JPH01252603A - 5-fluorouracil carrier - Google Patents
5-fluorouracil carrierInfo
- Publication number
- JPH01252603A JPH01252603A JP7818088A JP7818088A JPH01252603A JP H01252603 A JPH01252603 A JP H01252603A JP 7818088 A JP7818088 A JP 7818088A JP 7818088 A JP7818088 A JP 7818088A JP H01252603 A JPH01252603 A JP H01252603A
- Authority
- JP
- Japan
- Prior art keywords
- chitin
- fluorouracil
- formula
- carrier
- reacting
- 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
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229960002949 fluorouracil Drugs 0.000 title claims abstract description 32
- 229920002101 Chitin Polymers 0.000 claims abstract description 39
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 26
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 10
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 6
- KYSXOUNBTJWDIW-UHFFFAOYSA-N 3-(5-fluoro-2,4-dioxopyrimidin-1-yl)propanoic acid Chemical compound OC(=O)CCN1C=C(F)C(=O)NC1=O KYSXOUNBTJWDIW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 231100000053 low toxicity Toxicity 0.000 abstract description 5
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 abstract description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000007259 addition reaction Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229920001661 Chitosan Polymers 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000006196 deacetylation Effects 0.000 description 4
- 238000003381 deacetylation reaction Methods 0.000 description 4
- MSWZFWKMSRAUBD-IVMDWMLBSA-N glucosamine group Chemical group OC1[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 238000001226 reprecipitation Methods 0.000 description 2
- 241000238424 Crustacea Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- -1 carboxyethyl 5FU Chemical compound 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、脱アセチル化グリコールキチンの低級アルキ
レン基を介したアミド結合による５−フルオロウラシル
担持体並びにその製造方法及び該担持体からなる抗腫瘍
剤に関する。Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a 5-fluorouracil carrier formed by an amide bond via a lower alkylene group of deacetylated glycol chitin, a method for producing the same, and an antitumor drug comprising the carrier. Regarding drugs.
（従来の技術）
キチンは、甲殻類や菌類の外骨格を形成する組織多糖で
セルロースと非常に良く似た化学構造及び物性を持ち、
地球上では非常に豊富な資源である。このキチンは強固
な結晶構造を持つため、溶解性や反応性に欠けるか、キ
チンを強アルカリ条件下で脱アセチル化したキトサンは
塩を作ると木溶性となり、またキチンをエチレンオキサ
イドでヒドロキシエチル化したグリコール化キチンも水
溶性となり、化学修飾が容易になる。(Prior art) Chitin is a tissue polysaccharide that forms the exoskeleton of crustaceans and fungi, and has a chemical structure and physical properties very similar to cellulose.
It is an extremely abundant resource on earth. This chitin has a strong crystal structure, so it lacks solubility and reactivity, or chitosan, which is deacetylated chitin under strong alkaline conditions, becomes wood-soluble when salt is made, and chitin can also be hydroxyethylated with ethylene oxide. The resulting glycolized chitin also becomes water-soluble, making it easier to chemically modify it.
これらキチン及びその誘導体は、一般に毒性が低く、生
体内分解吸収性であるなどバイオマテリアルに適した性
質を数多く備えた高分子物質である。これらの中でも特
に部分Ｎ−アセチル化キチン又は部分Ｎ−アセチル化キ
トサンは白血病Ｌ １２１０脱水ガン細胞を選択的に凝
集させ、その増殖を阻害し、また、キチンの水溶性低級
同族体のＮ−アセチルキトオリゴｖｉ（特にヘキサオー
ス）は強い免疫賦活抗腫瘍活性を示すことが近年報告さ
れ、キチン、キトサンが抗Ｉｌ！ｉ瘍活性を有する多糖
として脚光を浴びつつある（例えば特゛聞閉５９−２７
８２６号、同６２−１２３１２３号）、このように、キ
チン、キトサンは低毒性、生体内分解吸収性でＪｌｉｉ
σ細胞への選択的集積部な有しているので、見方を変え
れば、これらは高分子医薬のキャリアーとしての条件を
満たしていると言える。These chitins and their derivatives are polymeric substances that generally have many properties suitable for biomaterials, such as low toxicity and biodegradability and absorption. Among these, partially N-acetylated chitin or partially N-acetylated chitosan selectively aggregates leukemia L 1210 dehydrated cancer cells and inhibits their proliferation, and N-acetylated chitin's water-soluble lower homolog It has recently been reported that chitooligo vi (especially hexaose) exhibits strong immunostimulatory antitumor activity, and chitin and chitosan have anti-Il! It is attracting attention as a polysaccharide with tumor activity (for example,
826, No. 62-123123), chitin and chitosan have low toxicity and are biodegradable and absorbable.
From a different perspective, they can be said to meet the requirements as carriers for polymeric drugs, since they have a selective accumulation site in σ cells.
一方、５−フルオロウラシル（５ＦＵ）は、代謝拮抗阻
害剤として働く抗腫瘍剤で、強い抗腫瘍活性を有するが
同時に強い毒性があり、その副作用抑制が問題となって
いる。On the other hand, 5-fluorouracil (5FU) is an antitumor agent that acts as an antimetabolite inhibitor, and has strong antitumor activity, but is also highly toxic, and suppression of its side effects has been a problem.
（発明が解決しようとする課題）
したかって本発明の目的はこのような抗腫瘍活性、低毒
性、生体内分解吸収性及び腫瘍細胞への選択的束ｆｆ１
ｆＥを有するキチン、キトサン化合物と抗腫瘍剤として
有用な５−ＦＵとを組合わせた新規な化合物を提供する
ことにある。(Problems to be Solved by the Invention) Therefore, the purpose of the present invention is to provide such antitumor activity, low toxicity, biodegradability and absorption, and selective binding to tumor cells.
The object of the present invention is to provide a novel compound that combines chitin or chitosan compounds having fE and 5-FU useful as an antitumor agent.
（課題を解決するための手段）
本発明者は、５ＦＵの副作用の軽減、薬効の持続性、タ
ーゲツティング、活性の増大を期待して、キチン誘導体
への共有結合による５ＦＵの担持を行い、高分子プロト
ラグ（ＭａｃｒｏｍｏｌｅｃｕｌａｒＰｒｏｄｒｕｇ）
の観点から、５ＦＵ担持の結合様式、スペイサ−の有無
、グリコール化するか否かか、抗腫瘍活性に及ぼす影響
について検討し、この検討過程において、下記式（Ｉ）
で表わされる脱アセチル化グリコールキチンのアルキレ
ン基を介したアミド結合による５−フルオロウラシル担
持体が、５ＦＵの放出性能が高く、かつ、優れた抗腫瘍
活性を示すことを見いだし、本発明をなすに至った。(Means for Solving the Problems) The present inventor carries 5FU by covalent bonding to a chitin derivative, expecting to reduce the side effects of 5FU, maintain drug efficacy, increase targeting, and increase activity. Macromolecular Prodrug
From the viewpoint of
It has been discovered that a 5-fluorouracil supported by an amide bond via an alkylene group of deacetylated glycol chitin represented by the formula has high 5FU release performance and exhibits excellent antitumor activity, and the present invention has been completed. Ta.
すなわち、本発明は
（１）式（１）で表わされる５−フルオロウラシル１ｕ
持体、
（式中、ｎは１００以上の整数であり、好ましくＬ！：
２．５ｘ １０２〜４．８ｘ ｌＯＺであＺ＋。）（２
）式（Ｉ）で表わされる請求項１記載の５−フルオロウ
ラシル担持体を含有してなる抗腫瘍剤。That is, the present invention provides 5-fluorouracil 1u represented by formula (1)
carrier, (where n is an integer of 100 or more, preferably L!:
Z+ at 2.5x 102 to 4.8x lOZ. )(2
) An antitumor agent comprising the 5-fluorouracil carrier according to claim 1 represented by formula (I).
（３）キチンをアルカリ処理してアルカリキチンとし、
アルカリキチンにエチレンオキサイドを反応させて、部
分脱アセチル化グリコールキチンを得、次いで得られた
部分脱アセチル化グリコールキチンと１−β−カルボキ
シエチル−５−フルオロウラシルとを反応させることを
特徴とする式（Ｉ）て表わされる請求項１記載の５−フ
ルオロウラシル担持体の製造方法
を提供するものである。(3) Treat chitin with alkali to make alkali chitin,
A formula characterized by reacting alkali chitin with ethylene oxide to obtain partially deacetylated glycol chitin, and then reacting the obtained partially deacetylated glycol chitin with 1-β-carboxyethyl-5-fluorouracil. The present invention provides a method for producing the 5-fluorouracil carrier according to claim 1, which is represented by (I).
この５ＦＵ担持体は、そのままの形で腫瘍細胞に取り込
まれ、そこで５ＦＵがリリースして、５ＦＵとして作用
し、キャリアーの部分脱アセチル化゛グリコールキチン
は、目的達成後分解・吸収される。This 5FU carrier is taken up into tumor cells as it is, where 5FU is released and acts as 5FU, and the partially deacetylated glycol chitin of the carrier is degraded and absorbed after achieving its purpose.
したかってその投与量は５ＦＵ換算で従来の５ＦＵとほ
ぼ同様になるようにするのか好ましい。Therefore, it is preferable that the dosage should be approximately the same as conventional 5FU in terms of 5FU.
（実施例） 次に本発明を実施例に基づきさらに詳細に説明する。(Example) Next, the present invention will be explained in more detail based on examples.
実施例１
（ｉ）１−β−カルボキシエチル−５−フルオロウラシ
ルの合成
５ＦＵ残基として用いた１−β−カルボキシエ２を経て
以下のように合成した。Example 1 (i) Synthesis of 1-β-carboxyethyl-5-fluorouracil Synthesis was performed as follows via 1-β-carboxye 2 used as the 5FU residue.
エタノール４２８ｍ１に５ＦＵ１ １０ｇ （７７ｍ
ｍｏｌ）と金属ナトリウム０．０８６ｇを加えて水素の
発生か見られなくなってからエチルアクリレート９ 、
７ ｍ （８９ｍｍｏｌ）加えて反応系が透明になるま
で還流攪拌を行った。冷却後、減圧下に濃縮し、少量の
エタノールで再結晶することにより、５ＦＵへのエチル
アクリレートのマイケル付加物２を得た。収率８２％、
融点１２７〜１２８℃。10g of 5FU1 in 428ml of ethanol (77ml
mol) and 0.086 g of metallic sodium were added, and after no hydrogen generation was observed, ethyl acrylate 9,
7 m (89 mmol) was added and stirred under reflux until the reaction system became transparent. After cooling, the mixture was concentrated under reduced pressure and recrystallized from a small amount of ethanol to obtain Michael adduct 2 of ethyl acrylate to 5FU. Yield 82%,
Melting point 127-128°C.
続いてこの２ １４ ｇ （６９ｆｍｏｌ）を３Ｎ
ＨＣ立１４ｏｍｌ中、６０°Ｃて６時間加水分解させた
後。Next, add this 214 g (69 fmol) to 3N
After hydrolysis in 14 ml of HC at 60°C for 6 hours.
塩酸を除去し、水から再結晶することにより、無色針状
結晶の３を得た。収率９１％、融点１８６〜１８７℃。By removing hydrochloric acid and recrystallizing from water, colorless needle-like crystals of 3 were obtained. Yield 91%, melting point 186-187°C.
（ｉｉ）脱アセチル化グリコールキチンの合成Ｒ２二〇
Ｈ２ＱＣ）（２Ｃ）（２０ｆ−１重版のキチン４ Ｌ
ｏｇを２００ｍ１の４５重量％ＮａＯＨ水溶液中に投入
して２時間攪拌することにより、キチンは著しく膨潤し
てアルカリキチン５となった。これを濾過、圧搾するこ
とにより過剰のアルカリを除去した。このアルカリキチ
ンを１見の三ロフラスコに入れ、２００ｇの氷を加えて
、羽根付き撹拌棒で十分に攪拌し、氷浴下で、ＮａＯＨ
６５ｇを水３９０ｇに溶解したアルカリ水溶液をこの系
にさらに加えた。この時系のＮａＯＨ１度は約１８重量
％であった。氷が系内に存在する間にバブルしながらエ
チレンオキサイドをキチンの構成単位のモル数の８〜ｌ
Ｏ倍と大過剰に加えた。反応が進行するにつれて白濁し
ていた系は透明となり、粘度が増加した。反応後透明に
なった粘性溶液をメタノール／アセトン（９：１容量比
）に投入し、再沈殿させた。水可溶部の再沈を繰返すこ
とにより十分に精製した後、凍結乾燥して部分脱アセチ
ル化グリコールキチン６を得た。(ii) Synthesis of deacetylated glycol chitin R220H2QC) (2C) (20f-1 reprint chitin 4 L
By putting og into 200 ml of a 45% by weight NaOH aqueous solution and stirring for 2 hours, the chitin significantly swelled and became alkali chitin 5. Excess alkali was removed by filtering and squeezing this. This alkaline chitin was placed in a three-sided flask, 200 g of ice was added, stirred thoroughly with a bladed stirring rod, and NaOH was added under an ice bath.
An aqueous alkaline solution of 65 g dissolved in 390 g of water was further added to the system. The NaOH 1 degree in this time series was about 18% by weight. While ice is present in the system, ethylene oxide is added to 8 to 1 moles of chitin's constituent units while bubbling.
A large excess of O times was added. As the reaction progressed, the cloudy system became transparent and the viscosity increased. The viscous solution that became transparent after the reaction was poured into methanol/acetone (9:1 volume ratio) to cause reprecipitation. After sufficient purification by repeating reprecipitation of the water-soluble portion, partially deacetylated glycol chitin 6 was obtained by freeze-drying.
アルカリ処理時間、エチレンオキサイドのバブリング速
度など反応条件を変えることにより、６として次の第１
表の試料を調製した。By changing the reaction conditions such as the alkali treatment time and the bubbling speed of ethylene oxide, the following
The samples listed in the table were prepared.
第１表
注）ａ：グルコラミン・ユニット当りのグリコール化度
（％）で、元素分析値と脱アセチル化度から算出した。Table 1 Note) a: Degree of glycolization (%) per glucolamine unit, calculated from elemental analysis values and degree of deacetylation.
ｂ：脱アセチル化度（％）で、試料を０．５容量％−酢
酸水溶液に溶解し、これをｌ／４００ Ｎ−ポリビニル
硫酸カリウム水溶液で滴定することにより算出した。b: Deacetylation degree (%), calculated by dissolving a sample in a 0.5% by volume acetic acid aqueous solution and titrating this with a l/400 N-polyvinyl potassium sulfate aqueous solution.
ｃ；Ｐｎで、粘度をΔ１４定して次式より算出した。c: At Pn, the viscosity was determined by Δ14 and calculated from the following formula.
（ｉｉｉ）式（Ｉ）の化合物の合成
３ ３．６ｇ （１８ｍｍｏｌ）とＮ−ヒトロキシサ
クシンイミト（ｔｌＯＮｓｕ） ２． １ ｇ （１
９ｍｍｏｌ）を１００摺のテトラヒドロフラン（ＴＩＩ
Ｆ）に溶解する。溶液か透明になってから、系を氷で冷
やしながら。(iii) Synthesis of compound of formula (I) 3 3.6 g (18 mmol) and N-hydroxysuccinimit (tlONsu) 2. 1 g (1
9 mmol) and 100 drops of tetrahydrofuran (TII)
Dissolve in F). After the solution becomes clear, cool the system with ice.
Ｎ、Ｎ′−ジシクロへキシルカルボジイミド（ＤＣＣ）
３ 、９ ｇ （１９ｍｍｏｌ）を加えて２４時間攪拌
し、精製する尿素を除くことにより、３を活性化エステ
ルとし、１．５ｇの部分アセチル化グリコ−キチン６−
１を４００摺の水に溶かした水溶液をこのＴＨＦ溶液に
加えて、不均一下で、５０°Ｃで５日間攪拌した０反応
終了後、新たに生じた尿素をろ別し、ろ液を減圧ａ縮し
、その残渣をメタノール／アセトン（９：１容量比）に
投入することにより沈澱として目的の化合物（Ｉ）−１
を得た。N,N'-dicyclohexylcarbodiimide (DCC)
By adding 9 g (19 mmol) of 3 and 9 g (19 mmol) and stirring for 24 hours to remove the urea to be purified, 3 was converted into an activated ester, and 1.5 g of partially acetylated glyco-chitin 6-
An aqueous solution of 1 dissolved in 400 ml of water was added to this THF solution, and the mixture was stirred at 50°C for 5 days in a heterogeneous environment. After the reaction, the newly formed urea was filtered off, and the filtrate was filtered under reduced pressure. The desired compound (I)-1 was obtained as a precipitate by condensing a and pouring the residue into methanol/acetone (9:1 volume ratio).
I got it.
グルコサン・ユニット当りの５ＦＵの導入率（Ｄ５ＦＵ
）は、ｌ−β−カルボキシエチル５ＦＵの入”２０＝２
７０ｎｍ、６”２０＝９１００をｍａｘ
ｗａｘ基準にして、グ
リコールキチンへ５ＦＵ残渣か担持したままの形で、島
津製作所製ＵＶ−２４０型分光光度計を使用してＵｖス
ペクトルを測って算出した。Incorporation rate of 5FU per glucosan unit (D5FU
) contains l-β-carboxyethyl 5FU”20=2
70nm, 6”20=9100 max
The calculation was made by measuring the UV spectrum using a Shimadzu UV-240 spectrophotometer with the 5FU residue supported on glycol chitin based on wax.
試料（１）−１
グルコサミン・ユニット当、りの５ＦＵの導入率（Ｄ５
ＦＵ）＝７．７％
グルコサミン・ユニット当りのグリコール化度＝７８％
、脱アセチル化度＝４２％、百ｎ＝３２００、水に可溶
。Sample (1)-1 Introduction rate of 5FU per glucosamine unit (D5
FU) = 7.7% Degree of glycolization per glucosamine unit = 78%
, degree of deacetylation = 42%, 100n = 3200, soluble in water.
実施例２
部分脱アセチル化グリコールキチンの試料６−２を用い
て（ｉｉ）と全く同じ条件下で６−２と３とのカップリ
ング反応を行い、（Ｉ）−２を得た。Example 2 Using sample 6-2 of partially deacetylated glycol chitin, a coupling reaction between 6-2 and 3 was carried out under exactly the same conditions as in (ii) to obtain (I)-2.
試料（Ｉ）−２
グルコサミン・ユニット当りの５ＦＵの導入率（Ｄ５Ｆ
Ｕ）＝８．９％
グルコサミン・ユニット当りのグリコール化度＝７８％
、脱アセチル化度＝６１％、Ｐｎ＝２５００、水に可溶
。Sample (I)-2 Introduction rate of 5FU per glucosamine unit (D5F
U) = 8.9% Degree of glycolization per glucosamine unit = 78%
, degree of deacetylation = 61%, Pn = 2500, soluble in water.
実施例３（抗腫瘍活性試験）
ＣＤＦ、マウス（５退会）にＰ−３８８１ｙ＠ｐｈｏｃ
ｙｔｔｃ １ｅｕｋｅｓ＋ｉａ （白血病）細胞を１×
１０６個／マウスを腹腔内投与し、所定量の式（１）の
ポリマーを翌日と５日目に腹腔内投与した。Example 3 (Anti-tumor activity test) CDF, P-3881y@phoc in mice (5 withdrawals)
yttc 1eukes+ia (leukemia) cells 1x
106 cells/mouse were intraperitoneally administered, and a predetermined amount of the polymer of formula (1) was intraperitoneally administered on the next day and on the 5th day.
実験群には、ｌ投与レベルに対して各６匹を、対照群に
は３０匹を用いた。抗腫瘍活性の評価は、次式で第２表
に表わされる生存日数比率により行い、結果を第２表に
示す。For the experimental group, 6 animals were used for each dose level, and for the control group, 30 animals were used. The antitumor activity was evaluated using the survival days ratio shown in Table 2 using the following formula, and the results are shown in Table 2.
第 ２ 表（抗腫瘍活性）
なお、Ｔ／Ｃの値が１２０以上の場合に、その試料は活
性があると評価される。Table 2 (Antitumor Activity) When the T/C value is 120 or more, the sample is evaluated as having activity.
［急性毒性試験］
式（Ｉ）の化合物をマウスに投与したが、投与量が８０
０ ｍｇ／ ｋｇまでは、マウスの急激な体重減少は見
られず、急性毒性はないと判断できる。[Acute toxicity test] The compound of formula (I) was administered to mice, but at a dose of 80
At doses up to 0 mg/kg, no rapid weight loss was observed in mice, and it can be concluded that there is no acute toxicity.
従つて、ＬＤ５０もｓ ＯＯｍｇ／ ｋｇ以上であると
言える。Therefore, it can be said that the LD50 is also sOOmg/kg or more.
［５ＦＵの放出挙動試験］
０．０ＩＮ−ＮａＯＨ１０，Ｉ Ｎ−ＨＣｕ、生理食塩
水あるいはリン酸緩衝液中、３７°Ｃで本発明の化合物
（Ｉ）の加水分解を行った結果、このようなｉｎ ｖｊ
ｔｒｏにおいては、加水分解を受は易いことが分った。[Release behavior test of 5FU] As a result of hydrolyzing the compound (I) of the present invention in 0.0IN-NaOH10,1N-HCu, physiological saline or phosphate buffer at 37°C, the following results were obtained. in vj
It was found that tro was easily susceptible to hydrolysis.
化合物（Ｉ）の化合物が加水分解を受けると、１−β−
カルボキシエチル５ＦＵがまずリリースしてくることが
分った。When compound (I) undergoes hydrolysis, 1-β-
It was found that carboxyethyl 5FU was released first.
０３、明の効果）
本発明の５ＦＵ担持体は、５ＦＵの放出性か優れ、抗腫
瘍活性を示し、毒性の少ない有用な化合物である。03, Bright Effect) The 5FU carrier of the present invention is a useful compound that has excellent 5FU release properties, exhibits antitumor activity, and has low toxicity.
Claims (3)
持体。 ▲数式、化学式、表等があります▼・・・（ I ） （式中、ｎは１００以上の整数である。）(1) A 5-fluorouracil support represented by formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, n is an integer of 100 or more.)
オロウラシル担持体を含有してなる抗腫瘍剤。(2) An antitumor agent comprising the 5-fluorouracil carrier according to claim 1, which is represented by formula (I).
アルカリキチンにエチレンオキサイドを反応させて、部
分脱アセチル化グリコールキチンを得、次いで得られた
部分脱アセチル化グリコールキチンと１−β−カルボキ
シエチル−５−フルオロウラシルとを反応させることを
特徴とする式（ I ）で表わされる請求項１記載の５−
フルオロウラシル担持体の製造方法。(3) Treat chitin with alkali to make alkali chitin,
A formula characterized by reacting alkali chitin with ethylene oxide to obtain partially deacetylated glycol chitin, and then reacting the obtained partially deacetylated glycol chitin with 1-β-carboxyethyl-5-fluorouracil. 5- of claim 1 represented by (I)
Method for producing fluorouracil support.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7818088A JPH01252603A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil carrier |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7818088A JPH01252603A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil carrier |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01252603A true JPH01252603A (en) | 1989-10-09 |
Family
ID=13654768
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7818088A Pending JPH01252603A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil carrier |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01252603A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5020766A (en) * | 1989-03-24 | 1991-06-04 | Elerth Persson | Sound and vibration damper |
| WO1992003480A1 (en) * | 1990-08-17 | 1992-03-05 | Drug Delivery System Institute, Ltd. | N-acetylcarboxymethylchitosan derivative and production thereof |
| US5204107A (en) * | 1990-11-20 | 1993-04-20 | Unitika Ltd. | Slow-releasing composition of platinum-containing anticancer agent |
| JP2001031575A (en) * | 1999-07-16 | 2001-02-06 | Fujibio Co Ltd | Inhibition of side effect of 5-fluorouracil by chitin chitosan and formulation therefor |
| US7511023B2 (en) * | 2001-08-18 | 2009-03-31 | Korea Institute Of Science And Technology | Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof |
| JP2012046716A (en) * | 2010-08-30 | 2012-03-08 | Chungnam National Univ Industry Collaboration Foundation | Glycolchitosan derivative, method of producing the derivative, and drug carrier containing the derivative |
-
1988
- 1988-04-01 JP JP7818088A patent/JPH01252603A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5020766A (en) * | 1989-03-24 | 1991-06-04 | Elerth Persson | Sound and vibration damper |
| WO1992003480A1 (en) * | 1990-08-17 | 1992-03-05 | Drug Delivery System Institute, Ltd. | N-acetylcarboxymethylchitosan derivative and production thereof |
| US5204107A (en) * | 1990-11-20 | 1993-04-20 | Unitika Ltd. | Slow-releasing composition of platinum-containing anticancer agent |
| JP2001031575A (en) * | 1999-07-16 | 2001-02-06 | Fujibio Co Ltd | Inhibition of side effect of 5-fluorouracil by chitin chitosan and formulation therefor |
| US7511023B2 (en) * | 2001-08-18 | 2009-03-31 | Korea Institute Of Science And Technology | Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof |
| JP2012046716A (en) * | 2010-08-30 | 2012-03-08 | Chungnam National Univ Industry Collaboration Foundation | Glycolchitosan derivative, method of producing the derivative, and drug carrier containing the derivative |
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