, preferably is not particularly limited but include such as an alkylene group having 2 to 4 carbon atoms.
【００１８】前記（５）〜（８）において、親水性高分
子構造部分と光学活性なポリ−α−アスパラギン酸構造
部分の割合は、好ましくは１：０．１〜１０（重量
比）、より好ましくは１：０．２〜５（重量比）であ
り、又、前記（５）〜（８）のブロック共重合体の好ま
しい平均分子量は、５，０００〜５０，０００である。In the above (5) to (8), the ratio of the hydrophilic polymer structural portion to the optically active poly-α-aspartic acid structural portion is preferably 1: 0.1 to 10 (weight ratio), It is preferably 1: 0.2 to 5 (weight ratio), and the preferable average molecular weight of the block copolymers (5) to (8) is 5,000 to 50,000.
【００１９】前記（１）〜（４）で得られるブロック共
重合体又は、前記（４）〜（８）のブロック共重合体の
光学活性なポリ−α−アミノ酸構造部分の側鎖に抗癌性
物質を結合させることにより水溶性高分子抗癌剤が得ら
れる。光学活性なポリ−α−アミノ酸構造部分に結合さ
せる抗癌性物質としては、アドリアマイシン、ダウノマ
イシン、ピノルビン、メトトレキセート、マイトマイシ
ンＣ、エトポシド、シスプラチン等の抗癌性物質及びそ
の誘導体が挙げられるがこれらに限定されるものではな
い。例えば、前記式（１）のブロック共重合体にアドリ
アマイシンを反応させて得られる水溶性高分子抗癌剤
は、式（２）The side chains of the optically active poly-α-amino acid structural portion of the block copolymers obtained in the above (1) to (4) or the block copolymers in the above (4) to (8) are anticancer. A water-soluble polymeric anticancer agent can be obtained by binding a volatile substance. Examples of the anticancer substance bound to the optically active poly-α-amino acid structural moiety include, but are not limited to, anticancer substances such as adriamycin, daunomycin, pinorbin, methotrexate, mitomycin C, etoposide, cisplatin and derivatives thereof. It is not something that will be done. For example, a water-soluble polymer anticancer agent obtained by reacting the block copolymer of the formula (1) with adriamycin has the formula (2)
【００２０】[0020]
【化３】 （式中、Ｒ1 ，Ｒ2 ，ｎ，ｍは前記と同じ意味を有し、
Ｒ3 はそれぞれ独立して水酸基又は式（３）[Chemical 3] (In the formula, R 1 , R 2 , n and m have the same meanings as described above,
R 3 is independently a hydroxyl group or formula (3)
【００２１】[0021]
【化４】 を示すが、Ｒ3 の少なくとも１つは式（３）を示す。）
で表される構造を有する。[Chemical 4] Where at least one of R 3 represents formula (3). )
It has a structure represented by.
【００２２】本発明の水溶性高分子抗癌剤は、水溶性で
ある限りその分子量は特に限定されないが、好ましくは
１，０００〜１００，０００、特に好ましくは５，００
０〜５０，０００である。The molecular weight of the water-soluble polymeric anticancer agent of the present invention is not particularly limited as long as it is water-soluble, but it is preferably 1,000 to 100,000, particularly preferably 5,000.
It is 0 to 50,000.
【００２３】本発明の水溶性高分子抗癌剤中の、親水性
高分子構造部分と側鎖に抗癌性物質を結合せしめた光学
活性なポリ−α−アミノ酸（例えばポリ−α−アスパラ
ギン酸）構造部分の割合は本発明の高分子抗癌剤の水溶
性が保たれる限り特に限定されないが、好ましくは１：
０．１〜１０（重量比）、特に好ましくは１：０．２〜
５（重量比）である。前記式（１）及び式（２）におい
て、Ｒ1 はメチル基、エチル基、プロピル基、ブチル基
等の低級アルキル基を表すが、好ましいものはメチル基
である。また、ｎは５〜１，０００であるが、好ましく
は１５〜２５０であり、ｍは１〜３００であるが、好ま
しくは１０〜１００である。Optically active poly-α-amino acid (for example, poly-α-aspartic acid) structure in which an anticancer substance is bound to the hydrophilic polymer structure part and the side chain in the water-soluble polymer anticancer drug of the present invention. The proportion of the moiety is not particularly limited as long as the water solubility of the polymeric anticancer agent of the present invention is maintained, but it is preferably 1:
0.1-10 (weight ratio), particularly preferably 1: 0.2-
5 (weight ratio). In the above formulas (1) and (2), R 1 represents a lower alkyl group such as a methyl group, an ethyl group, a propyl group and a butyl group, and a methyl group is preferable. Further, n is 5 to 1,000, preferably 15 to 250, and m is 1 to 300, preferably 10 to 100.
【００２４】本発明において、光学活性なポリ−α−ア
ミノ酸構造の側鎖に結合させる抗癌性物質の量は特に限
定されず、任意の結合量とすることが可能であるが、本
発明の水溶性高分子抗癌剤中に含まれる上記側鎖に結合
した抗癌性物質の量は、通常３〜８０重量％であり、好
ましくは５〜６０重量％である。しかしながら、本発明
の高分子抗癌剤の水溶性が損なわれない限り、可能な限
り多く結合させることになんら問題はない。In the present invention, the amount of the anticancer substance bound to the side chain of the optically active poly-α-amino acid structure is not particularly limited, and it can be set to any binding amount. The amount of the anticancer substance bound to the side chain contained in the water-soluble polymer anticancer agent is usually 3 to 80% by weight, preferably 5 to 60% by weight. However, there is no problem in binding as many as possible unless the water solubility of the polymeric anticancer agent of the present invention is impaired.
【００２５】本発明の水溶性高分子抗癌剤は種々の方法
により製造することができる。例えば、ペプチド結合生
成法として知られている公知の常法に準じて行うことが
でき、酸塩化物法、酸無水物法、カップリング法等が使
用できるが、縮合剤を使用するカップリング法が望まし
い。ここで使用する縮合剤としては、１−エチル−３−
（３−ジメチルアミノプロピル）カルボジイミド（ＥＤ
Ｃ）、１−エチル−３−（３−ジメチルアミノプロピ
ル）カルボジイミド塩酸塩（ＥＤＣ．ＨＣＩ）、ジシク
ロヘキシルカルボジイミド（ＤＣＣ）、カルボニルジイ
ミダゾール（ＣＤＩ！％１−エトキシカルボニル−２−
エトキシ−１，２−ジヒドロキシキノリン（ＥＥＤ
Ｑ）、ジフェニルホスホリルアジド（ＤＰＰＡ）等が使
用できる。この際、Ｎ−ヒドロキシサクシンイミド（Ｈ
ＯＮＳｕ）、１−ヒドロキシベンゾトリアゾール（ＨＯ
Ｂｔ）、Ｎ−ヒドロキシ−５−ノルボルネン−２，３−
ジカルボン酸イミド（ＨＯＮＢ）等を共存させてもよ
い。The water-soluble polymer anticancer agent of the present invention can be produced by various methods. For example, it can be carried out according to a known ordinary method known as a peptide bond forming method, and an acid chloride method, an acid anhydride method, a coupling method and the like can be used, but a coupling method using a condensing agent Is desirable. The condensing agent used here is 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide (ED
C), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCI), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI!% 1-ethoxycarbonyl-2-
Ethoxy-1,2-dihydroxyquinoline (EED
Q), diphenylphosphoryl azide (DPPA) and the like can be used. At this time, N-hydroxysuccinimide (H
ONSu), 1-hydroxybenzotriazole (HO
Bt), N-hydroxy-5-norbornene-2,3-
You may make dicarboxylic acid imide (HONB) etc. coexist.
【００２６】以下に、ポリエチレングリコール誘導体由
来の親水性高分子構造部分と光学活性なポリ−α−アス
パラギン酸構造部分とからなるブロック共重合体で、ア
ドリアマイシンを光学活性なポリ−α−アスパラギン酸
の側鎖に結合させた高分子抗癌剤の場合を例にとり、本
発明をさらに詳細に説明する。The following is a block copolymer consisting of a hydrophilic polymer structural part derived from a polyethylene glycol derivative and an optically active poly-α-aspartic acid structural part. Adriamycin was converted into an optically active poly-α-aspartic acid. The present invention will be described in more detail by taking the case of a polymeric anticancer drug bound to a side chain as an example.
【００２７】この水溶性高分子抗癌剤の合成は、以下の
反応式に示すごとく行うことができる。即ち、β−ベン
ジル−Ｌ−アスパルテート−Ｎ−カルボン酸無水物（Ｂ
ＬＡ−ＮＣＡ）を、片末端にメトキシ基等のアルコキシ
基を有し、他の片末端に１級アミノ基を有するメトキシ
ポリエチレングリコール（ＰＥＧ−ＮＨ2 ）（好ましく
は分子量２５０〜２０，０００）を開始剤として、ジメ
チルホルムアミド、ジメチルスルホキシド、クロロホル
ム、ジクロロメタン、テトラヒドロフラン、アセトニト
リル、ジオキサン等の溶媒中で開環重合させ、ポリエチ
レングリコール−ポリ（β−ベンジル−Ｌ−アスパルテ
ート）ブロック共重合体（ＰＥＧ−ＰＢＬＡ）を得、次
いでこのＰＥＧ−ＰＢＬＡのベンジルエステルをトリフ
ルオロ酢酸等の溶媒中でトリフルオロメタンスルホン酸
等の酸を用いて加水分解して本発明のブロック共重合体
（薬物担持用担体）である光学活性ポリエチレングリコ
ール−ポリ−α−アスパラギン酸ブロック共重合体（Ｐ
ＥＧ−Ｐ（Ａｓｐ．））を得る。ここで得られた共重合
体は、アルカリ加水分解を行った場合にみられるポリア
スパラギン酸主鎖のβ転位は全くみられず、転位の無い
α体のポリアスパラギン酸共重合体であることがＮＭＲ
分析で確認された。このＰＥＧ−Ｐ（Ａｓｐ．）に抗癌
性物質のアドリアマイシン塩酸塩と縮合剤を加え、アド
リアマイシンの１級アミノ基とポリアスパラギン酸の側
鎖カルボキシル基とをアミド結合で結合させて、水溶性
高分子抗癌剤（ＰＥＧ−Ｐ（Ａｓｐ．）ＡＤＲ）を得
る。The water-soluble polymeric anticancer agent can be synthesized as shown in the following reaction formula. That is, β-benzyl-L-aspartate-N-carboxylic acid anhydride (B
LA-NCA) has methoxy polyethylene glycol (PEG-NH 2 ) (preferably a molecular weight of 250 to 20,000) having an alkoxy group such as a methoxy group at one end and a primary amino group at the other end. As an initiator, ring-opening polymerization is performed in a solvent such as dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, dioxane, and a polyethylene glycol-poly (β-benzyl-L-aspartate) block copolymer (PEG- PBLA), and then the benzyl ester of PEG-PBLA is hydrolyzed with an acid such as trifluoromethanesulfonic acid in a solvent such as trifluoroacetic acid to obtain the block copolymer (carrier for supporting a drug) of the present invention. An optically active polyethylene glycol-poly-α-a Sparagic acid block copolymer (P
EG-P (Asp.)) Is obtained. The copolymer obtained here has no β-rearrangement of the polyaspartic acid main chain observed when alkaline hydrolysis is performed, and it is an α-form polyaspartic acid copolymer without rearrangement. NMR
Confirmed by analysis. An anticancer substance, adriamycin hydrochloride and a condensing agent are added to this PEG-P (Asp.) To bond the primary amino group of adriamycin and the side chain carboxyl group of polyaspartic acid with an amide bond to form a highly water-soluble substance. A molecular anti-cancer drug (PEG-P (Asp.) ADR) is obtained.
【００２８】[0028]
【化５】 （式中、Ｒ3 はそれぞれ独立して水酸基あるいは[Chemical 5] (In the formula, R 3 is independently a hydroxyl group or
【００２９】[0029]
【化６】 を表し、ｎは５〜１，０００、ｍは１〜３００の整数を
示すが、Ｒ3 の少なくとも１つは、式（３）を表すもの
とする。） 本発明の水溶性高分子抗癌剤は高いアドリアマイシン置
換率（ポリアスパラギン酸のカルボキシル基の数のうち
のアドリアマイシンが結合したカルボキシル基の割合）
にもかかわらず良好な水溶性を有しており、凍結乾燥し
たり濃縮してもその水溶性は保たれている。[Chemical 6] And n is an integer of 5 to 1,000 and m is an integer of 1 to 300, and at least one of R 3 is represented by the formula (3). ) The water-soluble polymeric anticancer agent of the present invention has a high adriamycin substitution rate (ratio of carboxyl groups to which adriamycin is bound in the number of carboxyl groups of polyaspartic acid).
Nevertheless, it has good water-solubility and retains its water-solubility even when freeze-dried or concentrated.
【００３０】本発明の水溶性高分子抗癌剤の抗癌活性
は、表１に示すように元のアドリアマイシン塩酸塩自体
よりも高いものである。しかもその高い抗癌活性はアド
リアマイシンよりも少ない副作用の範囲で達成される。
本発明の水溶性高分子抗癌剤は、一般的に使用される種
々の剤型、例えば固形剤、軟膏、液剤等の形で使用しう
るが、通常注射剤として使用され、その投与量は、１週
間当り１〜３回投与で、総量１００〜１，０００mg／ｍ
2 ／週程度である。The anticancer activity of the water-soluble polymeric anticancer agent of the present invention is higher than that of the original adriamycin hydrochloride itself, as shown in Table 1. Moreover, its high anticancer activity is achieved in the range of fewer side effects than adriamycin.
The water-soluble polymer anticancer agent of the present invention can be used in various commonly used dosage forms, for example, solid dosage forms, ointments, liquid dosage forms, etc., but it is usually used as an injection, and its dose is 1 Administered 1 to 3 times a week, total dose 100 to 1,000 mg / m
It is about 2 / week.
【００３１】[0031]
【実施例】次に合成例、実施例、参考例により本発明を
具体的に説明する。EXAMPLES Next, the present invention will be specifically described with reference to Synthesis Examples, Examples and Reference Examples.
【００３２】合成例１ β−ベンジル−Ｌ−アスパルテート−Ｎ−カルボン酸無
水物（ＢＬＡ−ＮＣＡ）５．７ｇをＮ，Ｎ′−ジメチル
ホルムアミド（ＤＭＦ）２０mlに溶解した。片末端メト
キシ基、片末端３−アミノプロピル基のポリエチレング
リコール（ＰＥＧ−ＮＨ2 ）（分子量５，１００）をＤ
ＭＦ４０mlに溶解し、その溶液をＢＬＡ−ＮＣＡ溶液に
加えた。４０時間後に反応混合物をイソプロピルエーテ
ル２リットルに滴下して沈澱したポリマーを濾過で回収
し、イソプロピルエーテルで洗浄した後に真空乾燥して
ポリエチレングリコール−ポリ（β−ベンジル−Ｌ−ア
スパルテート）ブロック共重合体（ＰＥＧ−ＰＢＬＡ）
７．９９ｇ（収率９２．１％）を得た。Synthesis Example 1 5.7 g of β-benzyl-L-aspartate-N-carboxylic acid anhydride (BLA-NCA) was dissolved in 20 ml of N, N'-dimethylformamide (DMF). One end methoxy group, one end 3-aminopropyl group polyethylene glycol (PEG-NH 2 ) (molecular weight 5,100) D
It was dissolved in 40 ml of MF and the solution was added to the BLA-NCA solution. After 40 hours, the reaction mixture was added dropwise to 2 liters of isopropyl ether, and the precipitated polymer was collected by filtration, washed with isopropyl ether, and dried in vacuum, followed by polyethylene glycol-poly (β-benzyl-L-aspartate) block copolymerization. Combined (PEG-PBLA)
7.99 g (yield 92.1%) was obtained.
【００３３】合成例２ γ−ベンジル−Ｌ−グルタメート−Ｎ−カルボン酸無水
物（ＢＬＧ−ＮＣＡ）５．０ｇをＮ，Ｎ′−ジメチルホ
ルムアミド（ＤＭＦ）１０ml、クロロホルム４５mlに溶
解した。片末端メトキシ基、片末端３−アミノプロピル
基のポリエチレングリコール（分子量５，１００）をク
ロロホルム４５mlに溶解し、その溶液をＢＬＧ−ＮＣＡ
溶液に加えた。７０時間後に反応混合液をイソプロピル
エーテル２リットルに滴下して沈澱したポリマーを濾過
で回収し、イソプロピルエーテルで洗浄した後に真空乾
燥してポリエチレングリコール−ポリ（γ−ベンジル−
Ｌ−グルタメート）ブロック共重合体（ＰＥＧ−ＰＢＬ
Ｇ）８．９７ｇ（収率９８．０％）を得た。Synthesis Example 2 5.0 g of γ-benzyl-L-glutamate-N-carboxylic acid anhydride (BLG-NCA) was dissolved in 10 ml of N, N'-dimethylformamide (DMF) and 45 ml of chloroform. Polyethylene glycol (molecular weight 5,100) having a methoxy group at one end and a 3-aminopropyl group at one end was dissolved in 45 ml of chloroform, and the solution was BLG-NCA.
Added to the solution. After 70 hours, the reaction mixture was added dropwise to 2 liters of isopropyl ether, and the precipitated polymer was collected by filtration, washed with isopropyl ether, and vacuum dried to obtain polyethylene glycol-poly (γ-benzyl-).
L-glutamate) block copolymer (PEG-PBL
G) 8.97 g (yield 98.0%) was obtained.
【００３４】実施例１ 合成例１で得られたＰＥＧ−ＰＢＬＡ５．０ｇをトリフ
ルオロ酢酸７５mlに溶解し、チオアニソール１２．５m
l、ｍ−クレゾール１１．５ml、トリフルオロメタンス
ルホン酸９．５mlを加え、氷冷下３０分撹拌した。その
後反応混合液をイソプロピルエーテル１リットルに滴下
した。沈澱したポリマーを濾過で回収し、イソプロピル
エーテルで洗浄した後に真空乾燥してポリエチレングリ
コール−ポリ−Ｌ−アスパラギン酸ブロック共重合体
（ＰＥＧ−Ｐ（Ａｓｐ．））２．８２ｇを得た。このブ
ロック共重合体を重水中で 1Ｈ−ＮＭＲで解析したとこ
ろ、アルカリ加水分解を行った場合にみられるβ−転位
は全く認められず、α−体の共重合体であった。また水
中での比旋光度〔α〕は−１６．４°と光学活性体であ
った。得られた薬物担持用担体であるＰＥＧ−Ｐ（Ａｓ
ｐ．）は前記式（１）の構造を有し、Ｒ1 はメチル基、
Ｒ2 はトリメチレン基、ｎ＝１１５、ｍ＝１５である。Example 1 5.0 g of PEG-PBLA obtained in Synthesis Example 1 was dissolved in 75 ml of trifluoroacetic acid and 12.5 m of thioanisole was dissolved.
l, m-cresol 11.5 ml and trifluoromethanesulfonic acid 9.5 ml were added, and the mixture was stirred under ice cooling for 30 minutes. Then, the reaction mixture was added dropwise to 1 liter of isopropyl ether. The precipitated polymer was collected by filtration, washed with isopropyl ether and then vacuum dried to obtain 2.82 g of a polyethylene glycol-poly-L-aspartic acid block copolymer (PEG-P (Asp.)). When this block copolymer was analyzed by 1 H-NMR in heavy water, no β-rearrangement observed when alkali hydrolysis was carried out was found, and it was an α-form copolymer. The specific rotation [α] in water was -16.4 °, which was an optically active substance. The obtained drug-supporting carrier, PEG-P (As
p. ) Has the structure of the above formula (1), R 1 is a methyl group,
R 2 is a trimethylene group, n = 115 and m = 15.
【００３５】実施例２ 合成例２で得られたＰＥＧ−ＰＢＬＧ５．０ｇをトリフ
ルオロ酢酸２５mlに溶解し、アニソール５ml、メタンス
ルホン酸２５mlを加え、氷冷下６０分撹拌した。その後
反応混合液をイソプロピルエーテル１リットルに滴下し
た。沈澱したポリマーを濾過で回収し、イソプロピルエ
ーテルで洗浄した後に真空乾燥してポリエチレングリコ
ール−ポリ−Ｌ−グルタミン酸ブロック共重合体（ＰＥ
Ｇ−Ｐ（Ｇｌｕ．））３．１２ｇを得た。このブロック
共重合体を重水中で 1Ｈ−ＮＭＲで解析したところα−
体の共重合体であった。また０．２Ｍ ＮａＣｌ水溶液
中での比旋光度〔α〕はポリグルタミン酸組成算出で−
１００°（文献値−１０２°）と光学活性体であった。
得られた薬物担持用担体であるＰＥＧ−Ｐ（Ｇｌｕ．）
は前記式（１）の構造（但し、アミノ酸の側鎖部分は−
ＣＨ2 ＣＨ2 ＣＯＯＨである）を有し、Ｒ1 はメチル
基、Ｒ2 はトリメチレン基、ｎ＝１１５、ｍ＝２０であ
る。Example 2 5.0 g of PEG-PBLG obtained in Synthesis Example 2 was dissolved in 25 ml of trifluoroacetic acid, 5 ml of anisole and 25 ml of methanesulfonic acid were added, and the mixture was stirred for 60 minutes under ice cooling. Then, the reaction mixture was added dropwise to 1 liter of isopropyl ether. The precipitated polymer was collected by filtration, washed with isopropyl ether and then vacuum dried to obtain a polyethylene glycol-poly-L-glutamic acid block copolymer (PE
3.12 g of GP (Glu.)) Was obtained. When this block copolymer was analyzed by 1 H-NMR in heavy water, α-
It was a body copolymer. The specific optical rotation [α] in a 0.2 M NaCl aqueous solution was calculated by calculating the polyglutamic acid composition-
It was 100 ° (reference value −102 °) and was an optically active substance.
The obtained drug-supporting carrier, PEG-P (Glu.)
Is the structure of the above formula (1) (provided that the side chain portion of the amino acid is-
CH 2 CH 2 COOH), R 1 is a methyl group, R 2 is a trimethylene group, n = 115, and m = 20.
【００３６】実施例３ 実施例１で得られたＰＥＧ−Ｐ（Ａｓｐ．）１５７mgを
水に溶解した。アドリアマイシン塩酸塩３００mgをＤＭ
Ｆに懸濁し、氷冷下トリエチルアミン７２μｌを加えた
後ＰＥＧ−Ｐ（Ａｓｐ．）水溶液を加えた。この混合溶
液に１−エチル−３−（３−ジメチルアミノプロピル）
カルボジイミド（ＥＤＣ）１５０μｌを加え、氷冷下４
時間反応させた。その後ＥＤＣ１５０μｌを追加し室温
で１８時間反応させた。反応混合液を透析膜（分画分子
量＝１２，０００）を用いて０．１Ｍ酢酸ナトリウム緩
衝液（ｐＨ４．５）中で３時間透析した。透析後、ＡＤ
ＶＡＮＴＥＣ ＵＫ−５０（分画分子量＝５０，００
０）の限外濾過膜で限外濾過して、未反応のアドリアマ
イシンやその他の低分子物質を除いた。水洗と濃縮を繰
り返し、アドリアマイシン換算で２０mg／ml（紫外分光
光度計で４８５nmの吸収より算出）の水溶液１０．４ml
を得た。得られた水溶性高分子抗癌剤であるＰＥＧ−Ｐ
（Ａｓｐ．）ＡＤＲは前記式（２）の構造を有し、Ｒ1
はメチル基、Ｒ2 はトリメチレン基、ｎ＝１１５、ｍ＝
１５でＲの一部は水酸基で残りは前記残基（３）であ
る。アドリアマイシン結合量（含有率）は５６．５重量
％であるが良好な水溶性を示した。Example 3 157 mg of PEG-P (Asp.) Obtained in Example 1 was dissolved in water. Adriamycin hydrochloride 300mg DM
After suspending in F and adding 72 μl of triethylamine under ice cooling, an aqueous solution of PEG-P (Asp.) Was added. 1-Ethyl-3- (3-dimethylaminopropyl) was added to this mixed solution.
Add 150 μl of carbodiimide (EDC) and under ice cooling 4
Reacted for hours. After that, 150 μl of EDC was added and reacted at room temperature for 18 hours. The reaction mixture was dialyzed for 3 hours in 0.1 M sodium acetate buffer (pH 4.5) using a dialysis membrane (molecular weight cut-off = 12,000). After dialysis, AD
VANTEC UK-50 (molecular weight cut off = 50000)
Ultrafiltration was performed with the ultrafiltration membrane of 0) to remove unreacted adriamycin and other low molecular weight substances. Repeated washing with water and concentration, 10.4 ml of 20 mg / ml aqueous solution converted to adriamycin (calculated from UV absorption at 485 nm)
Got PEG-P, which is the obtained water-soluble polymer anticancer agent
(Asp.) ADR has the structure of the above formula (2) and R 1
Is a methyl group, R 2 is a trimethylene group, n = 115, m =
In R, part of R is a hydroxyl group and the rest is the residue (3). The amount of adriamycin bound (content) was 56.5% by weight, but it showed good water solubility.
【００３７】実施例４ 実施例３で合成した水溶性高分子抗癌剤ＰＥＧ−Ｐ（Ａ
ｓｐ．）ＡＤＲのミセル径を、レーザー光散乱法により
測定した。ＰＥＧ−Ｐ（Ａｓｐ．）ＡＤＲ（アドリアマ
イシンの結合量５６．５重量％）の水中でのミセル径
は、４０nmであった。また、この試料を２分間超音波処
理した場合、元のピークはほとんど１nmと低分子側に移
動することより、本水溶性高分子抗癌剤が水系溶媒中で
ミセルを形成することが判る。Example 4 PEG-P (A, a water-soluble polymer anticancer agent synthesized in Example 3
sp. ) The micelle diameter of ADR was measured by the laser light scattering method. The micelle diameter of PEG-P (Asp.) ADR (the amount of adriamycin bound was 56.5% by weight) in water was 40 nm. In addition, when this sample was subjected to ultrasonic treatment for 2 minutes, the original peak moved to 1 nm, which is almost 1 nm, indicating that the present water-soluble polymeric anticancer agent forms micelles in an aqueous solvent.
【００３８】参考例１ ＣＤＦ１メスのマウスの背側部皮下にマウス大腸癌Ｃｏ
ｌｏｎ２６細胞を移植し、腫瘍の体積が１００mm3 前後
に達した時点から実施例３で得られたＰＥＧ−Ｐ（Ａｓ
ｐ．）ＡＤＲ（ＡＤＲ結合量５６．５重量％のもの）又
はアドリアマイシン塩酸塩（ＡＤＲ）を４日間隔１回、
計３回静脈内に投与し、進行癌に対する効果を検討し
た。各薬剤は生理食塩水で用時希釈して用いた。なお、
ＰＥＧ−Ｐ（Ａｓｐ．）ＡＤＲはＡＤＲに換算した投与
量を用いた。薬剤の抗腫瘍効果は、コントロールに対す
る各群のメディアン生存日数の比Ｔ／Ｃ（％）と腫瘍増
殖曲線から判定した。結果を表１と図１に示す。Reference Example 1 Mouse colon cancer Co was subcutaneously implanted on the dorsal part of a CDF1 female mouse.
lon-26 cells were transplanted, and the PEG-P (As obtained in Example 3 from the time when the tumor volume reached around 100 mm 3
p. ) ADR (having an ADR binding amount of 56.5% by weight) or adriamycin hydrochloride (ADR) once every 4 days,
The drug was intravenously administered 3 times in total, and the effect on advanced cancer was examined. Each drug was diluted with physiological saline before use. In addition,
For PEG-P (Asp.) ADR, the dose converted to ADR was used. The antitumor effect of the drug was judged from the ratio T / C (%) of the median survival days of each group to the control and the tumor growth curve. The results are shown in Table 1 and FIG.
【００３９】[0039]
【表１】 表１ マウス大腸癌Ｃｏｌｏｎ２６に対する抗癌活性 サ ン プ ル 投与量 平均生存日数 Ｔ／Ｃ （mg／kg） （％） ＰＥＧ−Ｐ（Ａｓｐ．）ＡＤＲ ２５ ５９．８ １７６ ＰＥＧ−Ｐ（Ａｓｐ．）ＡＤＲ ５０ ６０．１ １７７ ＰＥＧ−Ｐ（Ａｓｐ．）ＡＤＲ １００ ６０．１ １７７ ＰＥＧ−Ｐ（Ａｓｐ．）ＡＤＲ ２００ ２０．０ ５９ ＡＤＲ ７．５ ４４．５ １３１ ＡＤＲ １０ ５９．８ １７６ ６０日までの結果 無処置群の平均生存日数は、３４．０日 表１から明らかなように本発明の高分子抗癌剤は、アド
リアマイシン塩酸塩に比べ有効投与量幅が大きく有用な
薬剤であることが判る。また、図１及び図２から明らか
なように、アドリアマイシン塩酸塩を投与した場合、移
植した腫瘍の増殖抑制効果は認められるが腫瘍の縮小は
ほとんど認められないのに対し、本発明の水溶性高分子
抗癌剤を１００mg／kg／day （１回当り）投与した場
合、３０日後には５匹中４匹で移植した腫瘍が消失し
た。同様に５０mg／kg／day で５匹中３匹、２５mg／kg
／day でも５匹中３匹腫瘍消失と幅広い投与量で有用な
薬剤であることが判った。[Table 1] Table 1 Anti-cancer activity sample against mouse colon cancer Colon26 Dose mean survival time T / C (mg / kg) (%) PEG-P (Asp.) ADR 25 59.8 176 PEG-P (Asp.) ADR 50 60.1 177 PEG-P (Asp.) ADR 100 60.1 177 PEG-P (Asp.) ADR 200 20.0 59 ADR 7.5 44.5 131 ADR 10 59.8 176 Results up to 60 days Average survival time in untreated group is 34.0 days As is clear from Table 1, the polymeric anticancer agent of the present invention has a large effective dose range compared to adriamycin hydrochloride and is a useful agent. I understand. Further, as is clear from FIG. 1 and FIG. 2, when adriamycin hydrochloride is administered, the growth inhibitory effect of the transplanted tumor is observed, but the tumor shrinkage is hardly observed. When the molecular anticancer drug was administered at 100 mg / kg / day (once), the tumors transplanted in 4 out of 5 mice disappeared after 30 days. Similarly, at 50 mg / kg / day, 3 out of 5 animals, 25 mg / kg
It was found that even 3 days a day, 3 out of 5 tumors disappeared and it was a useful drug with a wide dose range.
【００４０】[0040]
【発明の効果】本発明の方法で得られるブロック共重合
体を用いた水溶性高分子抗癌剤は、光学活性なα体の高
分子を用い構造的に均一性が良く、抗癌剤の結合量を多
くしても良好な水溶性を有している。しかもブロック共
重合体に結合させていない抗癌剤に比較して低い毒性の
範囲で高い抗腫瘍効果を示すことより、本発明により極
めて有用な医薬を提供できるものである。The water-soluble polymer anti-cancer agent using the block copolymer obtained by the method of the present invention uses an optically active α-form polymer and has good structural homogeneity and a large amount of the anti-cancer agent bound. However, it has good water solubility. Moreover, the present invention can provide an extremely useful drug because it exhibits a high antitumor effect in a range of low toxicity as compared with an anticancer agent not bound to a block copolymer.
【図１】ＰＥＧ−Ｐ（Ａｓｐ．）ＡＤＲを投与した場合
の、マウス大腸癌Ｃｏｌｏｎ２６の腫瘍増殖曲線。FIG. 1 is a tumor growth curve of mouse colon cancer Colon26 when PEG-P (Asp.) ADR is administered.
【図２】アドリアマイシン塩酸塩を投与した場合の、マ
ウス大腸癌Ｃｏｌｏｎ２６の腫瘍増殖曲線。FIG. 2 shows a tumor growth curve of mouse colon cancer Colon26 when adriamycin hydrochloride is administered.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０８Ｇ 69/10 ＮＲＮ 9286−4Ｊ (72)発明者 片岡 一則 千葉県柏市大室1083−４、柏ビレジ141− ９ (72)発明者 岡野 光夫 千葉県市川市国府台６−12−12 (72)発明者 ▲勢▼藤 隆 群馬県前橋市下川町45−３ (72)発明者 福島 重人 群馬県高崎市岩鼻町239 (72)発明者 浴本 久雄 東京都北区志茂２−11−１−803 (72)発明者 岡本 一也 東京都荒川区東尾久５−７−10−305─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification number Internal reference number in the agency FI technical display location C08G 69/10 NRN 9286-4J (72) Inventor Kazunori Kataoka 1083-4, Omuro, Kashiwa City, Chiba Prefecture Kashiwa Village 141-9 (72) Inventor Mitsuo Okano 6-12-12 Kokufudai, Ichikawa City, Chiba Prefecture (72) Inventor ▲ Takashi Fuji, 45-3 Shimokawa Town, Maebashi City, Gunma Prefecture (72) Inventor Shigeto Fukushima Gunma Gunma 239 Iwahana Town, Takasaki City, Japan (72) Inventor Hisao Yumoto 2-11-1-803 Shimo, Kita-ku, Tokyo (72) Inventor Kazuya Okamoto 5-7-10-305 Higashio, Arakawa-ku, Tokyo
Claims (11)
基が保護基で保護されている光学活性なポリ−α−アミ
ノ酸構造部分とを有するブロック共重合体から、保護基
を酸を用いて除去することを特徴とする、親水性高分子
構造部分と、光学活性なポリ−α−アミノ酸構造部分と
を有するブロック共重合体の製造法。1. A protective group is removed from a block copolymer having a hydrophilic polymer structural portion and an optically active poly-α-amino acid structural portion in which a carboxyl group is protected by a protective group, using an acid. The method for producing a block copolymer having a hydrophilic polymer structural portion and an optically active poly-α-amino acid structural portion.
リコール構造を有する、請求項１記載のブロック共重合
体の製造法。2. The method for producing a block copolymer according to claim 1, wherein the hydrophilic polymer structural portion has a polyethylene glycol structure.
ラギン酸又はポリ−α−グルタミン酸である、請求項１
又は２記載のブロック共重合体の製造法。3. The poly-α-amino acid is poly-α-aspartic acid or poly-α-glutamic acid.
Alternatively, the method for producing the block copolymer according to 2 above.
護基で保護されている、請求項１，２又は３記載のブロ
ック共重合体の製造法。4. The method for producing a block copolymer according to claim 1, wherein the carboxyl group is protected by a protecting group in the form of an ester structure.
リ−α−アスパラギン酸構造部分とを有するブロック共
重合体。5. A block copolymer having a hydrophilic polymer structural portion and an optically active poly-α-aspartic acid structural portion.
ック共重合体。 【化１】 （式中、Ｒ1 は低級アルキル基を表し、Ｒ2 は結合基を
表し、ｎは５〜１，０００、ｍは１〜３００の整数を示
す。）6. The block copolymer according to claim 5, which is represented by the formula (1). [Chemical 1] (In the formula, R 1 represents a lower alkyl group, R 2 represents a bonding group, n represents an integer of 5 to 1,000, and m represents an integer of 1 to 300.)
ロック共重合体。7. The block copolymer according to claim 6, wherein R 1 is a methyl group.
る請求項６又は７記載のブロック共重合体。8. The block copolymer according to claim 6, wherein R 2 is an alkylene group having 2 to 4 carbon atoms.
合体のポリ−α−アスパラギン酸構造部分の側鎖に抗癌
性物質を結合せしめた水溶性高分子抗癌剤。9. A water-soluble polymeric anticancer agent comprising an anticancer substance bound to the side chain of the poly-α-aspartic acid structural portion of the block copolymer according to claim 5, 6, 7 or 8.
請求項９の水溶性高分子抗癌剤。10. The water-soluble polymeric anticancer agent according to claim 9, wherein the anticancer substance is adriamycin.
ポリ−α−アスパラギン酸構造部分を内側に、親水性高
分子構造部分を外側とするミセルを形成するものである
請求項９又は１０に記載の水溶性高分子抗癌剤。11. A micelle having an optically active poly-.alpha.-aspartic acid structure part bound with an anticancer substance on the inside and a hydrophilic polymer structure part on the outside. The water-soluble polymer anticancer agent according to 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3313807A JPH05117385A (en) | 1991-10-31 | 1991-10-31 | Production of block copolymer, block copolymer and water-soluble polymeric carcinostatic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3313807A JPH05117385A (en) | 1991-10-31 | 1991-10-31 | Production of block copolymer, block copolymer and water-soluble polymeric carcinostatic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05117385A true JPH05117385A (en) | 1993-05-14 |
Family
ID=18045755
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3313807A Pending JPH05117385A (en) | 1991-10-31 | 1991-10-31 | Production of block copolymer, block copolymer and water-soluble polymeric carcinostatic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05117385A (en) |
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