JPH01252602A - 5-fluorouracil carrier of partially deacetylated glycol chitin - Google Patents
5-fluorouracil carrier of partially deacetylated glycol chitinInfo
- Publication number
- JPH01252602A JPH01252602A JP7817988A JP7817988A JPH01252602A JP H01252602 A JPH01252602 A JP H01252602A JP 7817988 A JP7817988 A JP 7817988A JP 7817988 A JP7817988 A JP 7817988A JP H01252602 A JPH01252602 A JP H01252602A
- Authority
- JP
- Japan
- Prior art keywords
- chitin
- fluorouracil
- glycol
- partially deacetylated
- formula
- 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
- 229920002101 Chitin Polymers 0.000 title claims abstract description 46
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960002949 fluorouracil Drugs 0.000 title claims abstract description 42
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims abstract description 41
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 7
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- DGMKFQYCZXERLX-UHFFFAOYSA-N proglumide Chemical compound CCCN(CCC)C(=O)C(CCC(O)=O)NC(=O)C1=CC=CC=C1 DGMKFQYCZXERLX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 231100000053 low toxicity Toxicity 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 4
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 abstract description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract 2
- 239000002994 raw material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229920001661 Chitosan Polymers 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 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 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 230000006196 deacetylation Effects 0.000 description 4
- 238000003381 deacetylation reaction Methods 0.000 description 4
- 230000000694 effects Effects 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
- 229920000642 polymer Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 208000032839 leukemia Diseases 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
- 238000000746 purification Methods 0.000 description 2
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 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
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation 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
- 239000012620 biological material Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 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
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- -1 hydroxyethyl 5FU Chemical compound 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 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
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 102220043690 rs1049562 Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 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
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、部分脱アセチル化グリコールキチンの５−フ
ルオロウラシル担持体及び該担持体からなる抗腫瘍剤に
関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a 5-fluorouracil carrier of partially deacetylated glycol chitin and an antitumor agent comprising the carrier.
（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が、キ
チンを強アルカリ条件下て脱アセチル化したキトサンは
塩を作ると水溶性となり、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、化学修飾か容易になる。(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 and lacks solubility and reactivity. However, chitosan, which is obtained by deacetylating chitin under strong alkaline conditions, becomes water-soluble when a salt is made, and chitin can also be hydroxyethylated with ethylene oxide. Glycolated chitin also becomes water-soluble and can be easily chemically modified.
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Ｌ１２１０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糖（特にヘキサオース）
は強い免疫賦活抗腫扇活性を示すことが近年報告され、
キチン、キトサンか抗腫瘍活性を有する多糖として脚光
を浴びつつある（例えば特開昭５９−２７８２６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腫瘍細胞への選択的集
積源な有しているので、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 L1210 dehydrated cancer cells and inhibits their proliferation. Oligosaccharides (especially hexaose)
It has been reported in recent years that it exhibits strong immunostimulatory antitumor activity.
Chitin and chitosan are attracting attention as polysaccharides having antitumor activity (for example, JP-A-59-27826 and JP-A-62-123123). In this way, chitin and chitosan have low toxicity, are biodegradable and absorbable, and are sources of selective accumulation in tumor cells, so from a different perspective, they meet the requirements as carriers for polymeric drugs. I can say that there is.
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か
同時に強い毒性があり、その副作用抑制か問題となって
いる。On the other hand, 5-fluorouracil (5FU) is an anti-tumor agent that acts as an antimetabolite inhibitor, and has strong anti-tumor activity and is also highly toxic, making it a problem to suppress its side effects.
（発明が解決しようとする課題）
したが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集蹟億を
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 object of the present invention is to provide chitin and chitosan compounds and antitumor agents that have antitumor activity, low toxicity, biodegradability and absorption, and selective aggregation to tumor cells. The object of the present invention is to provide a novel compound in combination with 5-FU that is useful as a compound.
（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が。(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 this point of view, the binding mode of 5FU-carrying, the presence or absence of a spacer, and whether it is glycolated or not.
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）で表わされる部分脱アセチル化
グリコールキチンの５−フルオロウラシル相持体が５Ｆ
Ｕの放出性に優れ、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。The influence on antitumor activity was investigated, and in the course of this investigation, it was found that 5-fluorouracil phase carrier of partially deacetylated glycol chitin represented by the following formula (I)
It was discovered that it has excellent U release properties and exhibits excellent antitumor activity, leading to the present invention.
すなわち１本発明は
（１）式（Ｉ）て表わされる部分脱アセチル化グリコー
ルキチンの５−フルオロウラシル担持体、（式中、Ｒ１
は水素原子又はアセチル基を示し、Ｒ２は一０ＣＨ２Ｃ
Ｈ２−５ＦＵ基（ただし５ＦＵは５−フルオロウラシル
基を示す）を示し、ｎは１０（３以上の整数を示す）
（２）式（１）で表わされる部分アセチル化グリコール
キチンの５−フルオロウラシル担持体を含有してなる抗
腫８剤、
（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、得られた部分脱
アセチル化グリコールキチンを臭素化して、部分脱アセ
チル化グリコールフロミドキチンを得、得られた部分脱
アセチル化グリコールプロミドキチンに５−フルオロウ
ラシルを反応させることを特徴とする式（Ｉ）で表わさ
れる部分説アセチル化グリコールキチンの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。That is, 1 the present invention provides (1) a 5-fluorouracil carrier of partially deacetylated glycol chitin represented by formula (I), (wherein R1
represents a hydrogen atom or an acetyl group, R2 is 10CH2C
H2-5FU group (where 5FU represents a 5-fluorouracil group), n is 10 (represents an integer of 3 or more) (2) 5-fluorouracil support of partially acetylated glycol chitin represented by formula (1) 8 antitumor agents containing (3) chitin treated with alkali to form alkaline chitin;
Alkaline chitin is reacted with ethylene oxide to obtain partially deacetylated glycol chitin, the obtained partially deacetylated glycol chitin is brominated to obtain partially deacetylated glycol furomido chitin, and the obtained partially deacetylated glycol chitin is obtained. The present invention provides a method for producing a 5-fluorouracil support for partially acetylated glycol chitin represented by formula (I), which comprises reacting glycol promid chitin with 5-fluorouracil.
この５ＦＵ担持体は、そのままの形て腫瘍細胞に取り込
まれ、そこで５ＦＵかリリースして、５ＦＵとして作用
し、キャリアーのキトサ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 it releases 5FU and acts as 5FU, and the carrier chitosan is decomposed and absorbed after achieving its purpose.
したがってその投与量は５ＦＵ換算で従来の５ＦＵとほ
ぼ同等になるようにするのが好ましい。Therefore, it is preferable that the dosage should be approximately equivalent to 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
５ＦＵ １ ３ｇ（２３ｍｍｏｌ）とＫＯＨ１，４８
ｇ（２０鳳ｍｏｌ）をメタノール１５０ｍ１中に加え、
室温で３時間攪拌後、メタノールを蒸発除去することに
より、５ＦＵのカリウム墳２を容易に得ることかできた
。２を減圧下に十分乾燥して次の反応にｌ＼ノ
供した。Example 1 5FU 1 3g (23mmol) and KOH 1,48
g (20 mol) was added to 150 ml of methanol,
After stirring at room temperature for 3 hours, methanol was removed by evaporation, and potassium mound 2 containing 5FU could be easily obtained. 2 was thoroughly dried under reduced pressure and used in the next reaction.
市販のキチン３ Ｌｏｇを２００摺の４５重量％Ｎａ
ＯＨ水溶液に投入して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４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。Commercially available Chitin 3 Log 200% 45% Na
By adding it to an OH aqueous solution and stirring for 2 hours, the chitin significantly swelled and became alkali chitin 4. Excess alkali was removed by filtering and squeezing this.
このアルカリキチンを１１の三ロフラスコに入れ、２０
０ｇの氷を加えて、羽付き撹拌棒で十分に攪拌し、氷浴
下で、ＮａＯＨ６５ｇ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ＮａＯＨ濃
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４ＸＩｉ成
単位のモル数の８〜１０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５を得た
。Put this alkaline chitin into a 11-meter flask, and put 20
0 g of ice was added and thoroughly stirred with a feathered stirring bar, and an aqueous alkaline solution prepared by dissolving 65 g of NaOH in 390 g of water was further added to the system under an ice bath. The NaOH concentration during this time series was approximately 18% by weight. While ice was present in the system, ethylene oxide was added in a large excess of 8 to 10 times the number of moles of the 4XIi component of chitin while bubbling. As the reaction progressed, the cloudy system became transparent and the viscosity increased. After the reaction, the transparent viscous solution was diluted with methanol/
It was poured into acetone (9:1 volume ratio) and reprecipitated. After sufficient purification by repeating reprecipitation of the water-soluble portion, partially deacetylated glycol chitin 5 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、５として次の第１
表の２つのサンプルを調製した。By changing the reaction conditions such as the alkali treatment time and the bubbling speed of ethylene oxide, the following 1st
Two samples in the table were prepared.
第１表
注）ａ；グルコサミン・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 glucosamine 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／４０ＯＮ−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 it with a 1/40 ON-polyvinyl potassium sulfate aqueous solution.
ｃ；Ｐｎで、粘度を測定して次式より算出した。c: The viscosity was measured at Pn and calculated from the following formula.
次に試料５３．０ｇ、テトラブチルアンモニウムプロミ
ド（Ｔｌｌ八Ｂへ ０ 、３３ ｇ （１，０ｍ１ｌａ
ｌ）、トリエチルアミン（ＴＥＡ） １ 、４４ ｍ
（１０！＋１１１０１）を３００ｍ１ベンゼン中に
分散させたところへ、水浴下で臭化チオニル０ 、８７
（１０ｍｍｏｌ）を徐々に滴下し、暗所で５時間攪拌
した後、ポリマーをろ別してクロロホルムで洗浄するこ
とにより６を得た。６２．２ｇと５ＦＵのカリウム塩２
３ 、７ ｇ （２２ｍｍｏｌ）、 ＴＢＡＢ １
、５ ｇ （４，５ｍ５ｏｌ）をクロロベンゼン２０
０ｍ１中に分散させ、８０°Ｃて４８時間攪拌した。ろ
別して得られるポリマーを水に溶解させ、アセトン／メ
タノール（９：ｌ容量比）に投入することにより再沈澱
を行った。このようにして得られた試料の未反応ＣＨＣ
ＨＢｒ基をＣＨ２ＣＨ２０Ｈ基に戻す２ま
ために、ＫＯＨ２，９ｇをｌＯＯ捕の水に溶解させたア
ルカリ水溶液中８０°Ｃで２４時間処理した。反応後、
塩酸で中和した後アンバーライトＩＲＡ−４００及びＩ
Ｒ−１２０Ｂイオン交換樹脂カラムを通すことにより、
脱塩、精製を行い（Ｉ）−１を得た。Next, 53.0 g of sample, 33 g of tetrabutylammonium bromide (1.0 ml
l), triethylamine (TEA) 1, 44 m
(10!+11101) was dispersed in 300 ml of benzene and thionyl bromide 0,87
(10 mmol) was gradually added dropwise and stirred in a dark place for 5 hours. The polymer was then filtered off and washed with chloroform to obtain 6. 62.2g and 5FU of potassium salt 2
3, 7 g (22 mmol), TBAB 1
, 5 g (4.5 m5 ol) of chlorobenzene 20
The mixture was dispersed in 0 ml of water and stirred at 80°C for 48 hours. The polymer obtained by filtration was dissolved in water and reprecipitated by adding it to acetone/methanol (9:l volume ratio). Unreacted CHC of the sample thus obtained
In order to convert the HBr group back to a CH2CH20H group, the mixture was treated in an alkaline aqueous solution prepared by dissolving 2.9 g of KOH in 100% water at 80°C for 24 hours. After the reaction,
Amberlite IRA-400 and I after neutralization with hydrochloric acid
By passing through an R-120B ion exchange resin column,
Desalting and purification were performed to obtain (I)-1.
グルコサミン・ユニット当りの５ＦＵの導入率（Ｄ５Ｆ
Ｕ）は、■−ヒドロキシエチル５ＦＵのλ１１２０ ＝
＝２７０ｎｍ、、Ｈ２０＝８９９０を、ＭＬｆに＋１ａ
Ｘ ｆｆ１ａＸ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スペクトルを測ッて算出した。Incorporation rate of 5FU per glucosamine unit (D5F
U) is λ1120 of ■-hydroxyethyl 5FU =
=270nm, , H20=8990, +1a to MLf
The calculation was performed by measuring the UV spectrum using a Shimadzu Uv-240 spectrophotometer while the 5FU residue was still supported on the glycol chitin.
試料（Ｉ）−１
グルコサミン・ユニット当りの５ＦＵの導入率（Ｄ５Ｆ
Ｕ）＝１６％
グルコサミン・ユニット当りのグリコール化度＝６７％
、脱アセチル化度＝９３％、Ｐｎ＝１２３０、水に可溶
。Sample (I)-1 Introduction rate of 5FU per glucosamine unit (D5F
U) = 16% Degree of glycolization per glucosamine unit = 67%
, degree of deacetylation = 93%, Pn = 1230, soluble in water.
実施例２
７白
Ｃｌノ製造例１と同じ方法により、サンプ
ル５−２３．０ｇ、 ＴＢＡＢ ０．３３ｇ、ＴＥＡ
１．４４摺、臭化チオニル１．２ｄ（１５朧■ｏｌ）、
ベンゼン３００摺を用いて、ＣＨ２ＣＨ２０Ｈ基を
ＣＨ２ＣＨ２Ｂｒ基に変えたサンプル６２．２ｇと２
５．０ｇ （３０ｍｍｏＩ）をＴＢＡｌｌｌ、Ｏｇ（
３ｍ＋５ｏｌ）存在下、クロロベンゼン２００ｍ１中、
９０℃で１２０時間反応させることにより、試料（Ｉ）
−２を得た。Example 2 7 white
Sample 5-23.0g, TBAB 0.33g, TEA were prepared using the same method as in Cl Production Example 1.
1.44 suri, thionyl bromide 1.2 d (15 oboro ■ ol),
Samples 62.2g and 2 in which CH2CH20H group was changed to CH2CH2Br group using benzene 300 rub
5.0 g (30 mmol) was added to TBAll, Og (
3 m + 5 ol) in 200 ml of chlorobenzene,
By reacting at 90°C for 120 hours, sample (I)
-2 was obtained.
試料（１）−２
グルコサミン・ユニット当りの５ＦＵの導入率（Ｄ５Ｆ
Ｕ）＝８．６％
グルコサミン・ユニット当りのグリコール化度＝６５％
、脱アセチル化度＝２３％、Ｐｎ＝９６０、水に可溶。Sample (1)-2 Introduction rate of 5FU per glucosamine unit (D5F
U) = 8.6% Degree of glycolization per glucosamine unit = 65%
, degree of deacetylation = 23%, Pn = 960, soluble in water.
実施例３ 抗腫瘍活性試験
ＣＤＦ、マウス（５週令）にＰ−３８８１ｙｍｐｈｏｃ
ｙｔｉｃ ｌｅｕｋｅｍｉａ （白血病）細胞を１ｘｌ
Ｏ６個／マウスを服腔内投与し、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 Antitumor activity test CDF, P-3881ymphoc in mice (5 weeks old)
1xl ytic leukemia (leukemia) cells
O6/mouse was administered intravenously, 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、１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１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。Six animals were used for each dose level in the experimental group, and 30 animals were used in the control group. The antitumor activity was evaluated using the survival days ratio shown in Table 1 using the following formula, and the results are shown in Table 2.
第２表
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 Note that if the T/C value is 120 or more, the sample is evaluated to be active.
［急性毒性試験］
式（１）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てきる。[Acute toxicity test] The compound of formula (1) was administered to mice, but the dose was 80
At doses up to 0 mg/kg, no rapid weight loss was observed in mice, and it was determined that there was no acute toxicity.
従って、ＬＤ５０６８００ ｍｇ／ ｋｇ以上であると
言える。Therefore, it can be said that LD506800 mg/kg or more.
［５ＦＵの放出挙動試験］
０．０１ Ｎ −Ｎ ａ ＯＨｌｏ、ＩＮ−ＨＣＪＩ、
生理食塩水あるいはリン酸緩衝液中、３７℃で本発明の
式（１）の化合煽漏水分解を行った結果、このようなｉ
ｎ ｖｉｔｒｏにおいては、加水分解を受は易いことが
分った。式（１）の化合物が加水分解を受けると、ｌ−
ヒドロキシエチル５ＦＵがまずリリースしてくることか
分った。[5FU release behavior test] 0.01 N -N a OHlo, IN-HCJI,
As a result of aqueous decomposition of the compound of formula (1) of the present invention at 37°C in physiological saline or phosphate buffer, such i.
In vitro, it was found that it is easily susceptible to hydrolysis. When the compound of formula (1) undergoes hydrolysis, l-
It turns out that hydroxyethyl 5FU is released first.
（発ｌＪＪの効果）
本発明の５ＦＵ担持体は、５ＦＵの放出能が優れ、かつ
抗腫瘍活性を示し、毒性の少ない有用な化合物である。(Effects of IJJ) The 5FU carrier of the present invention is a useful compound that has excellent 5FU release ability, exhibits antitumor activity, and has low toxicity.
Claims (4)
ールキチンの５−フルオロウラシル担持体。 ▲数式、化学式、表等があります▼・・・（ I ） （式中、Ｒ＿１は水素原子又はアセチル基を示し、Ｒ＿
２は−ＯＣＨ＿２ＣＨ＿２−５ＦＵ基（ただし５ＦＵは
５−フルオロウラシル基を示す）を示し、ｎは１００以
上の整数を示す。）(1) A 5-fluorouracil carrier of partially deacetylated glycol chitin represented by formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, R_1 represents a hydrogen atom or an acetyl group, and R_
2 represents an -OCH_2CH_2-5FU group (5FU represents a 5-fluorouracil group), and n represents an integer of 100 or more. )
請求項１記載の５−フルオロウラシル担持体。(2) The 5-fluorouracil carrier according to claim 1, wherein n is in the range of 9 x 10^2 to 13 x 10^2.
セチル化グリコールキチンの５−フルオロウラシル担持
体を含有してなる抗腫瘍剤。(3) An antitumor agent comprising the partially deacetylated glycol chitin 5-fluorouracil carrier according to claim 1, 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、得られた部分脱
アセチル化グリコールキチンを臭素化して部分脱アセチ
ル化グリコールプロミドキチンを得、得られた部分脱ア
セチル化グリコールプロミドキチンに５−フルオロウラ
シル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記載の部分脱アセチル化グリコールキチン
の５−フルオロウラシル担持体の製造方法。(4) Treat chitin with alkali to make alkali chitin,
Alkaline chitin is reacted with ethylene oxide to obtain partially deacetylated glycol chitin, the obtained partially deacetylated glycol chitin is brominated to obtain partially deacetylated glycol promid chitin, and the obtained partially deacetylated A method for producing a partially deacetylated glycol chitin-supported 5-fluorouracil according to claim 1, which is represented by formula (I) and comprises reacting glycol promid chitin with 5-fluorouracil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7817988A JPH01252602A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil carrier of partially deacetylated glycol chitin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7817988A JPH01252602A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil carrier of partially deacetylated glycol chitin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01252602A true JPH01252602A (en) | 1989-10-09 |
Family
ID=13654739
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7817988A Pending JPH01252602A (en) | 1988-04-01 | 1988-04-01 | 5-fluorouracil carrier of partially deacetylated glycol chitin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01252602A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 JP7817988A patent/JPH01252602A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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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