JPS6157315B2 - - Google Patents
Info
- Publication number
- JPS6157315B2 JPS6157315B2 JP16392079A JP16392079A JPS6157315B2 JP S6157315 B2 JPS6157315 B2 JP S6157315B2 JP 16392079 A JP16392079 A JP 16392079A JP 16392079 A JP16392079 A JP 16392079A JP S6157315 B2 JPS6157315 B2 JP S6157315B2
- Authority
- JP
- Japan
- Prior art keywords
- mitomycin
- value
- compound
- target product
- hydroxyphenyl
- 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
- 229960004857 mitomycin Drugs 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 4
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 4
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 4
- HYFMSAFINFJTFH-UHFFFAOYSA-N Mitomycin-A Natural products O=C1C(OC)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)N2CC2NC21 HYFMSAFINFJTFH-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical class C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- HYFMSAFINFJTFH-NGSRAFSJSA-N mitomycin A Chemical compound O=C1C(OC)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@]1(OC)N2C[C@@H]2N[C@@H]21 HYFMSAFINFJTFH-NGSRAFSJSA-N 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 206010003445 Ascites Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- YGUVTKJSUAJFQW-YDBSYXHISA-N n(6)-4-aminophenylmitomycin c Chemical compound C([C@@H]1N[C@@H]1[C@@]1([C@@H]2COC(N)=O)OC)N1C(C(C=1C)=O)=C2C(=O)C=1NC1=CC=C(N)C=C1 YGUVTKJSUAJFQW-YDBSYXHISA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 229940018563 3-aminophenol Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000008342 Leukemia P388 Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HNTGDFCASLOZEZ-QHLODZMVSA-N antibiotic m83 Chemical compound C1([C@@]2([C@@H]3COC(N)=O)OC)NC1CN2C(C(C=1C)=O)=C3C(=O)C=1NC1=CC=C(O)C=C1 HNTGDFCASLOZEZ-QHLODZMVSA-N 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 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
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- -1 etc.) Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規なマイトマイシンＣ誘導体に関す
る。さらに詳しくは一般式〔〕
（式中、Ｘはオルト水酸基、メタ水酸基、又はパ
ラクロルを示す）で表わされる7a−Ｎ−（置換フ
エニル）−マイトマイシンＣに関する。
一般式〔〕で表わされる化合物〔以下化合物
（）という〕は優れた抗腫瘍性を有し、医薬と
して有用である。
従来7a−Ｎ−（置換フエニル）−マイトマイシン
Ｃとして、該置換フエニル置換基がアミノもしく
はｐ−ヒドロキシルであるものが知られている
（特開昭54−39098号）。
毒性が低く優れた抗腫瘍活性を有する化合物が
求められており、この目的のために研究した結
果、化合物（）がかなり毒性が低いにもかかわ
らず優れた抗腫瘍活性を有することを見出した。
化合物（）は特公昭40−20718号公報に記載
の方法に準じて製造することができる。すなわ
ち、式〔〕
で表わされるマイトマイシンＡと、ｐ−クロロア
ニリンまたはｍ−アミノフエノールまたはｏ−ア
ミノフエノールとを適当な溶媒中で反応させるこ
とによつて得られる。
反応に用いられる溶媒としては、原料を溶解
し、原料と反応しない溶媒であれば何でもよい。
低級アルコール（例えばメタノール、エタノー
ル、プロパノール、ブタノールなど）、エーテル
系溶媒（例えばジオキサン、テトラヒドロフラン
など）などが使用できる。
反応は、マイトマイシンＡとアミン類とのモル
比を１：100〜３：１（好ましくは１：20〜１：
１）とし、マイトマイシンＡの濃度を10-6〜105
mole/（好ましくは10-3〜１mole/）とし、
温度を−30〜50℃（好ましくは５〜30℃）として
行なうとよく、30〜50時間で完了する。
反応混合物からの目的物の分離は、公知の手
法、例えばシリカゲルを用いるカラムクロマトグ
ラフ等の方法により精製することができる。
本発明の化合物について、急性毒性、抗腫瘍性
について下記の試験結果を得た。
化合物（１−１）：7a−Ｎ−（ｐ−クロロフエニ
ル）−マイトマイシンＣ
（１−２）：7a−Ｎ−（ｍ−ヒドロキシフエニル）
−マイトマイシンＣ
（１−３）：7a−Ｎ−（ｏ−ヒドロキシフエニル）
−マイトマイシンＣ
(1) 急性毒性試験
体重が20±１ｇろdd系マウス（１群５匹）
に、段階稀釈して作成した被検溶液の0.5mlず
つを、１回、腹腔内に投与した。投与後、14日
間観察し、それぞれ死亡率を用いて、Behrens
−Ka¨rber法でLD50値を求めた。結果を第１表
に示す。
第 １ 表
化合物No. LD50（mg/Kg）
１−１ 30.0
１−２ 18.0
１−３ 37.5
２*1 21
３*2 17
(注) ＊１：７−Ｎ−（ｐ−ヒドロキシフエニ
ル）−マイトマイシンＣ
＊２：７−Ｎ−（ｐ−アミノフエニル）−マ
イトマイシンＣ
(2) Leukemia Ｐ−388に対する抗腫瘍試験（ip
−ip系）
移植後、７日目のＰ−388腹水腫瘍担癌マウ
ス（DBA／２）の腹腔から滅菌注射筒で腹水
を採取した。得られた腹水中のＰ−388細胞数
を計測し、滅菌生理食塩水を用いて、５×106
個／mlの腫瘍細胞浮遊液を作製した。Ｐ−388
細胞浮遊液の0.2ml（１×106個）を、体重が20
〜25ｇのCDFマウスの腹腔内に移植した。腫
瘍移植後24時間目に、１群３匹に分けたCDF
マウスの腹腔内に被検サンプルを１回投与し、
生存日数を60日間観察した。薬剤の効果の判定
は、移植後60日目の平均生存日数を用いて対照
群（無処理群）に対する延命率（ILS％；
Increasein Life Span）で示した。
The present invention relates to novel mitomycin C derivatives. For more details, please refer to the general formula [] It relates to 7a-N-(substituted phenyl)-mitomycin C represented by (wherein, X represents an orthohydroxyl group, a metahydroxyl group, or a parachloride). The compound represented by the general formula [] [hereinafter referred to as compound ()] has excellent antitumor properties and is useful as a medicine. Conventionally, 7a-N-(substituted phenyl)-mitomycin C in which the substituted phenyl substituent is amino or p-hydroxyl is known (Japanese Patent Application Laid-open No. 39098/1983). There is a need for a compound with low toxicity and excellent anti-tumor activity, and as a result of research for this purpose, it was found that compound (2) has excellent anti-tumor activity despite considerably low toxicity. Compound () can be produced according to the method described in Japanese Patent Publication No. 40-20718. That is, the expression [] It can be obtained by reacting mitomycin A represented by p-chloroaniline, m-aminophenol, or o-aminophenol in a suitable solvent. Any solvent may be used for the reaction as long as it dissolves the raw material and does not react with the raw material.
Lower alcohols (eg, methanol, ethanol, propanol, butanol, etc.), ether solvents (eg, dioxane, tetrahydrofuran, etc.), and the like can be used. The reaction is carried out at a molar ratio of mitomycin A and amines of 1:100 to 3:1 (preferably 1:20 to 1:1).
1), and the concentration of mitomycin A is 10 -6 to 10 5
mole/(preferably 10 -3 to 1 mole/),
The process is preferably carried out at a temperature of -30 to 50°C (preferably 5 to 30°C), and is completed in 30 to 50 hours. The target product can be purified from the reaction mixture by a known method such as column chromatography using silica gel. The following test results were obtained regarding acute toxicity and antitumor properties of the compound of the present invention. Compound (1-1): 7a-N-(p-chlorophenyl)-mitomycin C (1-2): 7a-N-(m-hydroxyphenyl)
-Mitomycin C (1-3): 7a-N-(o-hydroxyphenyl)
-Mitomycin C (1) Acute toxicity test Rodd mice weighing 20±1g (5 mice per group)
Then, 0.5 ml of the test solution prepared by stepwise dilution was intraperitoneally administered once. After administration, observation was made for 14 days, and mortality rates were used for each
−LD 50 value was determined by Ka¨ber method. The results are shown in Table 1. Table 1 Compound No. LD 50 (mg/Kg) 1-1 30.0 1-2 18.0 1-3 37.5 2 *1 21 3 *2 17 (Note) *1: 7-N- (p-hydroxyphenyl) -Mitomycin C *2: 7-N-(p-aminophenyl)-Mitomycin C (2) Antitumor test against Leukemia P-388 (ip
-ip system) Seven days after transplantation, ascites was collected from the abdominal cavity of P-388 ascites tumor-bearing mice (DBA/2) using a sterile syringe. The number of P-388 cells in the obtained ascites was counted, and 5 × 10 6 cells were added using sterile physiological saline.
A tumor cell suspension was prepared at a concentration of cells/ml. P-388
Add 0.2 ml (1 x 106 cells) of cell suspension to a body weight of 20
~25 g CDF mice were implanted intraperitoneally. 24 hours after tumor implantation, CDF was divided into 3 animals per group.
The test sample was administered once intraperitoneally to the mouse,
Survival days were observed for 60 days. The effectiveness of the drug is determined by using the average survival days 60 days after transplantation as the survival rate (ILS%) compared to the control group (untreated group).
Increase in Life Span).
【表】
これらの抗腫瘍活性は、特開昭54−39098号に
記載の７−Ｎ−（ｐ−ヒドロキシフエニル）−マイ
トマイシンＣ、７−Ｎ−（ｐ−アミノフエニル）−
マイトマイシンＣのLeukemia Ｐ−388に対する
試験結果（試験方法は本願の方法と同じで、対照
群における平均生存日数もほぼ一致している）と
比較して優れており、毒性も低いところから、本
発明の化合物は公知の類似化合物に比較して抗腫
瘍剤として極めて優れた医薬となることが期待さ
れる。
本発明化合物を抗腫瘍剤として用いるに際して
は、本発明の化合物0.1〜0.5mg/Kgを注射用蒸溜
水、ブドウ糖注射液に溶解して、静脈内もしくは
腹腔内に１日１回投与すればよい。もちろん、年
令、症状により適宜増減できる。また、同様の投
与量で経口的に投与することができる。経口投与
に際しては、適当な賦形剤と共に、錠剤、粉剤、
粒剤として投与できる。さらに、症状により動脈
内注射、胸、腹腔注入、腫瘍部への直接注入が可
能である。
以下、本発明の目的化合物である一般式〔〕
で示されるマイトマイシンＣ誘導体の製法を具体
的に実施例で説明する。
実施例 １
7a−Ｎ−（ｐ−クロロフエニル）−マイトマイシ
ンＣ
マイトマイシンA0.4ｇおよびｐ−クロロアニ
リン0.8ｇをメタノール30mlに加え、混合物を一
昼夜撹拌する。反応終了後反応液を減圧濃縮し、
真空下に乾燥したのち、クロロホルム：アセトン
＝10：３の溶液10mlに溶解し、少量のイソプピル
エーテルを加えて析出する沈澱物を取し、次
に、クロロホルム：アセトン＝１：１を展開液と
したシリカゲルカラムクロマトで処理し、アセト
ン−ヘキサンにより結晶化させると、緑色針状結
晶として目的物が340mg得られる（収率66.6％）。
目的物は、アセトン：クロロホルム＝１：１を
展開液としたシリカゲル薄層クロマトグラフイー
により、Rf値0.28の緑色スポツトを示す。該目的
物は、明確な融点を示さない。日本電子JNM−
PMX60で測定した該目的物の代表的なプロトン
の60MHz n.m.r.ケミカルシフトなテトラメチル
シランを内部標準として、δ値（ppm）で示す
（測定溶媒；重水素置換ジメチルスルホキシド）。
(a)：6.3 (b)：3.18 (c)：1.40 (d)：8.37 (e)：
6.83〜7.33
該目的物のKBr錠剤法による赤外線吸収曲線を
第１図に示す。
元素分析値（％）
実測値 Ｃ：57.09 Ｈ：3.94 Ｎ：12.85 Cl：7.95
計算値（C21H17O5N4Cl）
Ｃ：57.22 Ｈ：3.89 Ｎ：12.71 Cl：8.04
実施例 ２
7a−Ｎ−（ｍ−ヒドロキシフエニル）−マイトマ
イシンＣ
実施例１において、ｐ−クロロアニリンの代わ
りに、ｍ−アミノフエノールを用いて、実施例１
と全く同様に処理すると目的物が緑色針状結晶と
して285mg得られる（収率58.3％）。
目的物は、アセトン：クロロホルム＝１：１を
展開液とした薄層クロマトグラフイーにより、
Rf値0.15の緑色スポツトを示す。該目的物は、明
確な融点を示さない。日本電子JNM−PMX60で
測定した該目的物の代表的なプロトンの60MHz
のn.m.r.のケミカルシフトを、テトラメチルシラ
ンを内部標準として、δ値（ppm）で示す（測
定溶媒；重水素置換ジメチルスルホキシド）。
(a)：6.3 (b)：3.18 (c)：1.42 (d)：8.13 (e)：
6.27〜6.6 (f)：9.3
該目的物のKBr錠剤法による赤外部吸収曲線を
第２図に示す。
元素分析値（％）
実測値 Ｃ：59.78 Ｈ：4.41 Ｎ：13.23
計算値（C21H18O6N4）
Ｃ：59.71 Ｈ：4.30 Ｎ：13.27
実施例 ３
7a−Ｎ−（ｏ−ヒドロキシフエニル）−マイトマ
イシンＣ
実施例１において、ｐ−クロロアニリンの代わ
りに、ｏ−アミノフエノールを用いて、実施例１
と全く同様に処理すると、目的物が緑色針状結晶
として115mg得られる（収率23.5％）。
目的物は、アセトン：クロロホルム＝１：１を
展開液としたシリカゲル薄層クロマトグラフイー
により、Rf値0.15の淡褐色がかつた緑色スポツト
を示す。該目的物は明確な融点を示さない。日本
電子JNM−PMX60で測定した該目的物の代表的
なプロトンの60MHzのn.m.r.のケミカルシフト
を、テトラメチルシランを内部標準として、δ値
で示す（測定溶媒：重水素置換ジメチルスルホキ
シド）。
(a)：6.32 (b)：3.18 (c)：1.43 (d)：7.73
(e)：6.87〜6.8 (f)：9.30
該目的物のKBr錠剤法による赤外部吸収曲線を
第３図に示す。
元素分析値（％）
実測値 Ｃ：59.68 Ｈ：4.38 Ｎ：13.06
計算値（C21H18O6N4）
Ｃ：59.71 Ｈ：4.30 Ｎ：13.27[Table] These antitumor activities are as follows: 7-N-(p-hydroxyphenyl)-mitomycin C, 7-N-(p-aminophenyl)-
The present invention is superior to the test results of mitomycin C against Leukemia P-388 (the test method is the same as the method of the present application, and the average survival days in the control group are also almost the same) and has low toxicity. The compound is expected to be an extremely superior antitumor agent compared to known similar compounds. When using the compound of the present invention as an antitumor agent, 0.1 to 0.5 mg/Kg of the compound of the present invention may be dissolved in distilled water for injection or glucose injection and administered once a day intravenously or intraperitoneally. . Of course, the dose can be increased or decreased as appropriate depending on age and symptoms. It can also be administered orally at similar dosages. For oral administration, tablets, powders,
Can be administered as granules. Furthermore, depending on the symptoms, intra-arterial injection, chest or abdominal injection, or direct injection into the tumor site is possible. Hereinafter, the general formula [] which is the object compound of the present invention
The method for producing the mitomycin C derivative shown below will be specifically explained in Examples. Example 1 7a-N-(p-chlorophenyl)-mitomycin C 0.4 g of mitomycin A and 0.8 g of p-chloroaniline are added to 30 ml of methanol and the mixture is stirred overnight. After the reaction is completed, the reaction solution is concentrated under reduced pressure.
After drying under vacuum, dissolve in 10 ml of a solution of chloroform:acetone = 10:3, add a small amount of isopropyl ether to collect the precipitate, then add chloroform:acetone = 1:1 as a developing solution. The product is treated with silica gel column chromatography and crystallized with acetone-hexane to obtain 340 mg of the desired product as green needle-like crystals (yield 66.6%). The target product showed a green spot with an Rf value of 0.28 by silica gel thin layer chromatography using acetone:chloroform=1:1 as a developing solution. The object does not exhibit a clear melting point. JEOL JNM−
The value is shown in δ value (ppm) using tetramethylsilane, which has a 60MHz nmr chemical shift of a representative proton of the target object measured with PMX60, as an internal standard (measurement solvent: deuterium-substituted dimethyl sulfoxide). (a): 6.3 (b): 3.18 (c): 1.40 (d): 8.37 (e):
6.83-7.33 The infrared absorption curve of the target product obtained by the KBr tablet method is shown in FIG. Elemental analysis value (%) Actual value C: 57.09 H: 3.94 N: 12.85 Cl: 7.95 Calculated value (C 21 H 17 O 5 N 4 Cl)
C: 57.22 H: 3.89 N: 12.71 Cl: 8.04 Example 2 7a-N-(m-hydroxyphenyl)-mitomycin C In Example 1, using m-aminophenol instead of p-chloroaniline, Example 1
When treated in exactly the same manner as above, 285 mg of the target product was obtained as green needle-shaped crystals (yield 58.3%). The target product was obtained by thin layer chromatography using acetone:chloroform=1:1 as a developing solution.
Shows a green spot with an Rf value of 0.15. The object does not exhibit a clear melting point. 60MHz of representative protons of the target object measured with JEOL JNM-PMX60
The nmr chemical shift of is shown in δ value (ppm) using tetramethylsilane as an internal standard (measurement solvent: deuterium-substituted dimethyl sulfoxide). (a): 6.3 (b): 3.18 (c): 1.42 (d): 8.13 (e):
6.27-6.6 (f): 9.3 The infrared absorption curve of the target product obtained by the KBr tablet method is shown in FIG. Elemental analysis value (%) Actual value C: 59.78 H: 4.41 N: 13.23 Calculated value (C 21 H 18 O 6 N 4 )
C: 59.71 H: 4.30 N: 13.27 Example 3 7a-N-(o-hydroxyphenyl)-mitomycin C In Example 1, using o-aminophenol instead of p-chloroaniline, Example 1
When treated in exactly the same manner as above, 115 mg of the target product was obtained as green needle-like crystals (yield 23.5%). The target product showed a light brownish green spot with an Rf value of 0.15 by silica gel thin layer chromatography using acetone:chloroform=1:1 as a developing solution. The target product does not exhibit a clear melting point. The 60MHz nmr chemical shift of a representative proton of the target object measured with JEOL JNM-PMX60 is shown as a δ value using tetramethylsilane as an internal standard (measurement solvent: deuterium-substituted dimethyl sulfoxide). (a): 6.32 (b): 3.18 (c): 1.43 (d): 7.73
(e): 6.87 to 6.8 (f): 9.30 The infrared absorption curve of the target product obtained by the KBr tablet method is shown in FIG. Elemental analysis value (%) Actual value C: 59.68 H: 4.38 N: 13.06 Calculated value (C 21 H 18 O 6 N 4 )
C: 59.71 H: 4.30 N: 13.27
第１図は7a−Ｎ−（ｐ−クロロフエニル）−マイ
トマイシンＣの、第２図は7a−Ｎ−（ｍ−ヒドロ
キシフエニル）−マイトマイシンＣの、第３図は
7a−Ｎ−（ｏ−ヒドロキシフエニル）−マイトマイ
シンＣのKBr錠剤法による赤外部吸収曲線を示
す。
Figure 1 shows 7a-N-(p-chlorophenyl)-mitomycin C, Figure 2 shows 7a-N-(m-hydroxyphenyl)-mitomycin C, and Figure 3 shows 7a-N-(p-chlorophenyl)-mitomycin C.
7a shows an infrared absorption curve of N-(o-hydroxyphenyl)-mitomycin C by the KBr tablet method.
Claims (1)
ラクロルを示す）で表わされる7a−Ｎ−（置換フ
エニル）−マイトマイシンＣ。 ２ 一般式〔〕 （式中、Ｘはオルト水酸基、メタ水酸基、又はパ
ラクロルを示す）で表わされる7a−Ｎ−（置換フ
エニル）−マイトマイシンＣを含有してなる抗腫
瘍剤。[Claims] 1. General formula [] 7a-N-(substituted phenyl)-mitomycin C represented by (wherein, X represents an orthohydroxyl group, a metahydroxyl group, or a parachloride). 2 General formula [] An antitumor agent containing 7a-N-(substituted phenyl)-mitomycin C represented by the formula (wherein, X represents an ortho-hydroxyl group, a meta-hydroxyl group, or a parachloride).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16392079A JPS5686184A (en) | 1979-12-17 | 1979-12-17 | Novel mitomycin c derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16392079A JPS5686184A (en) | 1979-12-17 | 1979-12-17 | Novel mitomycin c derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5686184A JPS5686184A (en) | 1981-07-13 |
| JPS6157315B2 true JPS6157315B2 (en) | 1986-12-06 |
Family
ID=15783328
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16392079A Granted JPS5686184A (en) | 1979-12-17 | 1979-12-17 | Novel mitomycin c derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5686184A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ199617A (en) * | 1981-05-15 | 1985-08-30 | University Patents Inc | Azirino(2',3',:3,4)pyrrolo(1,2-a)indole-4,7-dione derivatives and pharmaceutical compositions |
| JPS58106868A (en) * | 1981-12-18 | 1983-06-25 | Hitachi Ltd | Insulated gate type field-effect semiconductor device and manufacture thereof |
| NZ206932A (en) * | 1983-02-07 | 1987-08-31 | University Patents Inc | Certain 6-(heterocyclyl or amino) mitosanes and pharmaceutical compositions |
-
1979
- 1979-12-17 JP JP16392079A patent/JPS5686184A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5686184A (en) | 1981-07-13 |
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