JPS63188674A - 2-(2-fluoroethyl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative - Google Patents
2-(2-fluoroethyl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivativeInfo
- Publication number
- JPS63188674A JPS63188674A JP1815887A JP1815887A JPS63188674A JP S63188674 A JPS63188674 A JP S63188674A JP 1815887 A JP1815887 A JP 1815887A JP 1815887 A JP1815887 A JP 1815887A JP S63188674 A JPS63188674 A JP S63188674A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- tetrahydronaphthacene
- methoxy
- reaction
- solvent
- 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.)
- Granted
Links
- UOYDWLNFAFDQEW-UHFFFAOYSA-N 9-(2-fluoroethyl)-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical class C1C(O)(CCF)CCC2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O UOYDWLNFAFDQEW-UHFFFAOYSA-N 0.000 title 1
- -1 acyclic acetal Chemical class 0.000 claims abstract description 12
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 125000004429 atom Chemical group 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 abstract description 2
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 238000004458 analytical method Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
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- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 6
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- 238000005893 bromination reaction Methods 0.000 description 5
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
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- 150000002009 diols Chemical class 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
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- 150000007522 mineralic acids Chemical class 0.000 description 3
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 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
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- 125000004036 acetal group Chemical class 0.000 description 2
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- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
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- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- 230000005764 inhibitory process Effects 0.000 description 2
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- 150000003839 salts Chemical class 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
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- SAMGALZMSQPNHS-OAQYLSRUSA-N (9R)-9-acetyl-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound C1[C@@](O)(C(C)=O)CCC2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O SAMGALZMSQPNHS-OAQYLSRUSA-N 0.000 description 1
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- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- DWHYMKOUICVFHL-UHFFFAOYSA-N trimethyl(3-trimethylsilyloxypropoxy)silane Chemical compound C[Si](C)(C)OCCCO[Si](C)(C)C DWHYMKOUICVFHL-UHFFFAOYSA-N 0.000 description 1
- ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical compound C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
（式中、Ｒ１は水素原子または水酸基を表わし、Ｒ１及
びＲ＄は結合している炭素原子と一体となって環式ある
いは非環式アセタールを形成し、または、Ｒ鵞及びＲ３
は一体となって酸素原子を表わす、）で表わされる２−
（２−フルオロエチル）−２゜５．１２−）リヒドロキ
シ−７−メトキシ−１゜２．３．４−テトラヒドロナフ
タセン−６゜） １１−ジオン誘導体に関する。Detailed Description of the Invention [Industrial Application Field] (In the formula, R1 represents a hydrogen atom or a hydroxyl group, and R1 and R$ together with the bonded carbon atoms form a cyclic or acyclic acetal. or R and R3
together represent an oxygen atom, 2-
(2-Fluoroethyl)-2゜5.12-)lihydroxy-7-methoxy-1゜2.3.4-tetrahydronaphthacene-6゜) 11-dione derivative.
本発明の一般式（１）で表わされる２−（２−フルオロ
エチル）−２，５，１２−１−リヒドロキシ−７−メト
キシ−１，２，３，４−テトラヒドロナフタセン−６，
１１−ジオン誘導体は、ダウノサミン誘導体とのグリコ
ジル化反応により、優れた制癌活性を有する１４−フル
オロダウノルビシンに導くことができる重要合成中間体
である。2-(2-fluoroethyl)-2,5,12-1-lihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6 represented by the general formula (1) of the present invention,
11-dione derivatives are important synthetic intermediates that can be converted into 14-fluorodaunorubicin, which has excellent anticancer activity, through a glycosylation reaction with daunosamine derivatives.
優れた制癌剤の開発は社会の強力な要請であり、急務を
有する事項である。アドリアマイシンに代表されるアン
トラサイクリン誘導体は、その強力な制癌活性により制
癌剤として医薬における重要な位置をしめており、現在
までに数多くのアントラサイクリン誘導体が開発されて
いる。しかしながら、それらの誘導体は制癌活性と脱毛
、心筋毒性等の副作用の関連などにおいて、実際の癌の
治療に使用するには未だ不満足なものである。この事か
らより優れた特徴的な制癌活性を示す新規なアントラサ
イクリン類縁体の開発が強く望まれている。The development of excellent anticancer drugs is a strong demand from society and is an urgent matter. Anthracycline derivatives, represented by adriamycin, play an important role in medicine as anticancer agents due to their strong anticancer activity, and a large number of anthracycline derivatives have been developed to date. However, these derivatives are still unsatisfactory for use in actual cancer treatment due to the relationship between anticancer activity and side effects such as hair loss and myocardial toxicity. For this reason, there is a strong desire to develop novel anthracycline analogs that exhibit superior and characteristic anticancer activity.
（発明が解決しようとする問題点〕
上記の背景にあって、本発明者らは、優れた制癌活性を
有する新規なアントラサイクリン類縁体を探索した結果
、１４−フルオロダウノルビシンが強力な制癌活性を有
することを見い出し本発明を完成した。(Problems to be Solved by the Invention) Against the above background, the present inventors searched for novel anthracycline analogues with excellent anticancer activity, and found that 14-fluorodaunorubicin is a powerful anticancer agent. They discovered that it has activity and completed the present invention.
前記一般式（ｒ）で表わされる２−（２−フルオロエチ
ル）−２，５，１２−）リヒドロキシー−７−メトキシ
−１，２，３，４−テトラヒドロナフタセン−６，１１
−ジオン誘導体は、以下の反応式に従い製造することが
できる。2-(2-fluoroethyl)-2,5,12-)rihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11 represented by the above general formula (r)
-Dione derivatives can be produced according to the following reaction formula.
０Ｈ
ＣＨ３０００Ｈ
（式中、Ｒ４及びＲｓは結合している炭素原子と一体と
なって環式あるいは非環式アセタールを形成する。）
〔第１工程〕
本工程は（Ｒ）−２−アセチル−２，５，１２−トリヒ
ドロキシ−７−メトキシ−１，２，３゜４−テトラヒド
ロナフタセン−６，１１−ジオン（７−ジオキシダウノ
マイシノン）（■）と臭素化剤を反応させ、反応成績体
として得られる２−ブロモアセチル体を、一般式
％式％（［）
（式中、Ｍは四級アンモニウムまたは金属原子を表わす
、）で表わされるフッ化物と反応させることにより、前
記一般式（Ｉａ、）で表わされる（Ｒ）−２−（２−フ
ルオロアセチル）−２，５゜１２−トリヒドロキシ−７
−メトキシ−１，２゜３．４−テトラヒドロナフタセン
−６，１１−ジオン（７−ゾオキシー１４−フルオ口ダ
ウノマイジノン）を製造するものである。0H CH3000H (In the formula, R4 and Rs form a cyclic or acyclic acetal together with the carbon atoms to which they are bonded.) [First step] This step converts (R)-2-acetyl-2 ,5,12-trihydroxy-7-methoxy-1,2,3゜4-tetrahydronaphthacene-6,11-dione (7-dioxydaunomycinone) (■) and a brominating agent are reacted. By reacting the 2-bromoacetyl compound obtained as the product with a fluoride represented by the general formula % ([) (wherein M represents quaternary ammonium or a metal atom), (R)-2-(2-fluoroacetyl)-2,5°12-trihydroxy-7 represented by (Ia,)
-Methoxy-1,2°3.4-tetrahydronaphthacene-6,11-dione (7-zooxy-14-fluoro-daunomidinone) is produced.
本発明の原料である前記一般式（ｎ）で表わされる（Ｒ
）−２−アセチル−２，５，１２−トリヒドロキシ−７
−メトキシ−１，２，３，４−テトラヒドロナフタセン
−６，１１−ジオン（７−ジオキシダウノマイシノン）
は、放線菌（Ｓｔｒａ ｔｏｍ ｃｅｓ ｅｕ
ｃａｔｉｕｓ）の産生ずる市販のダウノルビシン塩酸塩
を加水素分解反応（Ｆ、Ａｒｃａｍｏｎｅ、ａｔ ａ
ｌ、。(R
)-2-acetyl-2,5,12-trihydroxy-7
-Methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione (7-dioxydaunomycinone)
is an actinomycete (Stra tom ces eu).
Commercially available daunorubicin hydrochloride produced by F. catius was subjected to a hydrolysis reaction (F, Arcamone, at a
l.
Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ、、３０゜３３４
９ （１９６８）、参照）することにより容易に得られ
る化合物である。Tetrahedron Lett, 30°334
9 (1968)).
化合物（Ｉｔ）の臭素化に用いられる臭素化側としては
、臭素、ピリジ、ニウムプロミドペルプロミド、フェニ
ルトリメチルアンモニウムトリプロミド等が例示できる
０反応は溶媒中で行うことが望ましく、反応溶媒として
は、テトラヒドロフラン、ジオキサン、ジオキソラン等
のエーテル系溶媒が好ましく用いられる０反応温度は、
０℃〜５０℃で円滑に進行する。Examples of the bromination side used in the bromination of compound (It) include bromine, pyridi, niumpromide perpromide, phenyltrimethylammonium tripromide, etc. It is preferable that the reaction is carried out in a solvent, and the reaction solvent is The reaction temperature is preferably an ether solvent such as tetrahydrofuran, dioxane, dioxolane, etc.
It progresses smoothly at 0°C to 50°C.
前記一般式（ＩＩ＋）で表わされるフン化物としては、
フン化テトラブチルアンモニウム、フン化テトラエチル
アンモニウムなどの四級アンモニウム塩、および、フン
化リチウム、フン化ナトリウム、フン化カリウム、フン
化セシウム、フン化銀などが例示できる。また、化合物
（■）の臭素化で得られる２−ブロモアセチル体にフッ
化物を反応させる際、無機または有機酸あるいはその塩
を共存させることにより、目的物を収率よく得ることが
できる。使用できる酸としては塩酸、臭化水素酸、硫酸
、リン酸などの無機酸、あるいは酢酸、プロピオン酸、
マレイン酸、コハク酸、安息香酸、メタンスルホン酸、
ｐ−トルエンスルホン酸、トリフルオロメタンスルホン
酸などの有機酸が例示でき、また、これらの酸との塩と
しては、ピリジン、トリブチルアミン、トリエチルアミ
ンなどの塩基から形成されるアンモニウム塩などが例示
できる。As the fluoride represented by the general formula (II+),
Examples include quaternary ammonium salts such as tetrabutylammonium fluoride and tetraethylammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, and silver fluoride. Further, when reacting a fluoride with a 2-bromoacetyl compound obtained by bromination of compound (■), the desired product can be obtained in good yield by allowing an inorganic or organic acid or a salt thereof to coexist. Acids that can be used include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as acetic acid, propionic acid,
maleic acid, succinic acid, benzoic acid, methanesulfonic acid,
Examples include organic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid, and examples of salts with these acids include ammonium salts formed from bases such as pyridine, tributylamine, and triethylamine.
本反応は溶媒中で行うことが望ましく、溶媒としてはテ
トラヒドロフラン、ジオキサン、ジオキソラン、ジグラ
イム等のエーテル系溶媒、ジメチルスルホキシド、Ｎ、
Ｎ−ジメチルホルムアミド、アセトニトリル等の非プロ
トン性溶媒が好適である０反応はθ℃〜１００℃で円滑
に進行する。This reaction is preferably carried out in a solvent, and examples of the solvent include ether solvents such as tetrahydrofuran, dioxane, dioxolane, and diglyme, dimethyl sulfoxide, N,
The reaction, in which an aprotic solvent such as N-dimethylformamide or acetonitrile is suitable, proceeds smoothly at θ°C to 100°C.
〔第２工程〕
本工程は、第１工程で得られた（Ｒ）−２−（２−フル
オロアセチル）−２，５，１２−１リヒドロキシ−７−
メトキシ−１，２，３，４−テトラヒドロナフタセン−
６，１１−ジオン（１，４−フルオロダウノマイシノン
） （Ｉａ）の２位のカルボニル基をアセタール基の
形で保護し、アセタール体（Ｉｂ）を得るものである。[Second step] In this step, the (R)-2-(2-fluoroacetyl)-2,5,12-1-lihydroxy-7- obtained in the first step
Methoxy-1,2,3,4-tetrahydronaphthacene-
The carbonyl group at the 2-position of 6,11-dione (1,4-fluorodaunomycinone) (Ia) is protected in the form of an acetal group to obtain an acetal compound (Ib).
アセタール化反応は、たとえば、トリメチルシリルトリ
フレート存在下、トリアルコキシメタンを作用させるこ
とによって行われる。トリアルコキシメタンとしては、
トリメトキシメタン、トリエトキシメタン、トリプロポ
キシメタンなどが例示できる０本工程は溶媒中で行なう
ことが望ましく、メタノール、エタノール、プロパツー
ル等のアルコール系溶媒、塩化メチレン、１．２−ジク
ロロエタン、クロロホルム、四塩化炭素等のハロゲン化
炭化水素系溶媒、テトラヒドロフラン、ジオキサン等の
エーテル系溶媒、あるいは、これらの混合溶媒が用いら
れる０反応温度は、０℃〜室温で円滑に進行する。The acetalization reaction is carried out, for example, by reacting trialkoxymethane in the presence of trimethylsilyl triflate. As trialkoxymethane,
Examples include trimethoxymethane, triethoxymethane, tripropoxymethane, etc. This step is preferably carried out in a solvent, and alcoholic solvents such as methanol, ethanol, propatool, methylene chloride, 1,2-dichloroethane, chloroform, The reaction proceeds smoothly at a temperature of 0°C to room temperature when a halogenated hydrocarbon solvent such as carbon tetrachloride, an ether solvent such as tetrahydrofuran or dioxane, or a mixed solvent thereof is used.
また、ここで得られた非環式アセタール誘導体は、エチ
レングリコール、トリメチレングリコール、２．２−ジ
メチルプロパン−１，３−ジオールなどのジオール類を
用いて、酸触媒存在下、アセタール交績反応を行うこと
により、環式アセタール誘導体に効率よく導くことがで
きる。アセタール交換反応に用いられる酸触媒としては
、ｐ−）ルエンスルホン酸、ベンゼンスルホン酸、メタ
ンスルホン酸、トリフルオロメタンスルホン酸などのス
ルホン酸、硫酸、塩酸などの無機酸が例示できる。また
、トリメチルシリルトリフレート存在下、各種ジオール
のジシリル体を用いることによってもアセタール交換反
応を達成することができる。In addition, the acyclic acetal derivative obtained here is subjected to an acetal cross-reaction reaction in the presence of an acid catalyst using diols such as ethylene glycol, trimethylene glycol, and 2,2-dimethylpropane-1,3-diol. By performing this, it is possible to efficiently lead to a cyclic acetal derivative. Examples of the acid catalyst used in the acetal exchange reaction include sulfonic acids such as p-)luenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid. Furthermore, the acetal exchange reaction can also be achieved by using disilyls of various diols in the presence of trimethylsilyl triflate.
用いられるジオールとしては上記ジオール類のジシリル
体、すなわち１．２−ビス（トリメチルシリルオキシ）
エタン、１．３−ビス（トリメチルシリルオキシ）プロ
パン、２．２−ジメチル−１゜３−ビス（トリメチルシ
リルオキシ）プロパンなどが例示できる。The diol used is the disilyl form of the above diols, i.e. 1,2-bis(trimethylsilyloxy)
Examples include ethane, 1,3-bis(trimethylsilyloxy)propane, and 2,2-dimethyl-1°3-bis(trimethylsilyloxy)propane.
反応溶媒としては、塩化メチレン、１．２−ジクロロエ
タン、クロロホルム、四基化炭”１８のハロゲン化炭化
水素系溶媒、または、ベンゼン、トルエン、キシレ゛ン
等の芳香族炭化水素系溶媒が好ましく用いられる０反応
混度はｏ℃〜１ｏｏ℃で円滑に進行する。As the reaction solvent, methylene chloride, 1,2-dichloroethane, chloroform, halogenated hydrocarbon solvents such as tetracarbohydrate, or aromatic hydrocarbon solvents such as benzene, toluene, and xylene are preferably used. The reaction mixture proceeds smoothly at 0°C to 100°C.
〔第３工程〕
本工程は、一般式（Ｉｂ）で表わされる化合物の４位を
臭素化し、得られた臭化物の水酸化物への変換、さらに
、アセタール基の除去により、一般式（Ｉ ｃ） Ｔ！
表わされ！ （２３，４３）−２−（２−フルオロアセ
チル）−２，５，４，１２−テトラヒドロキシ−７−メ
トキシ−１，２，３゜４−テトラヒドロナフタセン−６
，１１−ジオン（１４−フルオロダウノマイシノン）を
製造するものである。[Third Step] In this step, the 4-position of the compound represented by the general formula (Ib) is brominated, the obtained bromide is converted to a hydroxide, and the acetal group is removed. ) T!
Represented! (23,43)-2-(2-fluoroacetyl)-2,5,4,12-tetrahydroxy-7-methoxy-1,2,3°4-tetrahydronaphthacene-6
, 11-dione (14-fluorodaunomycinone).
臭素化は、塩化メチレン、クロロホルム、１．２−ジク
ロロエタン、四塩化炭素などのハロゲン系溶媒中、臭素
、Ｎ−ブロモコハク酸イミド、Ｎ−ブロモアセトアミド
、１．３−ジブロモ−５，５−ジメチルヒダントインな
どを臭素化剤に用いて行われる０反応は０℃〜Ｌｏｏｔ
’で円滑に進行する。臭化物を水酸基で置換する反応は
臭素化反応の反応液を０．１〜１．ＯＭのアルカリ水溶
液で処理することによって行われる０反応はｏ℃〜５（
１で円滑に進行する。Bromination is performed using bromine, N-bromosuccinimide, N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin in a halogenated solvent such as methylene chloride, chloroform, 1,2-dichloroethane, or carbon tetrachloride. The 0 reaction carried out using brominating agents such as
' to proceed smoothly. In the reaction of substituting bromide with hydroxyl group, the reaction solution for bromination reaction is adjusted to 0.1 to 1. The 0 reaction carried out by treatment with an alkaline aqueous solution of OM is carried out at 0 °C ~ 5 (
1 will proceed smoothly.
アルカリ水溶液としては、水酸化ナトリウム、水酸化カ
リウム、水酸化バリウムなどの水溶液が例示できる。Examples of the alkaline aqueous solution include aqueous solutions of sodium hydroxide, potassium hydroxide, barium hydroxide, and the like.
アセタールの脱保護は、テトラヒドロフラン、ジオキサ
ン、１．２−ジメトキシメタン等の溶媒中、酸性条件下
に行うことができる。酸性条件に用いられる酸としては
、塩酸、硫酸などが好ましく用いられる０反応は室温〜
１００’Ｃの間で行われる。Deprotection of acetal can be carried out under acidic conditions in a solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxymethane, or the like. As the acid used in acidic conditions, hydrochloric acid, sulfuric acid, etc. are preferably used.
It is carried out between 100'C.
以下、参考例、実施例、試験例により本発明の詳細な説
明するが、本発明はこれらに限定されるものではない。Hereinafter, the present invention will be explained in detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.
なお、例中の略号の意味は次のとおりである。The meanings of the abbreviations in the examples are as follows.
ＴＨＦ ：テトラヒドロフラン
ｐＮＢｌ：ｐ−二トロベンゾイル基
参考例１
ダウノルビシン塩酸塩１５２■（０，２６９ｍｍｏｌ）
をメタノール３０−に溶解し、５％Ｐｄ−硫酸バリウム
１６５■を加えて室温で２時間加水素分解を行った０反
応混合物を酢酸エチルで希釈した後触媒を濾去し、濾液
を水で洗浄した。THF: Tetrahydrofuran pNBl: p-nitrobenzoyl group Reference Example 1 Daunorubicin hydrochloride 152■ (0,269 mmol)
was dissolved in methanol (30 mm), 165 μm of 5% Pd-barium sulfate was added, and hydrogenolysis was performed at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, the catalyst was removed by filtration, and the filtrate was washed with water. did.
無水硫酸ナトリウム上で乾燥し、溶媒を減圧下留去して
得た赤色残渣をカラムクロマトグラフィー（シリカゲル
、ベンゼン−酢酸エチル５：１）を用いて精製して（Ｒ
）−７−ジオキシダウノマイシノン１０４■（１００％
）を赤色固体として得た。The red residue obtained by drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure was purified using column chromatography (silica gel, benzene-ethyl acetate 5:1) (R
)-7-dioxydaunomycinone 104■ (100%
) was obtained as a red solid.
このものをさらにベンゼンから再結晶し、純品を得た。This product was further recrystallized from benzene to obtain a pure product.
ｍｐ、２２８〜２２０℃。mp, 228-220°C.
（文献値：）’、Ａｒｃａｍｏｎｅ、ａｔ ａｌ、。(Literature value:)', Arcamone, at al.
Ｊ、Ａｍ、Ｃｈｅｍ、Ｓｏｃ、、エロー、５３３４（１
９６４）、２２９〜２３１℃）。J, Am, Chem, Soc,, Hérault, 5334 (1
964), 229-231°C).
（α）♂０＋８５° （Ｃ−０，１１８，クロロホルム
）。(α)♂0+85° (C-0,118, chloroform).
（文献値二同上、 〔α〕げ・土コ＋９１”（Ｃ−０，
１１，クロロホルム））。(Literature value 2 ditto, [α]ge・earth+91”(C-0,
11, Chloroform)).
ＮＭＲ（ＣＤＣＩｓ）：δ−１，８８〜２．１２（２Ｈ
，ｍ）、２．４２ （３Ｈ，ａ）、２．７３〜３．３５
（４Ｈ，ｍ）、３．７６ （ＩＨ，ｓ）。NMR (CDCIs): δ-1,88~2.12 (2H
, m), 2.42 (3H, a), 2.73-3.35
(4H, m), 3.76 (IH, s).
４．１２ （３Ｈ，ｓ）、７．４２ （ＩＨ，ｄｄ。4.12 (3H, s), 7.42 (IH, dd.
Ｊ−８及びＩＨｚ）、７．７８ （ＩＨ，ｔ。J-8 and IHz), 7.78 (IH, t.
Ｊ−８Ｈｚ）、８．０５ （ＩＨ，ｄｄ、Ｊ−８及びＩ
Ｈｚ）、１３．４５ （ＩＨ，ｓ）。J-8Hz), 8.05 (IH, dd, J-8 and I
Hz), 13.45 (IH,s).
１３．８５ （Ｉ Ｈ，ａ）。13.85 (IH, a).
ＩＲ（ＫＢｒ）：３５２０．１７１５゜１６１５、 １
５８５ｃｓ−’。IR (KBr): 3520.1715°1615, 1
585cs-'.
実施例１
（Ｒ）−７−ジオキシダウノマイシノン２１．０ｍ （
０，０５４９ｍｍｏ ＋） 、ピリジニウムプロミド
ヘルブロミド２５．７＋ｗ （０，０８０４ｍｍｏ １
）、ＴＨＦ４−の混合物を室温で３．５時間攪拌した。Example 1 (R)-7-dioxydaunomycinone 21.0m (
0,0549mmo +), pyridinium bromide
Helbromide 25.7+w (0,0804mmo 1
), THF4- was stirred at room temperature for 3.5 hours.
反応混合物を酢酸エチルで希釈し、５０％食塩水、飽和
食塩水で順次洗浄した後、無水硫酸ナトリウム上で乾燥
した。溶媒を減圧上留去し、粗製の７−ジオキシ−１４
−ブロモダウノマイシノンを赤色粉末として得た。この
ものをＴＨＦ４−に懸濁し、無水ｐ−トルエンスルホン
Ｍ３０．９■（０，１７９ｍｍｏ １） 、フン化テト
ラブチルアンモニウム−ＴＨＦＩＭ溶液０．２９ｄ （
０，２９ｍｍｏｌ）を順次加えて室温で３０分間攪拌し
た後加熱還流を行った。１時間後、フン化テトラブチル
アンモニウム０．０４ｄ （０，０４ｍｍｏ １）を追
加し、さらに２０分間加熱還流を行った。The reaction mixture was diluted with ethyl acetate, washed successively with 50% brine and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude 7-dioxy-14
- Bromodaunomycinone was obtained as a red powder. This material was suspended in THF4-, anhydrous p-toluenesulfone M30.9 (0,179 mmol 1), and tetrabutylammonium fluoride-THFIM solution 0.29 d (
0.29 mmol) were added one after another, stirred at room temperature for 30 minutes, and then heated under reflux. After 1 hour, 0.04 d (0.04 mmol 1) of tetrabutylammonium fluoride was added, and the mixture was further heated under reflux for 20 minutes.
冷却後、反応混合物を５０％食塩水中に注ぎ酢酸エチル
で抽出した。抽出液を水、飽和食塩水で順次洗浄し、無
水硫酸ナトリウム上で乾燥した。After cooling, the reaction mixture was poured into 50% brine and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
溶媒を減圧上留去して得られた赤色残渣をカラムクロマ
トグラフィー（シリカゲル、ベンゼン−酢酸エチル１０
：ｌ→５：１）を用いて精製し、（Ｒ）−７−ジオキシ
−１４−フルオロダウノマイシノン１２．１■（５５％
）を赤色粉末として得た。The red residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (silica gel, benzene-ethyl acetate 10
:1 → 5:1) to produce (R)-7-dioxy-14-fluorodaunomycinone 12.1■ (55%
) was obtained as a red powder.
このものの一部をトルエンから再結晶して暗赤色針状結
晶を得、分析用サンプルとした。A portion of this product was recrystallized from toluene to obtain dark red needle crystals, which were used as a sample for analysis.
ｆｆ１９．２５３〜２５７℃。ff19.253-257°C.
〔α〕カ・−１９＠ （ｅ−０，０５２，ジオキサン）
。[α] Ka-19@ (e-0,052, dioxane)
.
ＮＭＲ（ＣＤＣＩｍ）： δ−１，９５〜２．２０（２
Ｈ，ｍ）、 ２．９２ （ＬＨ，ｓ）、 ２．８
５〜３．４０ （４Ｈ，ｍ）、４．１２ （３Ｈ，
ｓ）。NMR (CDCIm): δ-1,95 to 2.20 (2
H, m), 2.92 (LH, s), 2.8
5-3.40 (4H, m), 4.12 (3H,
s).
５．４６ （２Ｈ，ｄ、Ｊ−４７Ｈｚ）、 ７．４
３（ＩＨ，ｄｄ、Ｊ−８棹及びＩＨｚ）。5.46 (2H, d, J-47Hz), 7.4
3 (IH, dd, J-8 rod and IHz).
７．７９ （ＩＨ，ｔ、 Ｊ−８Ｈｚ）、 ８．
０５（ＬＨ，ｄｄ、Ｊ−８及びＩＨｚ）。7.79 (IH, t, J-8Hz), 8.
05 (LH, dd, J-8 and IHz).
１３．３７ （ＩＨ，ｓ）、 １３．７９ （Ｉ
Ｈ，ｓ）。13.37 (IH,s), 13.79 (I
H,s).
ＩＲ（ＫＢｒ） ＝ ３５００． １７４０゜１６１
５、 １５９０ｍ−’。IR(KBr) = 3500. 1740°161
5, 1590m-'.
ＭＳ （ｍ／ｅ）４００ ＣＭ”）、 ３８２．
３３９゜元素分析値： Ｃ＊ ＋ Ｈｌｑ Ｆ Ｏ？
として計夏値： Ｃ，６３，００； Ｈ，４，２８％、
・分析値： Ｃ，６２，７０； Ｈ，４，２７％
。MS (m/e) 400 CM”), 382.
339゜Elemental analysis value: C* + Hlq F O?
Total summer value: C, 63,00; H, 4,28%,
・Analysis value: C, 62,70; H, 4,27%
.
実施例２
（Ｒ）−７−ジオキシ−１４−フルオロダウノマイシノ
ン７１．５ｗ （０，１７９ｍｍｏ Ｉ）を塩化メチレ
ン２１−に懸濁し、オルトギ酸メチル０．４ｄ （３，
６６ｍｍｏ ｌ） 、トリメチルシリルトリフレート−
ヘキサ７１Ｍ溶液０．０４ｄ （０，０４ｍｍｏ １）
を加えて水冷下３０分、室温で２時間攪拌した。Example 2 71.5 w (R)-7-dioxy-14-fluorodaunomycinone (0,179 mmol I) was suspended in methylene chloride 21- and 0.4 d (3,
66 mmol), trimethylsilyl triflate-
Hexa 71M solution 0.04d (0.04mmo 1)
was added and stirred for 30 minutes under water cooling and for 2 hours at room temperature.
反応混合物を飽和重曹水中に注ぎ、塩化メチレンで伸出
した。抽出液を水、飽和食塩水で順次洗浄し、無水硫酸
ナトリウム上で乾燥した。溶媒を減圧上留去した後、赤
色残渣をカラムクロマトグラフィー（シリカゲル、ベン
ゼン−酢酸エチル２０＝１）を用いて情製し、（Ｒ）−
２−（２−フルオロ−１，１−ジメトキシエチル）−２
，５，１２−トリヒドロキシ−７−メトキシ−１，２，
３゜４−テトラヒドロナフタセン−６，１１−ジオン７
３．６■（９２％）を赤色粉末として得た。The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the red residue was analyzed using column chromatography (silica gel, benzene-ethyl acetate 20=1) to obtain (R)-
2-(2-fluoro-1,1-dimethoxyethyl)-2
,5,12-trihydroxy-7-methoxy-1,2,
3゜4-tetrahydronaphthacene-6,11-dione 7
3.6 (92%) was obtained as a red powder.
ｍｐ、 ２４２．５〜２４４°Ｃ０
ＮＭＲ（ＣＤ Ｃｌ ｓ） ：δ−１，５７〜２．３
２（２Ｈ，ｍ）、２．５２ （ＩＨ，ｓ）、２．６７〜
３．３４ （４Ｈ，ｍ）、３．５５ （３Ｈ，ｓ）。mp, 242.5~244°C0 NMR (CDCls): δ-1,57~2.3
2 (2H, m), 2.52 (IH, s), 2.67~
3.34 (4H, m), 3.55 (3H, s).
３．５８ （３Ｈ，ｓ）、４．１０ （３Ｈ，ｓ）。3.58 (3H, s), 4.10 (3H, s).
４．６２ （２Ｈ，ｄ、Ｊ−４７Ｈｚ）、７．３９（Ｉ
ＩＬ ｄｄ、Ｊ−８及びＩＨｚ）。4.62 (2H, d, J-47Hz), 7.39 (I
IL dd, J-8 and IHz).
７．７７ （ＩＨ，ｔ、Ｊ−８Ｈｚ）、８．０４（ＩＨ
，ｄｄ、Ｊ！＝８及びＩＨｚ）。7.77 (IH, t, J-8Hz), 8.04 (IH
, dd, J! = 8 and IHz).
１３．５４ （ＬＨ，ｓ）、１３．８８ （ＩＨ，ｓ）
。13.54 (LH, s), 13.88 (IH, s)
.
ＩＲ（ＫＢｒ）：３４５０，１６１５゜１５８５ ｃｍ
−’。IR (KBr): 3450, 1615° 1585 cm
-'.
ＭＳ （ｍ／ ｅ） ４４６ （Ｍ”） 、 １０７
゜実施例３
（Ｒ）−７−ジオキシ−１４−フルオロダウノマイシノ
ン１６．５ｍ （０，０４１２ｍｍｏ １） 、塩化メ
チレン５．０＋ｄ、オルトギ酸メチル０．０９ｓｄ（０
，８２３ｍｍｏ Ｉ） 、１．２−ビス（トリメチルシ
リルオキシ）エタン１．０ｍ （４，０８ｍｍｏ １）
の混合物にトリメチルシリルトリフレート−ヘキサンＩ
Ｍｔ＠液０．０１５ｍ （０，０１５ｍｍｏ ｌ）を加
え、水冷下３０分、室温で２１．５時間攪拌した。MS (m/e) 446 (M”), 107
゜Example 3 (R)-7-dioxy-14-fluorodaunomycinone 16.5m (0,0412mmo 1), methylene chloride 5.0+d, methyl orthoformate 0.09sd (0
,823mmo I), 1.2-bis(trimethylsilyloxy)ethane 1.0m (4,08mmo 1)
trimethylsilyl triflate-hexane I to a mixture of
0.015 m (0.015 mmol) of Mt@ solution was added, and the mixture was stirred for 30 minutes under water cooling and for 21.5 hours at room temperature.
反応混合物を飽和重曹水中に注ぎ、酢酸エチルで抽出し
た。抽出液を水、飽和食塩水で順次洗浄し、無水硫酸ナ
トリウム上で乾燥した。溶媒を減圧上留去し、得られた
赤色残渣をカラムクロマトグラフィー（シリカゲル、ベ
ンゼン−酢酸エチルｌＯ：１）を用いて精製して、（Ｒ
）−２−（２−フルオロメチル−１，３−ジオキソラン
−２−イル）−２，５，１２−）リヒドロキシ−７−メ
トキシ−１，２，３，４−テトラヒドロナフタセン−６
゜１１−ジオン１６．１■（８８％）を赤色固体として
得た。The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting red residue was purified using column chromatography (silica gel, benzene-ethyl acetate lO:1) to obtain (R
)-2-(2-fluoromethyl-1,3-dioxolan-2-yl)-2,5,12-)lihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6
16.1 (88%) of 11-dione was obtained as a red solid.
ｍｐ、２５９〜２６４℃。mp, 259-264°C.
ＮＭＲ（ＣＤＣＩｓ）：δ−１，５８〜２．２４（２Ｈ
，ｍ）、２．０４ （ＩＨ，ｓ）、２．７３〜３．３５
（４Ｈ，ｍ）、４．１０ （３Ｈ，ｓ）。NMR (CDCIs): δ-1,58~2.24 (2H
, m), 2.04 (IH, s), 2.73-3.35
(4H, m), 4.10 (3H, s).
４．０３〜４．３１ （４Ｈ，ｍ）、４．７５（２Ｈ，
ｄ、 Ｊ＝４８Ｈｚ） 、 ７．４０ （ＩＨ。4.03-4.31 (4H, m), 4.75 (2H,
d, J=48Hz), 7.40 (IH.
ｄ、Ｊ−８Ｈｚ）、７．７８ （ＩＨ，ｔ、Ｊ＝８Ｈｚ
）、８．０６ （ＩＨ，ｄｄ、Ｊ−８及びＩＨｚ）、１
３．５２ （１１（、ｓ）。d, J-8Hz), 7.78 (IH, t, J=8Hz
), 8.06 (IH, dd, J-8 and IHz), 1
3.52 (11(,s).
１３．８８ （Ｉ Ｈ，ｓ）。13.88 (IH,s).
ＩＲ（ＫＢｒ） ：３５２０． ３４５０゜１６１５
． １５９５ｃｍ−’。IR (KBr): 3520. 3450°1615
．． 1595cm-'.
ＭＳ （ｍ／ｅ） ： ４４４ （Ｍ”″）、
１０５゜実施例４
（Ｒ）−２−（２−フルオロ−１，１−ジメトキシエチ
ル）−２，５，１２−トリヒドロキシ−７−メトキシ−
１，２，３，４−テトラヒドロナフタセン−６，１１−
ジオン３３．３ｗ （０，０７４６ｍｍｏ＋）、クロロ
ホルム３．３−１四塩化炭素２．４ｄ、水２．５−の混
合物に臭素−四塩化炭素０．１４Ｍ溶液０．３０ｄ （
０，０４１ｍｍｏ ｌ）を加え、６０Ｗタングステンラ
ンプ照射下６０℃油浴上で加熱還流を行った。１５分後
さらに臭素溶液回に分けて加え、さらに２時間反応を行
った。MS (m/e): 444 (M""),
105゜Example 4 (R)-2-(2-fluoro-1,1-dimethoxyethyl)-2,5,12-trihydroxy-7-methoxy-
1,2,3,4-tetrahydronaphthacene-6,11-
0.30 d of 0.14 M solution of bromine-carbon tetrachloride in a mixture of 33.3 w (0,0746 mmo+) of dione, 3.3-1 chloroform, 2.4 d of carbon tetrachloride, and 2.5-d of water (
0,041 mmol) was added thereto, and heated to reflux on a 60° C. oil bath under irradiation with a 60 W tungsten lamp. After 15 minutes, the bromine solution was further added in portions, and the reaction was further carried out for 2 hours.
冷却後、０℃にて１０％水酸化ナトリウム水溶液０．１
５ｍ （０，３７５ｍｍｏ １）を加え、同温度で１０
分、室温で１５分間攪拌した０反応混合物に１Ｍ塩酸０
．４−を加えて中和し、クロロホルムで抽出した。抽出
液を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウム
上で乾燥した。溶媒を減圧上留去して得た赤色残渣を次
いでＴＨＥ３．５−に溶解し、製塩ａＯ，３５−を加え
て室温で１６時間攪拌した０反応混合物を水で希釈し、
クロロホルムで抽出した。抽出液を水、飽和食塩水で順
次洗浄し、無水硫酸ナトリウム上で乾燥した。溶媒を減
圧上留去し、残渣をカラムクロマトグラフィー（シリカ
ゲル、ベンゼン−酢酸エチル１０：１→５：１）を用い
て分離精製して（＋）−１４−フルオロダウノマイシノ
ン！６．１■（５２％）ヲ赤色粉末として得た。After cooling, add 10% sodium hydroxide aqueous solution 0.1 at 0°C.
Add 5m (0,375mmo 1) and heat at the same temperature for 10
1M hydrochloric acid was added to the reaction mixture, which was stirred for 15 minutes at room temperature.
．． The mixture was neutralized by adding 4- and extracted with chloroform. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The red residue obtained by distilling off the solvent under reduced pressure was then dissolved in THE3.5-, and the salt-prepared aO,35- was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with water,
Extracted with chloroform. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified using column chromatography (silica gel, benzene-ethyl acetate 10:1 → 5:1) to obtain (+)-14-fluorodaunomycinone! 6.1 (52%) was obtained as a red powder.
このものをベンゼンおよびベンゼン−へ牛サン混合溶媒
から再結晶して分鯉用サンプルを得た。This product was recrystallized from benzene and a benzene-beef san mixed solvent to obtain a sample for carp separation.
ｍｐ、 ２１３〜２１８℃。mp, 213-218°C.
（α）Ｄ”＋ １７９ ’ （Ｃ−０，１０６，ジオ
キサン）。(α)D”+179′ (C-0,106, dioxane).
ＮＭＲ（ＣＤＣ１ｓ） ：δ−２，２２（ＩＨ，ｄｄ
。NMR (CDC1s): δ-2,22 (IH, dd
.
Ｊ−１５及び５Ｈｚ）、２．４４ （ＩＨ，ｄｔ。J-15 and 5Hz), 2.44 (IH, dt.
Ｊ−１５及び２Ｈｚ）、３．０５ （ＩＨ，ｄ。J-15 and 2Hz), 3.05 (IH, d.
Ｊ−１９Ｈｚ）、 ３．２７ （ＩＨ，ｄｄ。J-19Hz), 3.27 (IH, dd.
Ｊ−１９及び２Ｈｚ）、３．２９〜３．４９ （ＩＨ。J-19 and 2Hz), 3.29-3.49 (IH.
ｍ）、４．１３ （３Ｈ，ａ）、４．６６ （ＩＨ
。m), 4.13 (3H, a), 4.66 (IH
.
ｓ）、 ５．３４〜５．５１ （ＩＨ，ｍ）、
５．５９（２Ｈ，ｄ、Ｊ−４８Ｈｚ）、７．４６ （
ＩＨ。s), 5.34-5.51 (IH, m),
5.59 (2H, d, J-48Hz), 7.46 (
IH.
ｄｄ、Ｊ−８及びＩＨｚ）、７．８３ （ＩＨ。dd, J-8 and IHz), 7.83 (IH.
ｔ、Ｊ−８Ｈｚ）、８．０９ （ＬＨ，ｄｄ、Ｊ麿８及
びＩＨｚ）、１．３．２５ （ＩＨ，ｓ）。t, J-8Hz), 8.09 (LH, dd, J-8 and IHz), 1.3.25 (IH, s).
１４．０１ （ＩＨ，ｓ）。14.01 (IH, s).
ｆＲ（ＫＢｒ） ：３４５０． １７４０゜１６１５
、 １５９０（２）−１゜
ＭＳ （ｍ１０） ： ４１６ 〔Ｍ”） 、
３９８゜３８０、 ３３７゜
元素分析値： Ｃｚ＋Ｈ＋、ＦＯｍ・０．５Ｈ＊Ｏとし
て計算値： Ｃ，５９，３０； Ｈ，４，２７％。fR (KBr): 3450. 1740°1615
, 1590(2)-1°MS (m10): 416 [M”),
398° 380, 337° Elemental analysis value: Calculated value as Cz+H+, FOm・0.5H*O: C, 59,30; H, 4,27%.
分析値： Ｃ，５９，１２ｉ Ｈ，３，９８％。Analysis value: C, 59,12i H, 3,98%.
実施例５
（Ｒ）−２−（２−フルオロメチル−１，３−ジオキソ
ラン−２−イル）−２，５−１２−）すヒドロキシ−７
−メドキシー１． ２． ３． ４−テトラヒドロナフ
タセン−６，１１−ジオン１６．１四塩化炭素２．４−
１水２．５−の混合物に臭素−四塩化炭素０．１４Ｍ溶
液０．４０ｄ （０，０５４ｍｍｏ １）を４回に分け
て加え、６０Ｗタングステンランプ照射下１．５時間加
熱還流を行った。冷却後、０℃にて１０％水酸化ナトリ
ウム水溶液０．０７５ａｄ（０，１８８ｍｍｏ １）を
加え、同温度で１０分、室温で１５分間攪拌した０反応
混合物に１Ｍ塩酸０．２２を加えて中和したのち、実施
例４と同様に後処理を行って赤色残渣を得た。Example 5 (R)-2-(2-fluoromethyl-1,3-dioxolan-2-yl)-2,5-12-)hydroxy-7
-Medoxy 1. 2. 3. 4-Tetrahydronaphthacene-6,11-dione 16.1 Carbon tetrachloride 2.4-
0.40 d (0,054 mmol) of a bromine-carbon tetrachloride 0.14 M solution was added in four portions to a mixture of 1 water and 2.5 mm, and heated under reflux for 1.5 hours under irradiation with a 60 W tungsten lamp. After cooling, 0.075 ad (0.188 mmol) of a 10% aqueous sodium hydroxide solution was added at 0°C, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 15 minutes. After the mixture was mixed, post-treatment was performed in the same manner as in Example 4 to obtain a red residue.
このものを次いでＴＨＦ３−に溶解し、濃塩酸６−を加
えて１５時間加熱還流を行った。冷却後、実施例４と同
様に処理し、残渣をカラムクロマトグラフィー（シリカ
ゲル、ベンゼン−酢酸エチル１０：１−５：１）を用い
て分離精製して（＋）−１４−フルオロダウノマイシノ
ン３．２■（２１％）を赤色粉末として得た。This product was then dissolved in THF3-, concentrated hydrochloric acid 6- was added, and the mixture was heated under reflux for 15 hours. After cooling, the same treatment as in Example 4 was carried out, and the residue was separated and purified using column chromatography (silica gel, benzene-ethyl acetate 10:1-5:1) to obtain (+)-14-fluorodaunomycinone. 3.2 (21%) was obtained as a red powder.
このもののＮＭＲスペクトルは実施例４で得たものに一
敗した。The NMR spectrum of this product was inferior to that obtained in Example 4.
参考例２
２．３．６−）リゾオキシ−１，４−ジー〇−ｐ−ニト
ロベンゾイル−３−トリフルオロアセトアミド−α−Ｌ
−リキソヘキソピラノース４０．７Ｎ （０，０７５２
ｍｍｏ １） 、モレキュラーシープス４Ａ２６７ｑ、
塩化メチレン４．０−、エーテル３．２−の混合物に、
アルゴン雰囲気下、−４０℃にてトリメチルシリルトリ
フレー）０．０４ｍ（０，２０７ｍｍｏ ｌ）を加え、
水冷下２５分間攪拌した０次いで反応液を一３０℃に冷
却し、（＋）−１４−フルオロダウノマイシノン１９．
５■（０，０４６８ｍｍｏ １）のＴＨＦｔｇＪ液７−
を滴下して−７〜−１５℃で６時間反応を行った０反応
混合物を飽和重曹水−酢酸エチル混合溶液中に注ぎ、酢
酸エチルで抽出した。抽出液を水、飽和食塩水で順次洗
浄した後無水硫酸ナトリウム上で乾燥し、溶媒を減圧上
留去して粗製のグリコシドを得た。Reference Example 2 2.3.6-) Lysooxy-1,4-di〇-p-nitrobenzoyl-3-trifluoroacetamide-α-L
-Lixohexopyranose 40.7N (0,0752
mmo 1), Molecular Sheeps 4A267q,
In a mixture of 4.0-methylene chloride and 3.2- ether,
Under an argon atmosphere, add 0.04 m (0,207 mmol) of trimethylsilyl trifle at -40°C,
The reaction solution was stirred for 25 minutes under water cooling and then cooled to -30°C.
5 ■ (0,0468 mmo 1) THFtgJ solution 7-
was added dropwise and the reaction was carried out at -7 to -15°C for 6 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate-ethyl acetate mixed solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude glycoside.
このものを塩化メチレン２−に溶解し、メタノール４０
−１０．１Ｍ水酸化ナトリウム水溶液０．７５ｍを順次
加えて水冷下２０分間攪拌した。１０％酢酸で中和した
後、水で希釈し、酢酸エチルで抽出した。抽出液を水、
飽和食塩水で順次洗浄し、無水硫酸ナトリウム上で乾燥
した。溶媒を減圧上留去し、得られた赤色残渣をカラム
クロマトグラフィー（シリカゲル、クロロホルム−クロ
ロホルム−アセトン３０：１）にて分離精製し、（＋）
−３’ −Ｎ−）リフルオロアセチル−１４−フルオ
ロダウノルビシン２７．２■（９１％）を赤色粉末とし
て得た。Dissolve this in methylene chloride and 40 methanol.
-0.75 m of a 10.1 M sodium hydroxide aqueous solution was added one after another and stirred for 20 minutes under water cooling. After neutralizing with 10% acetic acid, it was diluted with water and extracted with ethyl acetate. Add the extract to water,
It was washed successively with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting red residue was separated and purified by column chromatography (silica gel, chloroform-chloroform-acetone 30:1).
-3'-N-) Lifluoroacetyl-14-fluorodaunorubicin 27.2 µ (91%) was obtained as a red powder.
ｍｐ、１６１．５〜１６４℃。mp, 161.5-164°C.
（α）１）”＋１７３ ＠（Ｃ−０，１０８，ジオキサ
ン）。(α)1)”+173 @(C-0,108, dioxane).
ＮＭＲ（ＣＤＣＩｓ）：δ−１，３３（３Ｈ。NMR (CDCIs): δ-1,33 (3H.
ｄ、Ｊ＝６Ｈｚ）、１．６５〜２．５５ （４Ｈ。d, J=6Hz), 1.65-2.55 (4H.
ｍ）、３．０９ （ＩＨ，ｄ、Ｊ＝１９Ｈｚ）。m), 3.09 (IH, d, J=19Hz).
３．３２ （ＩＨ，ｄ、Ｊ−１９Ｈｚ）、３．５５〜３
．８０ （ＩＨ，ｍ）、３．９５〜４．４０（２Ｈ，ｍ
）、４．１２ （３Ｈ，ｓ）、４．４１（ＩＨ，ｓ）、
５．３６ （ＩＨ，ｔ、Ｊ−５Ｈｚ）、５．５４ （２
Ｈ，ｄ、Ｊ＝４８Ｈｚ）。3.32 (IH, d, J-19Hz), 3.55-3
．． 80 (IH, m), 3.95-4.40 (2H, m
), 4.12 (3H, s), 4.41 (IH, s),
5.36 (IH, t, J-5Hz), 5.54 (2
H, d, J = 48Hz).
５．５０〜５．６７ （ＩＨ，ｍ）、６．６６ （１１
（。5.50-5.67 (IH, m), 6.66 (11
(.
ｂｒｄ、Ｊ＝８Ｈｚ）、７．４５ （ＬＨ，ｄ。brd, J=8Hz), 7.45 (LH, d.
Ｊ″′８Ｈｚ）、 ７．８３ （ＩＨ，ｔ、Ｊ−８
Ｈ２）、 ８．０８ （ＩＨ，ｄ、 Ｊ＝８Ｈｚ
）。J'''8Hz), 7.83 (IH, t, J-8
H2), 8.08 (IH, d, J=8Hz
).
１３．２９ （ＩＨ，ｓ）、１４．０５ （ＩＨ，
ｓ）。13.29 (IH,s), 14.05 (IH,
s).
ＩＲ（ＫＢｒ）：３５００，３４５０゜１７４０、 １
７２−０．１６１５． １５９００１−’。IR (KBr): 3500, 3450°1740, 1
72-0.1615. 159001-'.
ＭＳ （ｍ／ａ） ： ６４１ （Ｍ′″）、４
１６゜３９８、 ３８０． ３３７゜
元素分析値： Ｃｚ＊ＨｘｔＦ４ＮＯ□として＼５ＬＬ
３０７
計算値：Ｃ１＃牢ヰ；Ｈ，４，２４二 Ｎ、２．１８％
。MS (m/a): 641 (M'''), 4
16°398, 380. 337゜Elemental analysis value: Cz*HxtF4NO□＼5LL
307 Calculated value: C1# prison; H, 4,242 N, 2.18%
.
分析値： Ｃ，５４，２１；Ｈ，４，４５： Ｎ、１．
９８％。Analysis value: C, 54,21; H, 4,45: N, 1.
98%.
参考例３
（＋） −３’−Ｎ−）リフルオロアセチル−１４−フ
ルオロダウノルビシンＩ Ｌ、２ｍ （０，０２９９ｍ
ｍｏ１）をＴＨＦｏ、７７ｉｄに懸濁し、０．０５Ｍ水
酸化ナトリウム水溶液３．０−を加えて０℃で１５分、
室温で４０分間攪拌した０反応混合物を１Ｍ塩酸を用い
てｐＨ９に調製し、クロロホルムで抽出した。抽出液を
水で洗浄し、無水硫酸ナトリウム上で乾燥した。溶媒を
減圧上駒２−に濃縮し、０．２５Ｍ塩酸−メタノール溶
液０．６−を加えた後に約２０−のエーテルを加えて沈
殿を析出させた。Reference Example 3 (+)-3'-N-)Lifluoroacetyl-14-fluorodaunorubicin IL, 2m (0,0299m
mo1) was suspended in THFo, 77id, 0.05M sodium hydroxide aqueous solution 3.0- was added, and the mixture was heated at 0°C for 15 minutes.
The reaction mixture was stirred at room temperature for 40 minutes, adjusted to pH 9 using 1M hydrochloric acid, and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure in an upper chamber, and 0.6 mm of 0.25 M hydrochloric acid-methanol solution was added, followed by addition of about 20 mm of ether to precipitate.
上清をデカンテーシタンによって除き、さらにエーテル
でトリチュレートすることにより（＋）−１４−フルオ
ロダウノルビシン塩酸塩８．６■（４９％）を赤色粉末
として得た。The supernatant was removed with decantane and further triturated with ether to obtain 8.6 µ (49%) of (+)-14-fluorodaunorubicin hydrochloride as a red powder.
ｍｐ、２０９℃（ｄ ｅ ｃ ａｍｐ、 ） 。mp, 209°C (d e c amp, ).
（α）ＤＩ１１＋１７６ ’″ （ｃ＝＝ ０．０９１
． メ９）−ル）。(α) DI11+176 ''' (c== 0.091
．． 9)-L).
ＮＭＲ（（ＣＤｓ）＊ＳＯ）：δ−１，１６（３Ｈ，ｄ
、Ｊ＝６．５Ｈｚ）、１．６８ （ＩＨ。NMR ((CDs)*SO): δ-1,16(3H,d
, J=6.5Hz), 1.68 (IH.
ｄｄ、Ｊ−１２，５及び３．［（ｚ）、１．８８（Ｉ
Ｈ，、ｄ ｔ、Ｊ−１２，５及び３．２Ｈｚ）。dd, J-12, 5 and 3. [(z), 1.88(I
H,, d t, J-12,5 and 3.2 Hz).
２．１４ （ＩＨ，ｄｄ、 Ｊ麿１４．１及び５．３Ｈ
ｚ） 、 ２．２１ （ＩＨ，ｄ、 Ｊ−１４，１Ｈｚ
）、２．８９ （ＩＨ，ｄ、Ｊ＝１８．３Ｈｚ）。2.14 (IH, dd, Jmaro 14.1 and 5.3H
z), 2.21 (IH, d, J-14, 1Hz
), 2.89 (IH, d, J=18.3Hz).
３．０９ （ＩＨ，ｄ、Ｊ−１８，３Ｈｚ）。3.09 (IH, d, J-18, 3Hz).
３．５７ （ＩＨ，ｂｒｄ、Ｊ−６，１Ｈｚ）。3.57 (IH,brd,J-6,1Hz).
４．００ （３Ｍ、ｓ）、４．１７ （ＩＨ，Ｑ。4.00 (3M, s), 4.17 (IH, Q.
Ｊ−６，５Ｈｚ）、４．９８ （ＩＨ，ｄｄ、Ｊ−５
，３及び２．９Ｈｚ）、５．３１ （ＩＨ，ｄ。J-6,5Hz), 4.98 (IH, dd, J-5
, 3 and 2.9 Hz), 5.31 (IH, d.
Ｊ−３，２Ｈｚ）、５．４７ （ＩＨ，ｄ、Ｊ−６，
１Ｈｚ）、５．５７ （ＬＨ，ｄｄ、Ｊ −４７，２
及び１７．６Ｈ２）、５．６４ （ＩＨ，ｄｄ。J-3, 2Hz), 5.47 (IH, d, J-6,
1Hz), 5.57 (LH, dd, J -47,2
and 17.6H2), 5.64 (IH, dd.
Ｊ＝４７．２及び１７．６Ｈｚ）、５．６３ （ＩＨ，
ｓ）。J = 47.2 and 17.6Hz), 5.63 (IH,
s).
７．６４〜７．７０ （ＩＨ，ｍ）、７．８６ （
３Ｈ。7.64-7.70 (IH, m), 7.86 (
3H.
ｂ ｒ Ｓ）、７．９０〜？、’ｊり（２Ｈ，ｍ）。b r S), 7.90~? , 'jri (2H, m).
１３．２６ （ＩＨ，ｓ）、１４．０５ （ＩＨ，
ｓ）。13.26 (IH,s), 14.05 (IH,
s).
ＩＲ（ＫＢｒ）：３４５０，１７３５゜１６１５、 １
５９０ｃｍ−’。IR (KBr): 3450, 1735° 1615, 1
590cm-'.
試 験 例（癌細胞増殖阻害作用）
マウスリンパ性白血病培養細胞（Ｐ ３８８）を１０％
仔牛脂児血清含有のＲＰＭＩ−１６４０培養液に加え、
培養細胞数を５Ｘ１０’個／ｍｌに調製し、本発明の新
規１４−フルオロダウノルビシン塩酸塩を所定の濃度と
なるように添加し、３７℃で２日間培養した。コールタ
−カウンターを用い、浮遊細胞数を計数して、対照区に
対する増殖阻害率から、５０％細胞増殖阻害濃度ＩＣ５
ｏを求めた結果を表１に示す。Test example (cancer cell growth inhibition effect) Mouse lymphocytic leukemia cultured cells (P388) at 10%
In addition to RPMI-1640 culture solution containing calf fat serum,
The number of cultured cells was adjusted to 5×10′ cells/ml, the novel 14-fluorodaunorubicin hydrochloride of the present invention was added to a predetermined concentration, and the cells were cultured at 37° C. for 2 days. Using a Coulter counter, count the number of floating cells and determine the 50% cell growth inhibition concentration IC5 from the growth inhibition rate relative to the control group.
Table 1 shows the results of determining o.
表１ （＋３−１４−フルオロダウノルビシン塩酸
塩のマウスリンパ性白血病培養細胞
（Ｐ３８Ｂ）対するＩＣｓ。Table 1 (ICs of +3-14-fluorodaunorubicin hydrochloride against mouse lymphocytic leukemia cultured cells (P38B).
Claims (1)
２及びＲ＾３は結合している炭素原子と一体となって環
式あるいは非環式アセタールを形成し、または、Ｒ＾２
及びＲ＾３は一体となって酸素原子を表わす。 で表わされる２−（２−フルオロエチル）−２，５，１
２−トリヒドロキシ−７−メトキシ−１，２，３，４−
テトラヒドロナフタセン−６，１１−ジオン誘導体。[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a hydroxyl group, and R^
2 and R^3 together with the carbon atom to which they are bonded form a cyclic or acyclic acetal, or R^2
and R^3 together represent an oxygen atom. 2-(2-fluoroethyl)-2,5,1 represented by
2-trihydroxy-7-methoxy-1,2,3,4-
Tetrahydronaphthacene-6,11-dione derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1815887A JPS63188674A (en) | 1987-01-30 | 1987-01-30 | 2-(2-fluoroethyl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1815887A JPS63188674A (en) | 1987-01-30 | 1987-01-30 | 2-(2-fluoroethyl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63188674A true JPS63188674A (en) | 1988-08-04 |
| JPH0544937B2 JPH0544937B2 (en) | 1993-07-07 |
Family
ID=11963803
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1815887A Granted JPS63188674A (en) | 1987-01-30 | 1987-01-30 | 2-(2-fluoroethyl)-2,5,12-trihydroxy-7-methoxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63188674A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR25495A (en) * | 1990-11-12 | 1993-05-01 | Menarini Farma Ind | NEW FLORO-NAFTACENDIONS AND ITS GLUSILATED DERIVATIVES AND MANUFACTURED ITEMS |
-
1987
- 1987-01-30 JP JP1815887A patent/JPS63188674A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR25495A (en) * | 1990-11-12 | 1993-05-01 | Menarini Farma Ind | NEW FLORO-NAFTACENDIONS AND ITS GLUSILATED DERIVATIVES AND MANUFACTURED ITEMS |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0544937B2 (en) | 1993-07-07 |
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