JPH0349923B2 - - Google Patents
Info
- Publication number
- JPH0349923B2 JPH0349923B2 JP17683383A JP17683383A JPH0349923B2 JP H0349923 B2 JPH0349923 B2 JP H0349923B2 JP 17683383 A JP17683383 A JP 17683383A JP 17683383 A JP17683383 A JP 17683383A JP H0349923 B2 JPH0349923 B2 JP H0349923B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- adriamycin
- anthracycline antibiotic
- divema
- general 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.)
- Expired
Links
- 239000003817 anthracycline antibiotic agent Substances 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 14
- 229920001577 copolymer Polymers 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 30
- 230000001093 anti-cancer Effects 0.000 description 19
- 238000000862 absorption spectrum Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229940009456 adriamycin Drugs 0.000 description 15
- 239000000047 product Substances 0.000 description 12
- DQJJMWZRDSGUJP-UHFFFAOYSA-N ethenoxyethene;furan-2,5-dione Chemical compound C=COC=C.O=C1OC(=O)C=C1 DQJJMWZRDSGUJP-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 7
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 239000013543 active substance Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 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
- GUGHGUXZJWAIAS-QQYBVWGSSA-N Daunorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GUGHGUXZJWAIAS-QQYBVWGSSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012607 strong cation exchange resin Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960000834 vinyl ether Drugs 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Description
本発明は新規な化合物であるアントラサイクリ
ン系抗生物質誘導体及びその製造方法に関し、さ
らに詳しくは、低毒性かつ制ガン効果に優れたア
ントラサイクリン系抗生物質誘導体及びその製造
方法に関するものである。
近年、抗生物質の中で優れた制ガン効果を有す
るものが種々見出されており、なかでもアドリア
マイシンやダウノマイシンなどのアントラサイク
リン系抗生物質は、急性白血病や小児ガンに対す
る効果が顕著であつて、これらは臨床的に広く用
いられている。
しかしながら、これらのアントラサイクリン系
抗生物質は優れた制ガン効果を有すると同時に、
正常細胞に対しても強い毒性を示し、例えば白血
球や血小板の減少、肝障害、その他の副作用が認
められている。したがつてその使用に際しては、
副作用に対して十二分な注意が必要であり、その
ため少量づつ多数回投与するなど煩雑な方法がと
られている。
ところで、前記のような低分子化合物である制
ガン活性物質を高分子化合物に結合させた場合、
該制ガン活性物質は体内で徐々に放出されてその
濃度が一定に保たれ、またそのものの体内分布が
変り、毒性が軽減されて制ガン効果が高まること
が期待される。
本発明者らは、このような事情に鑑み、制ガン
活性をもつアントラサイクリン系抗生物質である
アドリアマイシンやダウノマイシンを結合させる
高分子化合物について鋭意研究を重ねた結果、ジ
ビニルエーテル−無水マレイン酸共重合体は、そ
れ自体優れた制ガン効果を有し、かつ分子中に多
数の酸無水物構造を有しているため、該アントラ
サイクリン系抗生物質中のアミノ基と容易に反応
してアミド結合を形成し、しかもこの反応物は温
和な条件下で該アントラサイクリン系抗生物質を
徐々に放出するなど、制ガン活性物質である該ア
ントラサイクリン系抗生物質の担体として極めて
優れていることを見出し、この知見に基づいて本
発明を完成するに至つた。
すなわち、本発明は、一般式
〔式中のＲは、一般式
（ただし、R′は水酸基又はメチル基である）
で示されるアントラサイクリン系抗生物質残基、
ｎは２以上200以下の整数である〕
で表わされるアントラサイクリン系抗生物質誘導
体及びその塩類、並びに有機溶媒の存在下、一般
式
（式中のｎは前記と同じ意味をもつ）
で表わされるジビニルエーテル−無水マレイン酸
共重合体に、一般式
（式中R′は水酸基又はメチル基である）
で表わされるアントラサイクリン系抗生物質又は
その塩を反応させたのち加水分解し、次いで所望
に応じ塩に変えることを特徴とする、前記一般式
（Ｉ）で表わされるアントラサイクリン系抗生物
質誘導体及びその塩類の製造方法を提供するもの
である。
本発明に用いるジビニルエーテル−無水マレイ
ン酸共重合体は、前記一般式（）で示される化
合物であつて、ジビニルエーテルと無水マレイン
酸とを公知の方法に従つて共重合させることによ
り得られる。
このジビニルエーテル−無水マレイン酸共重合
体は、それ自体種々の腫瘍に対して優れた制ガン
効果を有しており、なかでも分子量10万以下、特
に３万以下のものは毒性が極めて低く、LD50も
700mg／Kg以上であつて好ましい。
また、前記共重合体は、その分子中に多数の酸
無水物構造を有しているため、前記のアントラサ
イクリン系抗生物質中のアミノ基と容易に反応し
てアミド結合を形成しうる。
本発明に用いる制ガン活性物質であるアントラ
サイクリン系抗生物質は、前記一般式（）で示
される化合物であつて、一般式（）中のR′が
水酸基であればアドリアマイシン、メチル基であ
ればダウノマイシンである。これらは急性白血病
や小児ガンなどに対して優れた制ガン効果を有す
る。
本発明のアントラサイクリン系抗生物質誘導体
は、例えばＮ−メチルピロリドンなどの有機溶
媒、トリエチルアミンなどの触媒の存在下、前記
のジビニルエーテル−無水マレイン酸共重合体と
アントラサイクリン系抗生物質とを反応させたの
ち加水分解し、次いでイオン交換樹脂や限外ろ過
膜などを用いて目的物以外のものを取り除いたの
ち、凍結乾燥などを行うことによつて得られる。
また、所望に応じ、前記の加水分解後、ナトリウ
ム塩、カリウム塩、カルシウム塩、マグネシウム
塩などの薬理的に許容しうる塩に変えたのち、限
外ろ過、凍結乾燥などを行い、塩として取り出し
てもよい。
このようにして得られたアントラサイクリン系
抗生物質誘導体中のアントラサイクリン系抗生物
質の含有量は、好ましくは５〜40重量％の範囲で
ある。
このアントラサイクリン系抗生物質誘導体にお
いては、温和な条件下でも遊離のカルボキシル基
が触媒の役目を果してそのアミド結合を徐々に開
裂し、制ガン活性物質であるアントラサイクリン
系抗生物質がゆつくり放出される。例えばアドリ
アマイシンとジビニルエーテル−無水マレイン酸
共重合体との結合物の場合、試験管内の0.1規定、
PH7.2のリン酸緩衝液中におけるアドリアマイシ
ンの放出速度は２週間で約20％であつた。
また、p388白血病マウスに対する制ガン活性
については、例えばダウノマイシンとジビニルエ
ーテル−無水マレイン酸共重合体との結合物では
最高延命率98％、ダウノマイシン単独では同48％
であつた。
このように、本発明の高分子量アントラサイク
リン系抗生物質誘導体は、制ガン活性物質である
アントラサイクリン系抗生物質の徐放性に優れ低
毒性である上に、それ自体制ガン活性をもつ該共
重合体との相乗効果により、該アントラサイクリ
ン系抗生物質を単独で用いる場合に比べて、優れ
た制ガン効果を有する。
次に実施例及び参考例によつて本発明をされに
詳細に説明する。
なお、ジビニルエーテル−無水マレイン酸共重
合体をDIVEMAと略記する。
実施例 １
アドリアマイシン−DIVEMA結合物
90mgのDIVEMA（分子量28500）を１mlの無水
Ｎ−メチルピロリドンに溶解し、かきまぜながら
アドリアマイシン塩酸塩90mgを含有したＮ−メチ
ルピロリドン溶液５mlを滴下した。次いで触媒と
して50μの無水トリエチルアミンを含むＮ−メ
チルピロリドン溶液５mlを10分間で滴下した。反
応は室温で12時間光を遮断して行つた。反応後、
１のｎ−ヘキサン中に激しくかきまぜながら反
応液を滴下し、沈殿した赤い固形物を新しい１
のｎ−ヘキサンで洗浄した。この沈殿物を集めて
再蒸留水50mlに浮遊させ、かきまぜながら１重量
％炭酸水素ナトリウム水溶液でPH7.0に調整した。
１時間後に固形物はすべて溶解して赤色の溶液と
なつた。次に、未反応のアドリアマイシンと触媒
のトリエチルアミンを除くため、２回強陽イオン
交換樹脂（ダウエツクス）200mgを加えて10分間
かきまぜたのちろ過し、10mlの水で洗浄した。次
いでろ液を分子量１万の分別に相当する限外ろ過
膜（アミコン社製、PM10）を用い、再蒸留水に
よりろ過し、洗浄した。ろ液の色が完全になくな
つた時点でろ過を止め、0.22μ孔径のミリポアフ
イルターを通したのち、凍結乾燥し、177mgの赤
橙色の綿状固体物を得た。このものは、490nmの
可視部の吸収により求めたところ、31.3重量％の
アドリアマイシンを含んでいた。また、水の他に
DMSO、DMF、Ｎ−メチルピロリドンのような
極性溶媒に可溶であつたが、ジエチルエーテル、
ｎ−ヘキサン、ベンゼンなどには不溶であつた。
さらに赤外吸収スペクトルは3450、2930、1720、
1670、1630、1610、1580、1530、1440、1410、
1380、1280、1250、1200、1110、1070、1010、
980cm-1に吸収をもち、可視・紫外吸収スペクト
ルには491、292、253、234nmに吸収があつた。
得られたアドリアマイシン−DIVEMA結合物
の赤外吸収スペクトルを第１図Ａに、可視・紫外
吸収スペクトルを第１図Ｂに示す。
実施例 ２
アドリアマイシン−DIVEMA結合物
（塩型）
実施例１により得られたアドリアマイシン−
DIVEMA結合物の水溶液を0.1重量％炭酸水素ナ
トリウム水溶液でPH7.0に調整したのち、0.22μ孔
径のミリポアフイルターを通して凍結乾燥した。
暗赤色の綿状固体物が実施例１に対して定量的に
得られ、このものは、実施例１で得られた生成物
よりも水溶性が高い。その赤外吸収スペクトルで
は1580cm-1に大きな吸収が現われ、1720cm-1にお
ける吸収が減少した。また、可視・紫外吸収スペ
クトルは変化しなかつた。
得られた生成物の赤外吸収スペクトルを第２図
に示す。
実施例 ３
アドリアマイシン−DIVEMA結合物
実施例１と同様にして100mgのDIVEMA（分子
量28500）と15mgのアドリアマイシン塩酸塩とを、
トリエチルアミン5.4μを触媒として10mlの無水
Ｎ−メチルピロリドン中で反応させたのち、実施
例１と同じ処理方法により、赤橙色の綿状固形物
130mgを得た。このものは、可視部の吸収スペク
トルより、アドリアマイシンを9.4重量％含有し
ていることが分つた。また、その赤外吸収スペク
トル及び可視・紫外吸収スペクトルは実施例１の
生成物と同様であつた。
実施例 ４
ダウノマイシン−DIVEMA結合物
実施例１と同様に、50mgのDIVEMA（分子量
28500）と50mgのダウノマイシン塩酸塩とを、ト
リエチルアミン10μを触媒として10mlの無水Ｎ
−メチルピロリドン中で反応させたのち、実施例
１と同じ処理方法により、赤橙色の綿状固体物
104mgを得た。このものは、可視部の吸収スペク
トルよりダウノマイシンを24.8重量％含有してい
ることが分つた。
実施例 ５
ダウノマイシン−DIVEMA結合物（塩型）
実施例２と同様に、実施例４の生成物を処理し
て、暗赤色の綿状固体物を実施例４に対して定量
的に得た。このものは実施例４の生成物より水溶
性が高く、その赤外吸収スペクトルでは1580cm-1
に大きな吸収が現われ、1720cm-1における吸収が
減少した。また、可視・紫外吸収スペクトルは実
施例４の生成物と変りなかつた。
参考例 １
0.1規定、PH7.2のリン酸緩衝生理食塩水
（PBS）中におけるアドリアマイシン（Ad）−
DIVEMA結合物からのアドリアマイシン放出を
検討した。
すなわち、実施例１で得た生成物3.3mgを溶解
させたPBS10mlの溶液を37℃に保ち、所定時間
後0.1μサンプリングし、0.1規定塩酸0.4mlを加
えて該結合物を沈殿させ、遠心分離した上澄液の
可視部（490nm）の吸光度を測定し、アドリアマ
イシン放出量を求めた。その結果を第３図に示
す。なお、放出量は３つのサンプルの平均値であ
る。
この図から、２週間経過後、約20％のアドリア
マイシンが放出されたことが分る。
参考例 ２
アドリアマイシン（Ad）−DIVEMA結合物及
びダウノマイシン（Dau）−DIVEMA結合物の制
ガン活性評価をp388白血病マウスを用いて行つ
た。
すなわち、８〜10週令の雄のCDF1、マウスの
腹腔内に１×106個のP388白血病細胞を移植し、
24時間後に前記結合物の溶液を該腹腔内に投与し
た。１群６匹のマウスを実験群として用い、生存
日数の中央値を対照群と比較し、次の式により延
命率を求めた。
延命率ILS＝Ｔ−Ｃ／Ｃ×100（％）
ただし、Ｔ：治療群生存日数中央値
Ｃ：対照群治療日数中央値
第１表にAd−DIVEMA結合物（塩型）の制ガ
ン活性を、第２表にDau−DIVEMA結合物の制
ガン活性を示す。
The present invention relates to an anthracycline antibiotic derivative, which is a novel compound, and a method for producing the same, and more particularly, to an anthracycline antibiotic derivative with low toxicity and excellent anticancer effect, and a method for producing the same. In recent years, various antibiotics have been found to have excellent anticancer effects, and among them, anthracycline antibiotics such as adriamycin and daunomycin have remarkable effects on acute leukemia and childhood cancer. These are widely used clinically. However, these anthracycline antibiotics have excellent anticancer effects and, at the same time,
It is also highly toxic to normal cells, such as a decrease in white blood cells and platelets, liver damage, and other side effects. Therefore, when using it,
Sufficient attention must be paid to side effects, which is why complicated methods such as administering small doses multiple times are used. By the way, when the anticancer active substance, which is a low-molecular compound as described above, is bound to a high-molecular compound,
It is expected that the anticancer active substance will be gradually released in the body, its concentration will be kept constant, and its distribution in the body will change, reducing toxicity and increasing the anticancer effect. In view of these circumstances, the present inventors have conducted extensive research on polymeric compounds that bind adriamycin and daunomycin, which are anthracycline antibiotics with anticancer activity, and have discovered a divinyl ether-maleic anhydride copolymer. The combination itself has an excellent anticancer effect, and since it has many acid anhydride structures in the molecule, it easily reacts with the amino group in the anthracycline antibiotic to form an amide bond. Furthermore, we discovered that this reaction product is extremely excellent as a carrier for the anthracycline antibiotic, which is an anticancer active substance, as it gradually releases the anthracycline antibiotic under mild conditions. Based on this knowledge, we have completed the present invention. That is, the present invention provides the general formula [R in the formula is a general formula (However, R' is a hydroxyl group or a methyl group) Anthracycline antibiotic residues,
n is an integer of 2 or more and 200 or less] In the presence of an anthracycline antibiotic derivative represented by and its salts and an organic solvent, the general formula (n in the formula has the same meaning as above) The divinyl ether-maleic anhydride copolymer represented by the general formula (In the formula, R' is a hydroxyl group or a methyl group.) An anthracycline antibiotic or its salt represented by the above formula (wherein R' is a hydroxyl group or a methyl group) is reacted, hydrolyzed, and then converted into a salt as desired. The present invention provides a method for producing the anthracycline antibiotic derivative represented by I) and its salts. The divinyl ether-maleic anhydride copolymer used in the present invention is a compound represented by the above general formula (), and is obtained by copolymerizing divinyl ether and maleic anhydride according to a known method. This divinyl ether-maleic anhydride copolymer itself has an excellent anticancer effect against various tumors, and among them, those with a molecular weight of less than 100,000, especially less than 30,000, have extremely low toxicity. LD 50 too
It is preferably 700 mg/Kg or more. Furthermore, since the copolymer has many acid anhydride structures in its molecule, it can easily react with the amino groups in the anthracycline antibiotic to form an amide bond. The anthracycline antibiotic which is the anticancer active substance used in the present invention is a compound represented by the above general formula (), in which R′ in the general formula () is a hydroxyl group, adriamycin, and a methyl group, It is daunomycin. These have excellent anticancer effects against acute leukemia and childhood cancer. The anthracycline antibiotic derivative of the present invention can be obtained by reacting the divinyl ether-maleic anhydride copolymer with an anthracycline antibiotic in the presence of an organic solvent such as N-methylpyrrolidone or a catalyst such as triethylamine. It can then be obtained by hydrolyzing, removing non-target substances using an ion exchange resin, ultrafiltration membrane, etc., and then freeze-drying.
If desired, after the above hydrolysis, it can be converted into a pharmacologically acceptable salt such as sodium salt, potassium salt, calcium salt, magnesium salt, etc., and then subjected to ultrafiltration, freeze-drying, etc., and then extracted as a salt. It's okay. The content of anthracycline antibiotic in the anthracycline antibiotic derivative thus obtained is preferably in the range of 5 to 40% by weight. In this anthracycline antibiotic derivative, the free carboxyl group acts as a catalyst to gradually cleave the amide bond even under mild conditions, and the anthracycline antibiotic, which is an anticancer substance, is slowly released. Ru. For example, in the case of a conjugate of adriamycin and divinyl ether-maleic anhydride copolymer, 0.1N in a test tube,
The release rate of adriamycin in phosphate buffer at pH 7.2 was approximately 20% in 2 weeks. Regarding anticancer activity against p388 leukemia mice, for example, the combination of daunomycin and divinyl ether-maleic anhydride copolymer has a maximum survival rate of 98%, while daunomycin alone has a survival rate of 48%.
It was hot. As described above, the high molecular weight anthracycline antibiotic derivative of the present invention has excellent sustained release properties of anthracycline antibiotics, which are anticancer active substances, and has low toxicity. Due to the synergistic effect with the polymer, it has a superior anticancer effect compared to when the anthracycline antibiotic is used alone. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Note that the divinyl ether-maleic anhydride copolymer is abbreviated as DIVEMA. Example 1 Adriamycin-DIVEMA conjugate 90 mg of DIVEMA (molecular weight 28500) was dissolved in 1 ml of anhydrous N-methylpyrrolidone, and 5ml of an N-methylpyrrolidone solution containing 90mg of adriamycin hydrochloride was added dropwise while stirring. Then, 5 ml of an N-methylpyrrolidone solution containing 50 μm of anhydrous triethylamine as a catalyst was added dropwise over 10 minutes. The reaction was carried out at room temperature in the absence of light for 12 hours. After the reaction,
The reaction solution was added dropwise to the n-hexane from No. 1 while stirring vigorously, and the precipitated red solid was added to the new No. 1 n-hexane.
of n-hexane. This precipitate was collected and suspended in 50 ml of redistilled water, and the pH was adjusted to 7.0 with a 1% by weight aqueous sodium bicarbonate solution while stirring.
After 1 hour all the solids had dissolved into a red solution. Next, in order to remove unreacted adriamycin and the catalyst triethylamine, 200 mg of a strong cation exchange resin (Dowex) was added twice, stirred for 10 minutes, filtered, and washed with 10 ml of water. Next, the filtrate was filtered and washed with double-distilled water using an ultrafiltration membrane (PM10, manufactured by Amicon) corresponding to fractionation with a molecular weight of 10,000. When the color of the filtrate completely disappeared, filtration was stopped, and the filtrate was passed through a Millipore filter with a pore size of 0.22 μm, and then freeze-dried to obtain 177 mg of a reddish-orange flocculent solid. This product contained 31.3% by weight of adriamycin as determined by visible absorption at 490 nm. Also, in addition to water
It was soluble in polar solvents such as DMSO, DMF, N-methylpyrrolidone, but diethyl ether,
It was insoluble in n-hexane, benzene, etc.
Furthermore, the infrared absorption spectrum is 3450, 2930, 1720,
1670, 1630, 1610, 1580, 1530, 1440, 1410,
1380, 1280, 1250, 1200, 1110, 1070, 1010,
It has an absorption at 980 cm -1 , and its visible and ultraviolet absorption spectra show absorption at 491, 292, 253, and 234 nm. The infrared absorption spectrum of the obtained adriamycin-DIVEMA conjugate is shown in FIG. 1A, and the visible and ultraviolet absorption spectra are shown in FIG. 1B. Example 2 Adriamycin-DIVEMA conjugate (salt form) Adriamycin obtained in Example 1
The aqueous solution of the DIVEMA conjugate was adjusted to pH 7.0 with a 0.1% by weight aqueous sodium bicarbonate solution, and then lyophilized through a Millipore filter with a 0.22 μm pore size.
A dark red flocculent solid is obtained quantitatively for Example 1, which is more water soluble than the product obtained in Example 1. In its infrared absorption spectrum, a large absorption appeared at 1580 cm -1 and the absorption at 1720 cm -1 decreased. Moreover, the visible and ultraviolet absorption spectra did not change. The infrared absorption spectrum of the obtained product is shown in FIG. Example 3 Adriamycin-DIVEMA conjugate In the same manner as in Example 1, 100 mg of DIVEMA (molecular weight 28500) and 15 mg of Adriamycin hydrochloride,
After reaction in 10 ml of anhydrous N-methylpyrrolidone with 5.4μ of triethylamine as a catalyst, a red-orange flocculent solid was obtained using the same procedure as in Example 1.
Obtained 130 mg. This product was found to contain 9.4% by weight of adriamycin based on the absorption spectrum in the visible region. Moreover, its infrared absorption spectrum and visible/ultraviolet absorption spectrum were similar to those of the product of Example 1. Example 4 Daunomycin-DIVEMA conjugate Similarly to Example 1, 50 mg of DIVEMA (molecular weight
28500) and 50 mg of daunomycin hydrochloride in 10 ml of anhydrous N using 10μ of triethylamine as a catalyst.
- After reaction in methylpyrrolidone, a red-orange flocculent solid was produced by the same treatment method as in Example 1.
Obtained 104 mg. This product was found to contain 24.8% by weight of daunomycin based on the absorption spectrum in the visible region. Example 5 Daunomycin-DIVEMA conjugate (salt form) The product of Example 4 was processed analogously to Example 2 to give a dark red flocculent solid quantitatively relative to Example 4. This product has higher water solubility than the product of Example 4, and its infrared absorption spectrum shows 1580 cm -1
A large absorption appeared at , and the absorption at 1720 cm -1 decreased. Further, the visible and ultraviolet absorption spectra were unchanged from those of the product of Example 4. Reference example 1 Adriamycin (Ad) in phosphate buffered saline (PBS) at 0.1 normal and pH 7.2.
Adriamycin release from DIVEMA conjugates was investigated. That is, a solution of 10 ml of PBS in which 3.3 mg of the product obtained in Example 1 was dissolved was kept at 37°C, a 0.1μ sample was taken after a predetermined time, 0.4 ml of 0.1N hydrochloric acid was added to precipitate the bound product, and the mixture was centrifuged. The absorbance in the visible region (490 nm) of the supernatant was measured to determine the amount of adriamycin released. The results are shown in FIG. Note that the release amount is the average value of three samples. This figure shows that approximately 20% of adriamycin was released after 2 weeks. Reference Example 2 The anticancer activity of adriamycin (Ad)-DIVEMA conjugate and daunomycin (Dau)-DIVEMA conjugate was evaluated using p388 leukemia mice. That is, 1×10 6 P388 leukemia cells were intraperitoneally transplanted into 8- to 10-week-old male CDF 1 mice.
After 24 hours, a solution of the conjugate was administered intraperitoneally. Using 6 mice per group as an experimental group, the median survival days were compared with that of the control group, and the survival rate was calculated using the following formula. Survival prolongation rate ILS = T-C/C x 100 (%) Where, T: Median number of survival days in the treatment group C: Median number of treatment days in the control group Table 1 shows the anticancer activity of the Ad-DIVEMA conjugate (salt form). Table 2 shows the anticancer activity of the Dau-DIVEMA conjugate.
【表】【table】
【表】【table】
第１図Ａ及びＢはそれぞれ実施例１におけるア
ドリアマイシン−DIVEMA結合物の赤外吸収ス
ペクトル及び可視・紫外吸収スペクトル、第２図
は実施例２におけるアドリアマイシン−
DIVEMA結合物（塩型）の赤外吸収スペクトル
であり、第３図は0.1規定、PH7.2のリン酸緩衝生
理食塩水中におけるアドリアマイシン−
DIVEMA結合物からのアドリアマイシンの放出
量と経過日数との関係を示すグラフである。
Figure 1 A and B are the infrared absorption spectrum and visible/ultraviolet absorption spectrum of the adriamycin-DIVEMA conjugate in Example 1, respectively, and Figure 2 is the adriamycin-DIVEMA conjugate in Example 2.
Figure 3 shows the infrared absorption spectrum of the DIVEMA conjugate (salt form).
It is a graph showing the relationship between the amount of adriamycin released from the DIVEMA conjugate and the number of days elapsed.
Claims (1)
り、かつ（Ｉ）と（）とのモル比が72：28から
97：３である〕アントラサイクリン系抗生物質誘
導体及びその塩類。 ２ 有機溶媒の存在下、一般式 （式中のｎは２以上200以下の整数である） で表わされるジビニルエーテル−無水マレイン酸
共重合体に、一般式 （式中のR′は水酸基又はメチル基である） で表わされるアントラサイクリン系抗生物質又は
その塩を反応させたのち加水分解し、次いで所望
に応じ塩に変えることを特徴とする、一般式 〔式中のＲは一般式 （ただし、R′は水酸基又はメチル基である） で表わされる繰り返し単位２以上200以下より成
り、かつ（Ｉ）と（）とのモル比が72：28から
97：３である〕アントラサイクリン系抗生物質誘
導体及びその塩類の製造方法。[Claims] 1. General formula [R in the formula is a general formula (However, R' is a hydroxyl group or a methyl group) consisting of 2 to 200 repeating units, and the molar ratio of (I) to () is 72:28 or less.
97:3] Anthracycline antibiotic derivatives and salts thereof. 2 In the presence of an organic solvent, the general formula (n in the formula is an integer of 2 or more and 200 or less) is added to the divinyl ether-maleic anhydride copolymer represented by the general formula (R' in the formula is a hydroxyl group or a methyl group) An anthracycline antibiotic or its salt represented by the formula is reacted, hydrolyzed, and then converted into a salt as desired. [R in the formula is a general formula (However, R' is a hydroxyl group or a methyl group) consisting of 2 to 200 repeating units, and the molar ratio of (I) to () is 72:28 or less.
97:3] A method for producing an anthracycline antibiotic derivative and its salts.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17683383A JPS6067490A (en) | 1983-09-24 | 1983-09-24 | Anthracycline antibiotic derivative and its preparation |
| US06/651,343 US4520162A (en) | 1983-09-24 | 1984-09-17 | Polymeric compounds with sustained anti-tumor activity and a method for the preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17683383A JPS6067490A (en) | 1983-09-24 | 1983-09-24 | Anthracycline antibiotic derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6067490A JPS6067490A (en) | 1985-04-17 |
| JPH0349923B2 true JPH0349923B2 (en) | 1991-07-31 |
Family
ID=16020629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17683383A Granted JPS6067490A (en) | 1983-09-24 | 1983-09-24 | Anthracycline antibiotic derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6067490A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63307825A (en) * | 1987-06-08 | 1988-12-15 | Nippon Beet Sugar Mfg Co Ltd | Antitumor agent and production thereof |
| US5378456A (en) * | 1993-03-25 | 1995-01-03 | American Cyanamid Company | Antitumor mitoxantrone polymeric compositions |
-
1983
- 1983-09-24 JP JP17683383A patent/JPS6067490A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6067490A (en) | 1985-04-17 |
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