JPS63277689A - Anthracyclin compound and its production - Google Patents
Anthracyclin compound and its productionInfo
- Publication number
- JPS63277689A JPS63277689A JP3370887A JP3370887A JPS63277689A JP S63277689 A JPS63277689 A JP S63277689A JP 3370887 A JP3370887 A JP 3370887A JP 3370887 A JP3370887 A JP 3370887A JP S63277689 A JPS63277689 A JP S63277689A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- benzyl
- present
- benzyl group
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- -1 benzyl halide Chemical class 0.000 claims abstract description 4
- 230000003115 biocidal effect Effects 0.000 claims abstract description 4
- 239000012442 inert solvent Substances 0.000 claims abstract description 4
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006704 dehydrohalogenation reaction Methods 0.000 abstract description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 abstract description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 4
- LKBBOPGQDRPCDS-YAOXHJNESA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-ethyl-4,6,9,10,11-pentahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@]([C@@H](C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)O)(O)CC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 LKBBOPGQDRPCDS-YAOXHJNESA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- LKBBOPGQDRPCDS-UHFFFAOYSA-N Oxaunomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C(O)=C2C(O)C(CC)(O)CC1OC1CC(N)C(O)C(C)O1 LKBBOPGQDRPCDS-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 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 2
- 241001465754 Metazoa Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000282326 Felis catus Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229930188522 aclacinomycin Natural products 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 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 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、抗腫瘍活性を有するアントラサイクリン化合
物及びその製造方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an anthracycline compound having antitumor activity and a method for producing the same.
アントラサイクリン化合物としては、従来より放線菌の
培養液より得られるダウノマイシン（米国特許第３６１
６２４２号明細書参照）、アドリアマイシン（米国特許
第３５９００２８号明細書参照）及びアクラシノマイシ
ン（特公昭５３−１２４８１号公報参照）等が知られて
おり、抗腫瘍剤として広く臨床的に利用されている。As an anthracycline compound, daunomycin (U.S. Pat. No. 361
6242), adriamycin (see US Pat. No. 3,590,028), and aclacinomycin (see Japanese Patent Publication No. 12481/1981), etc., and are widely used clinically as antitumor agents. There is.
一方、更に強力な抗腫瘍活性作用を示す化合物を開発す
べくこれらの各種誘導体、例えば４°−〇−テトラヒド
口ビラ二一ルアドリアマインン（特公昭５６−４７１９
４号公報参照）、Ｎ−トリフルオロアドリアマインン（
米国特許第４０３５５６６号明細書参照）、３′−デア
ミノ−３’−（４−モルホルニル）１０−ヒドロキシ−
１３−デオキシ力ルバノマイシン（特開昭６１−１６７
６９６号公報参照）が提供されている。On the other hand, in order to develop compounds that exhibit even stronger anti-tumor activity, various derivatives of these, such as 4°-〇-tetrahydradriamine (Japanese Patent Publication No. 56-4719
4), N-trifluoroadriamine (see Publication No. 4), N-trifluoroadriamine (
(see U.S. Pat. No. 4,035,566), 3'-deamino-3'-(4-morphonyl)10-hydroxy-
13-Deoxyrubanomycin (Japanese Patent Application Laid-Open No. 61-167
696) is provided.
上記のアントラサイクリン化合物は上述の如く、臨床的
に広く利用されるか、臨床試験に供されているものもあ
るが、必ず、しも、抗腫瘍作用、毒性双方について共に
満足できるものとはいえない。As mentioned above, some of the above anthracycline compounds are widely used clinically or are being subjected to clinical trials, but they are not always satisfactory in terms of both antitumor activity and toxicity. do not have.
しかも、抗腫瘍剤は試験管内試験と動物試験の結果が直
接ヒトの抗がん作用に対応するとは限らない。Moreover, the results of in vitro tests and animal tests for antitumor drugs do not necessarily correspond directly to the anticancer effects in humans.
そのため、抗腫瘍剤として一応の評価がなされているア
ントラサイクリン化合物の新たな部類に属するものの提
供が望まれている。Therefore, it is desired to provide a new class of anthracycline compounds that have been evaluated to some extent as antitumor agents.
そこで、本発明者らの一部によって発酵法による製造が
可能となった１０− ヒドロキシ−１３−デオキソカル
ミノマイシン（特開昭６１−３３１９４号公報参照。Therefore, some of the present inventors have made it possible to produce 10-hydroxy-13-deoxocarminomycin by a fermentation method (see JP-A-61-33194).
同公報中、抗生物質０７８８−７） の各種誘導体に
ついて研究したところ、そのダウノサミニル基のＮ−ベ
ンジル化物が実験動物腫瘍に対して、強い抗腫瘍活性を
示すことを見出し、本発明を完成した。As a result of research on various derivatives of the antibiotic 0788-7) described in the same publication, it was discovered that the N-benzylated product of the daunosaminyl group exhibited strong antitumor activity against tumors in experimental animals, and the present invention was completed.
（以下、この頁余白）
〔問題点を解決するための手段〕
しかして、本発明は次式
式中、Ｒ４はベンジル基を表し、Ｒ２は水素原子または
ベンジル基を表す。(Hereinafter, the margin of this page) [Means for solving the problem] Accordingly, the present invention provides the following formula in which R4 represents a benzyl group, and R2 represents a hydrogen atom or a benzyl group.
で示されるアントラサイクリン化合物及びその製造方法
を提供するものである。The present invention provides an anthracycline compound represented by the following formula and a method for producing the same.
すなわち、本発明は上記式（１）に示すごとく、ダウノ
サミニル基のＮ−モノベンジル置換体とＮ−ジベンジル
置換体の２種の新規アントラサイクリン化合物を提供す
るものであり、本発明者等は前者をＮ−ペンジルオキザ
ウノマイシン（Ｎ−ｂｅｎｚｙｌｏｘａｕｎｏｍｙｃｉ
ｎ） 、後者をＮ、Ｎ−ジベンジルオキザウノマイシ
ン（Ｎ、 Ｎ−ｄｉｂｅｎｚｙｌｏｘａｕｎｏｍｙｃｉ
ｎ） とそれぞれ命名し該明細書においては上記名称
で記載する。That is, the present invention provides two types of novel anthracycline compounds, an N-monobenzyl-substituted product and an N-dibenzyl-substituted product of a daunosaminyl group, as shown in the above formula (1). N-benzyloxaunomycin
n), the latter as N,N-dibenzyloxaunomycin (N,N-dibenzyloxaunomycin).
n) and will be described with the above names in the specification.
これらの化合物は後述するごとく、実験動物腫瘍に対し
て強抗腫瘍性作用を有し、それ自体抗ガン剤として有用
である。As described below, these compounds have strong antitumor activity against tumors in experimental animals, and are themselves useful as anticancer agents.
次に、これらの化合物は本明細書に開示する第２の発明
の方法によって製造することができる。These compounds can then be produced by the method of the second invention disclosed herein.
第２の発明は、次式
で示される抗生物質０７８８−７ （オキザウノマイシ
ンａｘａｕｎｏＢｃｉｎ）に不活性溶媒中ハロゲン化ベ
ンジルを脱ハロゲン化水素剤の存在下反応させることを
特徴とする特許
式中、Ｒ，はベンジル基を表し、Ｒ２は水素原子または
ベンジル基を表す。The second invention is characterized in that the antibiotic 0788-7 (oxaunomycin axaunoBcin) represented by the following formula is reacted with a benzyl halide in an inert solvent in the presence of a dehydrohalogenating agent. , R, represents a benzyl group, and R2 represents a hydrogen atom or a benzyl group.
で示されるアントラサイクリン化合物の製造方法である
。This is a method for producing an anthracycline compound shown in
この発明にいうオキザウノマイシン（ａｘａｕｎｏｍｙ
ｃｉｎ） とは実質的に同一の化合物であればそれが
化学合成法（例えば、特開昭６１−１６７６９６号公報
参照）によるか、発酵法（特開昭６１−３３１９４号公
報参′照）によるかを問わず包含され、本発明の出発原
料とすることができる。Oxaunomycin referred to in this invention
If the compound is substantially the same as cin), it can be synthesized by chemical synthesis (for example, see JP-A-61-167696) or fermentation method (see JP-A-61-33194). Any of these can be included and used as the starting material of the present invention.
不活性溶媒とは、本発明の脱ハロゲン化水素反応に実質
的に悪影響を与えないものであれば、その種類を問わな
いが、一般にＮ、Ｎ−ジメチルホルムアミド（以下ＤＭ
Ｆという）、ジメチルスルホキシド、テトラヒドロフラ
ン、ジオキサン等を好適なものとして挙げることができ
る。The inert solvent may be of any type as long as it does not substantially adversely affect the dehydrohalogenation reaction of the present invention, but it is generally N,N-dimethylformamide (hereinafter referred to as DM).
F), dimethyl sulfoxide, tetrahydrofuran, dioxane, etc. can be mentioned as suitable examples.
マタ、ハロゲン化ベンジルとは、塩素、臭素または、ヨ
ウ素化ベンジルをいい、反応性を考慮すると臭素化物が
好適である。The term halogenated benzyl refers to chlorine, bromine, or iodinated benzyl, and in consideration of reactivity, brominated compounds are preferred.
次いで、脱ハロゲン化水素剤としては炭酸カリウム等の
無機塩、トリエチルアミン、ジメチルアミノピリジン等
の有機アミン、酸化銀等の金属酸化物を用いることがで
き、好適なものとしては、トリエチルアミン、ジメチル
アニリン等を挙げることができる。Next, as the dehydrohalogenation agent, inorganic salts such as potassium carbonate, organic amines such as triethylamine and dimethylaminopyridine, and metal oxides such as silver oxide can be used, and preferred examples include triethylamine, dimethylaniline, etc. can be mentioned.
反応温度、反応時間等は用いる溶媒、脱ハロゲン化水素
剤の種類によって最適条件が異なり臨界的でないが、有
機アミンを用いた場合は通常、室温付近の温度下５〜６
０時間の条件を設定すればよい。Optimum conditions for reaction temperature, reaction time, etc. vary depending on the solvent used and the type of dehydrohalogenating agent and are not critical, but when an organic amine is used, it is usually 5 to 6 hours at a temperature around room temperature.
It is sufficient to set a condition of 0 hours.
かくして、上記式（Ｉ）で示されるＮ−ペンジルオキザ
ウノマイシン及びＮ、 ？Ｉ−ジベンジルオキザウノマ
イシンは混合物として生成するが、これらを単離するに
はアントラサイクリン化合物製造の技術分野において用
いられる精製方法によればよ（、例えばシリカゲル、吸
着性合成樹脂等を用いる各種クロマトグラフィーによる
か、イオン交換樹脂を用いるクロマトグラフィーまたは
有機溶媒抽出法等を単独または適宜組合わせて用いれば
よい。Thus, N-penzyloxaunomycin represented by the above formula (I) and N, ? I-dibenzyloxaunomycin is produced as a mixture, which can be isolated by purification methods used in the technical field of anthracycline compound production (e.g., using silica gel, adsorbent synthetic resins, etc.). Various chromatography methods, chromatography using ion exchange resins, organic solvent extraction methods, etc. may be used alone or in appropriate combinations.
上記式（Ｉ）で示される本発明のアントラサイクリン化
合物の作用は次の抗腫瘍性試験によって容易に確認する
ことができる。The action of the anthracycline compound of the present invention represented by the above formula (I) can be easily confirmed by the following antitumor test.
実験腫瘍動物に対する効果は、ＣＤＰＩマウスの腹腔内
へマウス白血病し１２１０細胞をＩ ＸＩＯ’ケ／マウ
ス移殖し、２４時間後より連日９日間本発明の化合物を
腹腔内へ投与するか、また、１．５および９日目にそれ
ぞれ間歇投与し、対照区（生理食塩水投与）に比較し算
定した延命率（Ｔ／Ｃ，％）で求めた。The effect on experimental tumor animals is determined by intraperitoneally transplanting murine leukemia 1210 cells into CDPI mice and intraperitoneally administering the compound of the present invention every day for 9 days starting 24 hours later. Intermittent administration was performed on the 1.5th and 9th day, respectively, and the survival rate (T/C, %) was calculated in comparison with the control group (physiological saline administration).
その結果を第１表及び第２表に示す。The results are shown in Tables 1 and 2.
第１表
Ｎ−ペンジルオキザウノマイシンの抗腫瘍性（Ｔ／Ｃ，
％）０毒性
第２表
９毒性
第１表及び第２表で明らかなごとく、本発明のアントラ
サイクリン化合物は実験動物腫瘍に対し、微量で著効を
表す。Table 1 Antitumor properties of N-penzyloxaunomycin (T/C,
%) 0 Toxicity Table 2 9 Toxicity As is clear from Tables 1 and 2, the anthracycline compound of the present invention is highly effective against tumors in experimental animals even in minute amounts.
以下に実施例を示し、本発明をより詳細に説明する。EXAMPLES The present invention will be explained in more detail with reference to Examples below.
実施例１
本発明のアントラサイクリン化合物の製造方法オキザウ
ノマイシンのフリーベース２０ｍｇをＤＭＦｌｒｎｌに
溶解させ、臭化ベンジル０．１５ｍ１とトリエチルアミ
ン１５μ！の存在下に室温、暗所で１６時間反応させた
。Example 1 Method for producing an anthracycline compound of the present invention 20 mg of free base of oxaunomycin was dissolved in DMFlrnl, and 0.15 ml of benzyl bromide and 15 μl of triethylamine were added. The reaction was carried out for 16 hours at room temperature in the dark.
反応終了後、反応液を冷水５０ｍ１中に注ぎ、過剰の試
薬等を除去する為、ヘキサン（４０ｍ、 ２〇ｍｆ計６
０１ｎｌ） にて洗った。水層を０．ＩＮ重曹水にて
ｐＨ８〜９として酢酸エチル（４０ｍ！、 ２（ｌｄ、
２０ＴＲ１計８〇−）にて抽出した。この酢酸エチル
層を水洗（２〇−９２〇−計４０ｍ１り Ｌ、ボウ硝
で乾燥した後濃縮乾固した。After the reaction is complete, pour the reaction solution into 50 ml of cold water, and add hexane (40 ml, 20 mf total 6
01nl). water layer to 0. Ethyl acetate (40 m!, 2 (ld,
Extracted with 20TR1 total 80-). The ethyl acetate layer was washed with water (20-920 liters in total, 40 ml), dried over sulfur salt, and then concentrated to dryness.
この粗生成物をクロロホルム／メタノール（９／１）を
展開溶媒とする単離用薄層クロマトグラフィーにて精製
し、Ｎ−ペンジルオキザウノマインン（以下（１）とい
う）を７．８ ｔｎｇ、 Ｎ、Ｎ−ジヘンジルオキザウ
ノマイシン（以下〔２〕という）を７．８ｍｇそれぞれ
フリーベートとして得た。This crude product was purified by isolation thin layer chromatography using chloroform/methanol (9/1) as a developing solvent to obtain 7.8 7.8 mg of each of tng, N, N-dihendyloxaunomycin (hereinafter referred to as [2]) was obtained as a freebate.
実施例２〜６
各種反応条件下による製造例
実施例１と同様な処理を各種反応条件下に行った結果を
以下にまとめる。Examples 2 to 6 Production Examples under Various Reaction Conditions The same treatments as in Example 1 were carried out under various reaction conditions and the results are summarized below.
以上より本発明の方法によれば、反応条件を選択するこ
とにより、本発明の化合物の生成比を調節可能である。As described above, according to the method of the present invention, the production ratio of the compound of the present invention can be adjusted by selecting the reaction conditions.
本発明の化合物の理化学的性質
Ｎ−ペンジルオキザウノマイシン〔１〕シリ力ゲル薄層
クロマトグラフィー（クロロホルム／メタノール（９／
１） ’） ：Ｒｆ＝０．３３融点＝１１９〜１２４
℃
〔α〕ル６： ＋２９５° （ｃｌ’１．１ クロロホ
ルム）プロトン−ＮＭＲ（９０Ｍ）Ｉｚ、 ＣＤ Ｃ１
，、内部標準テトラメチルシラン）：
δ（ｐｐｔｎ）
７、９３ （１）１． ｄｄ、 Ｈ−１）、 ７．７３
（ＩＩＩ、 ｔ、 Ｈ−２）、 ７．２〜７．４（Ｉ
Ｈ，Ｈ−３）、 （５Ｈ，−ＮＨＣＨ，Ｃｓ１ｌｓ）、
５．４７ （ｌｌ’ｌ、 ｍ、 Ｈ−１’ ）、 ５
．１７ （ＩＨ。Physicochemical properties of the compounds of the present invention N-penzyloxaunomycin [1] Silica gel thin layer chromatography (chloroform/methanol
1) '): Rf=0.33 Melting point=119-124
°C [α] Le 6: +295° (cl'1.1 chloroform) Proton-NMR (90M) Iz, CD C1
,, internal standard tetramethylsilane): δ(pptn) 7,93 (1)1. dd, H-1), 7.73
(III, t, H-2), 7.2-7.4 (I
H,H-3), (5H,-NHCH,Cs1ls),
5.47 (ll'l, m, H-1'), 5
．． 17 (IH.
ｍ、 Ｈ−７）、 ４．９２（ＬＨ，ｂｒｏａｄ ｓ、
Ｈ−１０）、 ４．１２（１）１． ｄＱ、 ｆ（−
５’ ）。m, H-7), 4.92 (LH, broad s,
H-10), 4.12(1)1. dQ, f(-
5').
３．７４（２Ｈ，八〇、 −ＮＨＣＬＣ−Ｌ）、 ｃａ
３．７ （ｌｔｌ、 Ｈ−４°）、 ｃａ３．０（ＩＨ
，ｍ、 Ｈ−３’ ）、 Ｃａ２．２ （２Ｈ，ｍ、
Ｈ−８）、 ｃａｔ、 ８ （２）１． ）ｌ−１３）
。3.74 (2H, 80, -NHCLC-L), ca
3.7 (ltl, H-4°), ca3.0 (IH
, m, H-3'), Ca2.2 (2H, m,
H-8), cat, 8 (2) 1. )l-13)
.
（２Ｈ，Ｈ−２°）、 １．３８ （３Ｈ，ｄ、 Ｉｔ
−５″）、 １．１１（３）１． ｔ、 Ｈ−１４）赤
外線吸収スペクトル（ＫＢｒ） ａｍ−’１６００、１
４６０．１４４０．１４０５．１２９０．１２４０．１
２００．１１７０．１１２０゜１０７０、１（１２０，
１０１０，９８ＯＮ、Ｎ−ジベンジルオキザウノマイシ
ン〔２〕シリ力ゲル薄層クロマトグラフィー（クロロホ
ルム／メタノール（９／ １ ） ） ：Ｒｆ＝０．
７７融点二８２〜８６℃
〔α） Ｂ” ： ＋２０５° （ｃＯ，１クロロホル
ム）プロトン−ＮＭＲ（９０ＭＨｚ、 ＣＤ Ｃ１ｓ、
内部標準テトラメチルシラン） ：
δ（ρｐｍ）
１３、６８（ＩＨ，ｂｒｏａｄ ｓ、 ｐｈｅｎｏｌｉ
ｃ ０ｆ（）、 １２．８５（ｌｔｌ、 ｂｒｏａｄｓ
、 ｐｈｅｎｏｌｉｃ ＯＨ）、 １２．１６（ＬＨ，
ｂｒｏａｄ ｓ、 ｐｈｅｎｏｌｉｃ ＯＨ）。(2H, H-2°), 1.38 (3H, d, It
-5''), 1.11(3)1.t, H-14) Infrared absorption spectrum (KBr) am-'1600, 1
460.1440.1405.1290.1240.1
200.1170.1120゜1070, 1 (120,
1010,98ON, N-dibenzyloxaunomycin [2] Silica gel thin layer chromatography (chloroform/methanol (9/1)): Rf=0.
77 Melting point 282-86℃ [α) B”: +205° (cO, 1 chloroform) Proton-NMR (90MHz, CD C1s,
Internal standard tetramethylsilane): δ (ρpm) 13, 68 (IH, broads, phenoli
c 0f(), 12.85(ltl, broads
, phenolic OH), 12.16 (LH,
broad s, phenolic OH).
７、９２ （ＩＨ，ｄｄ、 Ｈ−１＞、 ７．７３ （
ＩＨ，ｔ、 Ｈ−２） 、 ７．１〜７．４ （ＩＦＩ
。7, 92 (IH, dd, H-1>, 7.73 (
IH, t, H-2), 7.1~7.4 (IFI
.
Ｈ３） 、 （１０Ｈ，−ＮＨＣＨ，（：５Ｈｓ）、
５．４８ （ＩＨ，ｍ、 Ｈ’−１’ ）、 ５．１５
（ＩＨ，ｍ、 Ｈづ）、４．９４（ＩＨ，ｂｒｏａｄ
ｓ、Ｈ−１０）、 ３．６〜４．２（ＩＨ。H3), (10H, -NHCH, (:5Hs),
5.48 (IH, m, H'-1'), 5.15
(IH, m, Hzu), 4.94 (IH, broad
s, H-10), 3.6-4.2 (IH.
Ｈ−５°）、（１１（、Ｈ−４”）、（４Ｈ，−ＮＨＣ
Ｈ２Ｃ，Ｈ５）、ｃａ３．１（ＩＨ，ｒｎ、Ｈ−３°）
、 Ｃａ２．２ （２Ｈ，ｍ、 Ｉｆ−８）、 ｃａｌ
、 ８ （２Ｈ，ｆｌ−１３）、 （２Ｈ，Ｈ−２°）
。H-5°), (11(, H-4"), (4H, -NHC
H2C, H5), ca3.1 (IH, rn, H-3°)
, Ca2.2 (2H, m, If-8), cal
, 8 (2H, fl-13), (2H, H-2°)
.
１、３７ （ｌ）ｌ、 ｔｒ、 ）ｌ−６’ ＞、 １
．１３ （１）１． ｔ、 ）ｌ−１４）赤外線吸収ス
ペクトル（ＫＢｒ） ｃｍ−’１６００、１４５５．
１４４０．１４０５．１３７０．１２９０．１２４０．
１２００．１１７０゜１１３５、１０７０．１０２５．
９８０〔発明の効果〕
本発明の新規アントラサイクリン化合物は抗腫瘍活性を
有する有用な化合物であり、本発明の製法は同新規有用
な化合物を製造する方法である。1, 37 (l)l, tr, )l-6'>, 1
．． 13 (1)1. t, )l-14) Infrared absorption spectrum (KBr) cm-'1600, 1455.
1440.1405.1370.1290.1240.
1200.1170°1135, 1070.1025.
980 [Effects of the Invention] The novel anthracycline compound of the present invention is a useful compound having antitumor activity, and the production method of the present invention is a method for producing the novel useful compound.
このように、本発明は抗腫瘍剤の有効成分として極めて
有用な発明である。As described above, the present invention is extremely useful as an active ingredient of an antitumor agent.
Claims (1)
たはベンジル基を表す。 で示されるアントラサイクリン化合物。 ２、式▲数式、化学式、表等があります▼ で示される抗生物質Ｄ７８８−７（オキザウノマイシン
ａｘａｕｎｏｍｙｃｉｎ）に不活性溶媒中ハロゲン化
ベンジルを脱ハロゲン化水素剤の存在下、反応させるこ
とを特徴とする下記式、 ▲数式、化学式、表等があります▼ 式中、Ｒ＿１はベンジル基を表し、Ｒ＿２は水素原子ま
たはベンジル基を表す。 で示されるアントラサイクリン化合物の製造方法。[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R_1 represents a benzyl group, and R_2 represents a hydrogen atom or a benzyl group. An anthracycline compound represented by 2. The antibiotic D788-7 (axaunomycin) represented by the formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ is reacted with benzyl halide in an inert solvent in the presence of a dehydrohalogenating agent. The following formulas are characteristic: ▲Mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R_1 represents a benzyl group, and R_2 represents a hydrogen atom or a benzyl group. A method for producing an anthracycline compound represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3370887A JPS63277689A (en) | 1987-02-16 | 1987-02-16 | Anthracyclin compound and its production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3370887A JPS63277689A (en) | 1987-02-16 | 1987-02-16 | Anthracyclin compound and its production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63277689A true JPS63277689A (en) | 1988-11-15 |
Family
ID=12393913
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3370887A Pending JPS63277689A (en) | 1987-02-16 | 1987-02-16 | Anthracyclin compound and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63277689A (en) |
-
1987
- 1987-02-16 JP JP3370887A patent/JPS63277689A/en active Pending
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