JPH04290891A - New anthracycline-based compound - Google Patents
New anthracycline-based compoundInfo
- Publication number
- JPH04290891A JPH04290891A JP8149491A JP8149491A JPH04290891A JP H04290891 A JPH04290891 A JP H04290891A JP 8149491 A JP8149491 A JP 8149491A JP 8149491 A JP8149491 A JP 8149491A JP H04290891 A JPH04290891 A JP H04290891A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- hydroxyl group
- group
- protected
- compound
- 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 38
- 229940045799 anthracyclines and related substance Drugs 0.000 title claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 31
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 4
- 150000004820 halides Chemical class 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 239000011630 iodine Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 241000193738 Bacillus anthracis Species 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 230000002421 anti-septic effect Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical class C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 claims 1
- -1 (protected) hydroxyl Chemical group 0.000 abstract description 9
- 230000001093 anti-cancer Effects 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 abstract description 4
- NGYIMTKLQULBOO-UHFFFAOYSA-L mercury dibromide Chemical compound Br[Hg]Br NGYIMTKLQULBOO-UHFFFAOYSA-L 0.000 abstract description 3
- 239000000010 aprotic solvent Substances 0.000 abstract description 2
- 230000001747 exhibiting effect Effects 0.000 abstract description 2
- 229940101209 mercuric oxide Drugs 0.000 abstract description 2
- 239000002808 molecular sieve Substances 0.000 abstract description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 abstract description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- 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 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000005997 bromomethyl group Chemical group 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 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 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000004280 Sodium formate Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001734 carboxylic acid salts Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 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 2
- 238000006567 deketalization reaction Methods 0.000 description 2
- 238000005907 ketalization reaction Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 235000019254 sodium formate Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 1
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- UBZYKBZMAMTNKW-UHFFFAOYSA-J titanium tetrabromide Chemical compound Br[Ti](Br)(Br)Br UBZYKBZMAMTNKW-UHFFFAOYSA-J 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】[Detailed description of the invention]
【０００１】0001
【産業上の利用分野】本発明は新規なアンスラサイクリ
ン系化合物、その抗腫瘍剤としての用途および製造法に
関する。TECHNICAL FIELD The present invention relates to a novel anthracycline compound, its use as an antitumor agent, and its production method.
【０００２】0002
【従来の技術】ダウノマイシンおよびアドリアマイシン
に代表されるアンスラサイクリン系抗生物質は強い抗腫
瘍活性と広い制癌スペクトルを示し、世界的に最も広く
臨床に用いられている制癌剤の一つである。BACKGROUND OF THE INVENTION Anthracycline antibiotics, represented by daunomycin and adriamycin, exhibit strong antitumor activity and a broad anticancer spectrum, and are one of the most widely used anticancer agents in clinical practice worldwide.
【化１２】
（ダウノマイシン：Ｒ＝Ｈ，アドリアマイシン：Ｒ＝Ｏ
Ｈ）[Chemical formula 12] (daunomycin: R=H, adriamycin: R=O
H)
【０００３】しかしながら、これらの化合物は心臓毒性
、骨髄抑制などの副作用を有しているので安全な使用の
障害となっている。However, these compounds have side effects such as cardiotoxicity and bone marrow suppression, which hinders their safe use.
【０００４】一方、アンスラサイクリン系化合物はアグ
リコンや糖部分の僅かな構造変化によって副作用の軽減
や制癌活性の増大が現われることが次第に明かになり、
この分野の研究が活発に行われている。On the other hand, it has gradually become clear that anthracycline compounds reduce side effects and increase anticancer activity through slight structural changes in the aglycone and sugar moieties.
Research in this field is actively being conducted.
【０００５】そして、これらの化合物に弗素を導入する
ことも試みられており、アドリアマイシンの糖部Ｃ−２
′位に弗素がアキシャルに付いた化合物が最も良いこと
が知られている（梅沢ら、カーボハイドレート・リサー
チ、１６９巻、６９頁、１９８７年）。[0005] Attempts have also been made to introduce fluorine into these compounds.
It is known that a compound in which fluorine is axially attached to the ′ position is the best (Umezawa et al., Carbohydrate Research, Vol. 169, p. 69, 1987).
【０００６】[0006]
【発明が解決しようとする課題】しかしながら、副作用
や抗癌活性の面で従来のアンスラサイクリン系化合物は
未だ充分満足できるものではない。[Problems to be Solved by the Invention] However, conventional anthracycline compounds are still not fully satisfactory in terms of side effects and anticancer activity.
【０００７】[0007]
【課題を解決するための手段】本発明者らは前記の課題
を解決するために、新規なアンスラサイクリン系化合物
を探究した結果、同化合物の部分構造中、４位のメトキ
シ基と１１位の水酸基がなく、糖部分のＣ−２′位に弗
素がアキシャルに導入された化合物を得ることに成功し
た。[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors searched for a new anthracycline compound, and found that in the partial structure of the compound, a methoxy group at the 4-position and a methoxy group at the 11-position We succeeded in obtaining a compound that does not have a hydroxyl group and has fluorine axially introduced into the C-2' position of the sugar moiety.
【０００８】本発明は、次の式〔Ｉ〕The present invention provides the following formula [I]
【化１３】
〔式中、Ｒ１ は水素またはエステル化されもしくはさ
れない水酸基、ＯＲ２ は保護されまたはされない水酸
基を表す〕で表わされる新規なアンスラサイクリン系化
合物、同化合物を含有する抗腫瘍剤、および次の式〔Ｖ
ＩＩ 〕A novel anthracycline compound represented by the formula [wherein R1 represents hydrogen or an esterified or unesterified hydroxyl group, and OR2 represents a protected or unprotected hydroxyl group], an antitumor agent containing the same compound, and the following: The formula [V
II]
【化１４】
の４−デメトキシ−１１−デオキシダウノマイシノンを
次の式〔ＶＩＩＩ〕4-demethoxy-11-deoxydaunomycinone of [Chemical formula 14] is converted to the following formula [VIII]
【化１５】
〔式中、ＯＲ３ は保護された水酸基、Ｘは臭素、沃素
または塩素を表す〕で表される３，４位の水酸基の保護
された２，６−ジデオキシ−２−フルオロ−ａ−Ｌ−タ
ロピラノシル・ハライドと反応させて次の式〔ＩＸ〕2,6-dideoxy-2-fluoro-a with protected hydroxyl groups at the 3 and 4 positions represented by [Formula, OR3 is a protected hydroxyl group, and X represents bromine, iodine or chlorine] -L-talopyranosyl halide to form the following formula [IX]
【
化１６】
〔式中、ＯＲ３ は前記と同義〕で表されるアンスラサ
イクリン系化合物を生成させるか、続いて１４位のメチ
ル基をヒドロキシメチル基に変換させるかし、またはさ
らにそのヒドロキシメチル基の水酸基をエステル化し、
残存する保護基があれば必要に応じて離脱させることを
特徴とする式〔Ｉ〕の化合物の製造法である。[
Either an anthracycline compound represented by the formula [wherein OR3 has the same meaning as above] is produced, or the methyl group at position 14 is subsequently converted to a hydroxymethyl group, or the hydroxymethyl group is further converted to Esterifies the hydroxyl group,
This is a method for producing a compound of formula [I], which is characterized in that any remaining protecting groups are removed as necessary.
【０００９】上記の式〔Ｉ〕において、Ｒ１ で示され
るエステル化された水酸基のエステルを構成する酸残基
はＣ２ −Ｃ１０の脂肪族カルボン酸残基を包含する。
好ましいのは式ＨＯＯＣ（ＣＨ２ ）ｎＣＯＯＨ〔式中
、ｎは４−６〕で表わされる、ジカルボン酸、たとえば
、ピメリン酸の１個のカルボキシル基から水酸基を除い
た残基であり、この場合ヘミエステルが形成される。式
〔Ｉ〕においてＯＲ２ 、式〔ＶＩＩＩ〕および〔ＩＸ
〕においてＯＲ３ で示される保護された水酸基の保護
基としては、たとえば、アセチル、プロピオニル、ブチ
リルのようなＣ５ 以下の脂肪族カルボン酸のアシル基
やベンジル基などが好ましい。In the above formula [I], the acid residues constituting the ester of the esterified hydroxyl group represented by R1 include C2-C10 aliphatic carboxylic acid residues. Preferred is a dicarboxylic acid represented by the formula HOOC(CH2)nCOOH [where n is 4-6], for example, a residue obtained by removing the hydroxyl group from one carboxyl group of pimelic acid; in this case, the hemiester is It is formed. In formula [I], OR2, formula [VIII] and [IX
The protecting group for the protected hydroxyl group represented by OR3 in ] is preferably, for example, an acyl group or a benzyl group of a C5 or less aliphatic carboxylic acid such as acetyl, propionyl, butyryl.
【００１０】式〔ＶＩＩ 〕の化合物と式〔ＶＩＩＩ〕
のハライドとの反応は次の式で示すことができる。Compound of formula [VII] and formula [VIII]
The reaction of with halide can be shown by the following equation.
【化１７】
〔式中、ＯＲ３ は保護された水酸基、Ｘは塩素、臭素
、沃素を表す〕[Formula, OR3 represents a protected hydroxyl group, and X represents chlorine, bromine, or iodine]
【００１１】この反応はジクロロメタン、ジメチルホル
ムアミドなどの非プロトン性溶媒中行われ、脱ハロゲン
化水基剤、たとえば、黄色酸化第二水銀、臭化第二水銀
およびモレキュラーシーブ３Åの存在下に行うのが望ま
しい。The reaction is carried out in an aprotic solvent such as dichloromethane, dimethylformamide, etc. in the presence of a dehalogenated water base such as yellow mercuric oxide, mercuric bromide, and a 3A molecular sieve. desirable.
【００１２】上記の反応式に示されるように、反応の結
果２種類の天然型α−グリコシド化合物が生成し、それ
らはクロマトグラフィーにより容易に分別することがで
きる。この分別は後記する保護基の離脱反応または下記
する１４位への水酸基もしくはそのエステルの導入の後
に行ってもよい。As shown in the above reaction formula, two types of natural α-glycoside compounds are produced as a result of the reaction, and they can be easily separated by chromatography. This fractionation may be performed after the removal reaction of the protecting group described below or the introduction of a hydroxyl group or its ester at the 14-position described below.
【００１３】上記の化合物〔ＩＩ〕または〔ＩＩＩ 〕
の１４位のメチル基はヒドロキシメチル基に転換するこ
とができる。The above compound [II] or [III]
The methyl group at position 14 can be converted to a hydroxymethyl group.
【００１４】この反応は、たとえば、ジクロロメタン、
ジオキサンなどの溶媒中でオルトギ酸低級アルキルエス
テルを作用させて１３位のカルボニル基をケタール化し
て保護したのち、臭素を作用させて１４位のメチル基を
ブロモメチル基に変え、次いでアセトンを作用させて脱
ケタール化し、続いてギ酸ナトリウムを作用させてブロ
モメチル基をヒドロキシメチル基に変えることにより行
うことができる。なお、この工程でヒドロキシメチル基
の水酸基がホルミル化された副生物が多少生成するが、
アンモニア水のような弱アルカリまたは弱酸を作用させ
てホルミル基を除去することができる。This reaction can be carried out using, for example, dichloromethane,
The carbonyl group at position 13 is protected by ketalization by reacting with orthoformic acid lower alkyl ester in a solvent such as dioxane, and then the methyl group at position 14 is transformed into a bromomethyl group by reacting with bromine, and then acetone is reacted with the carbonyl group. This can be carried out by deketalization, followed by the action of sodium formate to convert the bromomethyl group into a hydroxymethyl group. In addition, in this step, some by-products are produced when the hydroxyl group of the hydroxymethyl group is formylated, but
The formyl group can be removed by the action of a weak alkali or weak acid such as aqueous ammonia.
【００１５】上記の反応は、化合物〔Ｖ〕を用いる場合
の例について、式示すれば次のとおりである。The formula for the above reaction using compound [V] is as follows.
【００１６】上記の反応における中間体のブロマイド化
合物〔Ｘ〕に、カルボン酸の塩を作用させてアシル化す
なわちエステル化された水酸基が１４位のメチル基に導
入された化合物を得ることもできる。反応は、たとえば
ジオキサンのような溶媒中で行われる。カルボン酸の塩
としては、たとえば、ナトリウム塩、トリエチルアミン
塩などが用いられる。ピメリン酸のようなジカルボン酸
でエステル化された水酸基を導入する場合は、たとえば
、ジカルボン酸のモノメチルエステルまたはモノベンジ
ルエステルのナトリウム塩をブロマイド化合物に反応さ
せたのち、メチルエステルは加水分解し、ベンジルエス
テルは還元してカルボキシル基に変えることによりジカ
ルボン酸のヘミエステルの形でエステル化された水酸基
を導入することができる。[0016] A compound in which an acylated or esterified hydroxyl group is introduced into the methyl group at the 14th position can also be obtained by reacting the intermediate bromide compound [X] in the above reaction with a carboxylic acid salt. The reaction is carried out in a solvent such as dioxane. Examples of carboxylic acid salts include sodium salts and triethylamine salts. When introducing a hydroxyl group esterified with a dicarboxylic acid such as pimelic acid, for example, after reacting the sodium salt of monomethyl ester or monobenzyl ester of dicarboxylic acid with a bromide compound, the methyl ester is hydrolyzed and the benzyl By reducing the ester and converting it into a carboxyl group, it is possible to introduce an esterified hydroxyl group in the form of a hemiester of dicarboxylic acid.
【００１７】目的とするグリコシド化合物の糖部分の水
酸基に残存する保護基がある場合は、たとえば保護基が
アシル基の場合、水酸化ナトリウムなどの存在下の加水
分解により、またベンジル基の場合は接触還元により離
脱させることができ、式If there is a protective group remaining on the hydroxyl group of the sugar moiety of the target glycoside compound, for example, if the protective group is an acyl group, it can be removed by hydrolysis in the presence of sodium hydroxide, or in the case of a benzyl group. It can be removed by catalytic reduction and the formula
【化１９】
〔式中、Ｒ１ は水素またはエステル化されもしくはさ
れない水酸基を表す〕で示される化合物が得られる。A compound represented by the formula [wherein R1 represents hydrogen or a hydroxyl group which may or may not be esterified] is obtained.
【００１８】かくして得られる本発明の化合物〔Ｉ〕は
抗腫瘍剤として投与される。投与法は多くの場合非経口
的であり、投与量は化合物の種類、剤形、症状などに左
右されるが、静脈内投与の場合、一般に１日数回、１回
量０．１−３ｍｇ、好ましくは０．３−０．６ｍｇであ
る。The compound [I] of the present invention thus obtained is administered as an antitumor agent. The administration method is parenteral in most cases, and the dosage depends on the type of compound, dosage form, symptoms, etc., but in the case of intravenous administration, it is generally administered several times a day, in a single dose of 0.1-3 mg. Preferably it is 0.3-0.6 mg.
【００１９】実験例 マウス白血病培養細胞に対する増殖阻害作用試験Experimental example Growth inhibitory effect test on mouse leukemia cultured cells
【００
２０】１０％仔牛血清及び抗生物質（ペニシリン２００
Ｕ／ｍｌ、ファンギゾン０．５μｇ／ｍｌ、ストレプト
マイシン２００Ｕ／ｍｌ）を含むＲＰＭＩ−１６４０培
地（ＧＩＢＣＯ社）にＬ１２１０細胞、Ｌ１２１０ＡＤ
Ｍ耐性細胞又はＰ３８８ 細胞を１×１０５ 個／ｍｌ
接種した。なお、Ｐ３８８ 細胞を用いた評価培地は２
−メルカプトエタノールを５×１０−５Ｍ濃度含有する
。これらの培地に被検物質を０．０２５−１０．０μｇ
／ｍｌの濃度で添加し、３７℃にて炭酸ガス培養器中で
３日間培養し、対照群（被検物質無添加群）に対して５
０％細胞増殖抑制阻害を示す被検物質濃度を求めた。結
果を次表に示す。00
20. 10% calf serum and antibiotics (penicillin 200
L1210 cells, L1210AD in RPMI-1640 medium (GIBCO) containing 0.5 μg/ml fungizone, 200 U/ml streptomycin)
M-resistant cells or P388 cells at 1 x 105 cells/ml
Inoculated. The evaluation medium using P388 cells was 2
- Contains mercaptoethanol at a concentration of 5 x 10-5M. 0.025-10.0μg of test substance in these media
/ml and cultured for 3 days in a carbon dioxide incubator at 37°C.
The concentration of the test substance exhibiting 0% inhibition of cell proliferation was determined. The results are shown in the table below.
【００２１】[0021]
【表１】[Table 1]
【００２２】参考例１ ３，４−ジ−Ｏ−アセチル−
２，６−ジデオキシ−２−フルオロ−ａ−Ｌ−タロピラ
ノシルブロマイド〔ＩＸ′：Ｒ３ ＝アセチル〕の製造
Reference Example 1 3,4-di-O-acetyl-
Production of 2,6-dideoxy-2-fluoro-a-L-talopyranosyl bromide [IX':R3 = acetyl]
【００２３】１，３，４−トリ−Ｏ−アセチル−２，４
−ジデオキシ−２−フルオロ−ａ−Ｌ−タロピラノース
５３ｍｇを無水ジクロロメタン−無水酢酸エチル（１０
：１）の混液２ｍｌに溶解させ、四臭化チタン１５０ｍ
ｇを加え２５℃で４８時間攪拌した。反応液に無水アセ
トニトリル４ｍｌを加えた後、無水酢酸ナトリウム３５
０ｍｇを加え、１時間室温で攪拌すると黄白色混合物を
得た。これに無水ベンゼン６ｍｌを加えた。沈澱を濾過
し、濾液を濃縮し、再度無水ベンゼンを加えて不溶物を
濾去し、濾液を濃縮してシロップを得、これを実施例の
反応に用いた。1,3,4-tri-O-acetyl-2,4
-Dideoxy-2-fluoro-a-L-talopyranose (53 mg) was added to anhydrous dichloromethane-anhydrous ethyl acetate (10
: Dissolve in 2 ml of the mixture of 1) and add 150 ml of titanium tetrabromide.
g was added thereto, and the mixture was stirred at 25°C for 48 hours. After adding 4 ml of anhydrous acetonitrile to the reaction solution, 35 ml of anhydrous sodium acetate was added.
0 mg was added and stirred at room temperature for 1 hour to obtain a yellow-white mixture. To this was added 6 ml of anhydrous benzene. The precipitate was filtered, the filtrate was concentrated, anhydrous benzene was added again, insoluble matter was filtered off, and the filtrate was concentrated to obtain a syrup, which was used in the reactions of Examples.
【００２４】実施例１ （７Ｒ，９Ｒ）−および（７
Ｓ，９Ｓ）−７−Ｏ−（３，４−ジ−Ｏ−アセチル−２
，６−ジデオキシ−２−フルオロ−α−Ｌ−タロピラノ
シル）−４−デメトキシ−１１−デオキシダウノマイシ
ノン〔ＩＩ′およびＩＩＩ ′，Ｒ２ ＝アセチル〕の
製造４−デメトキシ−１１−デオキシダウノマイシノン
〔ＶＩＩ 〕３５ｍｇ（０．０９９ｍ ｍｏｌ）、Ｈ
ｇＯ黄色８６ｍｇ（０．４０ｍ ｍｏｌ）、臭化第二
水銀３６．２ｍｇ（０．１０ｍ ｍｏｌ）、モレキュ
ラー・シーブ３Å０．５３ｇを無水ジクロロメタンに懸
濁させた。次に上記のシロップを無水ジクロロメタン３
ｍｌに溶かした溶液を室温で加え、遮光して４８時間攪
拌した。Example 1 (7R,9R)- and (7
S,9S)-7-O-(3,4-di-O-acetyl-2
, 6-dideoxy-2-fluoro-α-L-talopyranosyl)-4-demethoxy-11-deoxydaunomycinone [II' and III', R2 = acetyl] 4-demethoxy-11-deoxydaunomycinone Chinon [VII] 35mg (0.099m mol), H
86 mg (0.40 mmol) of gO yellow, 36.2 mg (0.10 mmol) of mercuric bromide, and 0.53 g of molecular sieve 3A were suspended in anhydrous dichloromethane. Next, add 3 parts of the above syrup to anhydrous dichloromethane.
ml of the solution was added at room temperature, and stirred for 48 hours while shielding from light.
【００２５】反応混合物を濾過し、濾液にクロロホルム
を加え、３０％沃化カリ水溶液とよく振り混ぜ、有機層
をＮａＨＣＯ３ 水溶液で洗浄後、ＮａＳＯ４ で乾燥
し、次いで溶媒を留去した。The reaction mixture was filtered, chloroform was added to the filtrate, and the mixture was thoroughly shaken with a 30% aqueous potassium iodide solution. The organic layer was washed with an aqueous NaHCO3 solution, dried over NaSO4, and then the solvent was distilled off.
【００２６】上記の操作を２回繰り返し生成物を合わせ
てシリカゲルプレート（ＣＨ２ Ｃｌ２ ：Ｅｔ２ Ｏ
＝４：１）にて展開し、分離精製し、黄色結晶〔ＩＩ′
〕２６ｍｇ（２２％）、黄色結晶〔ＩＩＩ ′〕２３ｍ
ｇ（２０％）を得た。The above operation was repeated twice and the products were combined and placed on a silica gel plate (CH2 Cl2 :Et2 O
= 4:1), separated and purified to give yellow crystals [II'
] 26 mg (22%), yellow crystal [III'] 23 m
g (20%) was obtained.
【００２７】化合物〔ＩＩ′〕Compound [II']
【００２８】ｍ．ｐ．１３５−１３８℃（ベンゼン−ｎ
−ヘキサン）m. p. 135-138℃ (benzene-n
-hexane)
【００２９】〔α〕（２４，Ｄ）−１９９．６°（Ｃ＝
０．１０，ＣＨＣｌ３ ）[α](24,D)-199.6°(C=
0.10, CHCl3)
【００３０】ＩＲν（ＣＨＣｌ３ ，ｍａｘ）ｃｍ−１
：１７４０，１６７０，１６３０，１５９０．IRν(CHCl3,max)cm-1
:1740,1670,1630,1590.
【００３
１】 １Ｈ−ＮＭＲ（ＣＤＣｌ３ ）δ：１．２７（ｄ
，３Ｈ，５′Ｍｅ，Ｊ＝７Ｈｚ）２．０１ ａｎｄ
２．１８（ｅａｃｈ ｓ， ６Ｈ，Ａｃ×２）２．０−
２．１２（ｍ，１Ｈ，８ａｘＨ）２．３６（ｓ，３Ｈ，
１４Ｍｅ）
２．４７（ｄ，１Ｈ，８ｅｑＨ，Ｊ＝１５Ｈｚ）３．１
８（ｄ，１Ｈ，１０ａｘＨ，Ｊ＝１８Ｈｚ）３．２９（
ｄ，１Ｈ，１０ｅｑＨ，Ｊ＝１８Ｈｚ）４．１１（ｓ，
１Ｈ，９０Ｈ）
４．５２（ｄ，１Ｈ，２′Ｈ，Ｊ＝４８Ｈｚ）４．６１
（ｑ，１Ｈ，５′Ｈ，Ｊ＝７Ｈｚ）５．０７（ｄｔ，１
Ｈ，３′Ｈ，Ｊ＝３３，３Ｈｚ）５．１９（ｍ，１Ｈ，
４′Ｈ）
５．４７（ｄ，１Ｈ，１′Ｈ，Ｊ＝９Ｈｚ）５．６２（
ｍ，１Ｈ，７Ｈ）
７．６６（ｓ，１Ｈ，１１Ｈ）
７．８３−７．８７（ｍ，２Ｈ，２ ａｎｄ ３Ｈ）
８．３０−８．３７（ｍ，２Ｈ，１ ａｎｄ ４Ｈ）
１３．４２（ｓ，１Ｈ，６０Ｈ）
ＦＡＢ−ＭＳ（ｎｅｇａｔｉｖｅ）ｍ／ｚ：５８４（Ｍ
− ）003
1] 1H-NMR (CDCl3) δ: 1.27 (d
,3H,5′Me,J=7Hz)2.01 and
2.18 (each s, 6H, Ac×2) 2.0-
2.12 (m, 1H, 8axH) 2.36 (s, 3H,
14Me) 2.47 (d, 1H, 8eqH, J=15Hz) 3.1
8(d, 1H, 10axH, J=18Hz) 3.29(
d, 1H, 10eqH, J=18Hz) 4.11(s,
1H, 90H) 4.52 (d, 1H, 2'H, J=48Hz) 4.61
(q, 1H, 5'H, J = 7Hz) 5.07 (dt, 1
H, 3′H, J=33,3Hz) 5.19(m, 1H,
4′H) 5.47(d, 1H, 1′H, J=9Hz) 5.62(
m, 1H, 7H) 7.66 (s, 1H, 11H) 7.83-7.87 (m, 2H, 2 and 3H)
8.30-8.37 (m, 2H, 1 and 4H)
13.42 (s, 1H, 60H) FAB-MS (negative) m/z: 584 (M
− )
【００３２】ＣＤ（Ｃ＝８．７×１０−５，Ｍｅ
ＯＨ）〔θ〕（２４，ｍａｘ）（ｎｍ）：＋２．９２×
１０４ （２８５），−３．２２×１０４ （３３６）
CD (C=8.7×10-5, Me
OH) [θ] (24, max) (nm): +2.92×
104 (285), -3.22×104 (336)
【００３３】化合物〔ＩＩＩ ′〕Compound [III']
【００３４】ｍ．ｐ．２２８−２３５℃（ベンゼン−ｎ
−Ｈｅｘａｎｅ）m. p. 228-235℃ (benzene-n
-Hexane)
【００３５】〔α〕（２４，Ｄ）＋５０．９°（Ｃ＝０
．１３，ＣＨＣｌ３）[α](24,D)+50.9°(C=0
．． 13, CHCl3)
【００３６】ＩＲν（ＣＨＣｌ３ ，ｍａｘ）ｃｍ−１
：１７４０，１７１０，１６７０，１６３０，１５９０
．IRν(CHCl3,max)cm-1
:1740,1710,1670,1630,1590
．．
【００３７】 １Ｈ−ＮＭＲ（ＣＤＣｌ３ ）δ：１
．２８（ｄ，３Ｈ，５′Ｍｅ，Ｊ＝７Ｈｚ）２．０４ａ
ｎｄ２．１８（ｅａｃｈ ｓ，６Ｈ，Ａｃ×２）２．
２２（ｄｄ，１Ｈ，８ａｘＨ，Ｊ＝１５ ａｎｄ ４
Ｈｚ）
２．４０（ｓ，３Ｈ，１４Ｍｅ）
２．４５−２．５５（ｍ，１Ｈ，８ｅｑＨ）３．０９（
ｄｄ，１Ｈ，１０ａｘＨ，Ｊ＝１８，１Ｈｚ）
３．２８（ｄ，１Ｈ，１０ｅｑＨ，Ｊ＝１８Ｈｚ）３．
８７（ｓ，１Ｈ，９０Ｈ）
４．３７（ｑ，１Ｈ，５′Ｈ，Ｊ＝７Ｈｚ）４．７０（
ｄ，１Ｈ，２′Ｈ，Ｊ＝４８Ｈｚ）５．０２（ｄｔ，１
Ｈ，３′Ｈ，Ｊ＝３２，３Ｈｚ）５．２４（ｍ，１Ｈ，
４′Ｈ）
５．３３（ｂｒｄ，１Ｈ，７Ｈ，Ｊ＝３Ｈｚ）５．６２
（ｄ，１Ｈ，１′Ｈ，Ｊ＝９Ｈｚ）７．６５（ｓ，１Ｈ
，１１Ｈ）
７．８２−７．８７（ｍ，２Ｈ，２ ａｎｄ ３Ｈ）
８．２８−８．３７（ｍ，２Ｈ，１ ａｎｄ ４Ｈ）
１３．３１（ｓ，１Ｈ，６０Ｈ）1H-NMR (CDCl3) δ:1
．． 28(d,3H,5′Me,J=7Hz)2.04a
nd2.18 (each s, 6H, Ac×2)2.
22 (dd, 1H, 8axH, J=15 and 4
Hz) 2.40 (s, 3H, 14Me) 2.45-2.55 (m, 1H, 8eqH) 3.09 (
dd, 1H, 10axH, J = 18, 1Hz) 3.28 (d, 1H, 10eqH, J = 18Hz) 3.
87 (s, 1H, 90H) 4.37 (q, 1H, 5'H, J=7Hz) 4.70 (
d, 1H, 2'H, J = 48Hz) 5.02 (dt, 1
H, 3′H, J=32,3Hz) 5.24(m, 1H,
4'H) 5.33 (brd, 1H, 7H, J=3Hz) 5.62
(d, 1H, 1′H, J=9Hz) 7.65(s, 1H
, 11H) 7.82-7.87 (m, 2H, 2 and 3H)
8.28-8.37 (m, 2H, 1 and 4H)
13.31 (s, 1H, 60H)
【００３８】ＦＡＢ−ＭＳ（ｎｅｇａｔｉｖｅ）ｍ／ｚ
：５８４（Ｍ− ）[0038] FAB-MS (negative) m/z
:584(M-)
【００３９】ＣＤ（Ｃ＝６．７×１０−５，ＭｅＯＨ）
〔θ〕（２４，ｍａｘ）（ｎｍ）：−１．６４×１０４
（２８４），＋０．８９×１０４ （３３４）CD (C=6.7×10-5, MeOH)
[θ] (24, max) (nm): -1.64×104
(284), +0.89×104 (334)
【００
４０】実施例２ （７Ｒ，９Ｒ）−７−Ｏ−（２，６
−ジデオキシ−２−フルオロ−α−Ｌ−タロピラノシル
）−４−デメトキシ−１１−デオキシダウノマイシノン
〔ＩＶ〕の製造
実施例１で得られたジアセチル化合物〔ＩＩ′〕２０ｍ
ｇを０．２Ｎ−ＮａＯＨ水溶液２．３ｍｌ中、０℃で３
時間攪拌した。次いでこの溶液に０℃で１Ｎ−ＨＣｌを
０．３ｍｌ加え、クロロホルムで抽出し、抽出液をＭｇ
ＳＯ４ で乾燥し、溶媒を留去した。残留物をベンゼン
−ｎ−ヘキサンより結晶化させて１２ｍｇの目的物〔Ｉ
Ｖ〕を得た。収率７０％。00
40] Example 2 (7R,9R)-7-O-(2,6
-dideoxy-2-fluoro-α-L-talopyranosyl)-4-demethoxy-11-deoxydaunomycinone [IV] Diacetyl compound [II'] obtained in Example 1 20m
g in 2.3 ml of 0.2 N NaOH aqueous solution at 0°C.
Stir for hours. Next, 0.3 ml of 1N HCl was added to this solution at 0°C, extracted with chloroform, and the extract was extracted with Mg
It was dried with SO4 and the solvent was distilled off. The residue was crystallized from benzene-n-hexane to give 12 mg of the target product [I
V] was obtained. Yield 70%.
【００４１】ｍ．ｐ．２４７−２５２℃m. p. 247-252℃
【００４２】〔
α〕（２３，Ｄ）−１５７．６°（Ｃ＝０．１０，ＣＨ
Ｃｌ３ ）[0042]
α〕(23,D)-157.6°(C=0.10,CH
Cl3)
【００４３】ＩＲν（ＣＨＣｌ３ ，ｍａｘ）ｃｍ−１
：１７１０，１６７０，１６３０，１５９０．IRν(CHCl3,max)cm-1
:1710,1670,1630,1590.
【００４
４】 １Ｈ−ＮＭＲ（ＣＤＣｌ３ ）δ：１．３５（ｄ
，３Ｈ，５′Ｍｅ，Ｊ＝７Ｈｚ）２．０２（ｄｄ，１Ｈ
，８ａｘＨ，Ｊ＝１５，４Ｈｚ）２．３７（ｓ，３Ｈ，
１４Ｍｅ）
２．４８（ｄ，１Ｈ，８ｅｑＨ，Ｊ＝１５Ｈｚ）３．１
６（ｄ，１Ｈ，１０ａｘＨ，Ｊ＝１８Ｈｚ）３．３０（
ｄ，１Ｈ，１０ｅｑＨ，Ｊ＝１８Ｈｚ）３．６２（ｄ，
１Ｈ，４′Ｈ，Ｊ＝１１Ｈｚ）３．７０（ｄｄ，１Ｈ，
３′Ｈ，Ｊ＝３２，１１Ｈｚ）４．１８（ｓ，１Ｈ，９
０Ｈ）
４．４０（ｑ，１Ｈ，５′Ｈ，Ｊ＝６Ｈｚ）４．５７（
ｄ，１Ｈ，２′Ｈ，Ｊ＝４９Ｈｚ）５．４３（ｄ，１Ｈ
，１′Ｈ，Ｊ＝１０Ｈｚ）５．５９（ｓ，１Ｈ，７Ｈ）
７．６５（ｓ，１Ｈ，１１Ｈ）
７．８２−７．８７（ｍ，２Ｈ，２ａｎｄ３Ｈ）８．２
８−８．３６（ｍ，２Ｈ，１ａｎｄ４Ｈ）１３．４０（
ｓ，１Ｈ，６０Ｈ）004
4] 1H-NMR (CDCl3) δ: 1.35 (d
, 3H, 5′Me, J=7Hz) 2.02(dd, 1H
,8axH,J=15,4Hz)2.37(s,3H,
14Me) 2.48 (d, 1H, 8eqH, J=15Hz) 3.1
6(d, 1H, 10axH, J=18Hz) 3.30(
d, 1H, 10eqH, J=18Hz) 3.62(d,
1H, 4'H, J=11Hz) 3.70 (dd, 1H,
3'H, J = 32, 11Hz) 4.18 (s, 1H, 9
0H) 4.40(q, 1H, 5'H, J=6Hz) 4.57(
d, 1H, 2'H, J = 49Hz) 5.43 (d, 1H
, 1'H, J=10Hz) 5.59 (s, 1H, 7H) 7.65 (s, 1H, 11H) 7.82-7.87 (m, 2H, 2and3H) 8.2
8-8.36 (m, 2H, 1 and 4H) 13.40 (
s, 1H, 60H)
【００４５】ＦＡＢ−ＭＳ（ｎｅｇａｔｉｖｅ）ｍ／ｚ
：５００（Ｍ− ）[0045] FAB-MS (negative) m/z
:500(M-)
【００４６】実施例３ （７Ｓ，９Ｓ）−７−Ｏ−（
２，６−ジデオキシ−２−フルオロ−α−Ｌ−タロピラ
ノシル）−４−デメトキシ−１１−デオキシダウノマイ
シノン〔Ｖ〕の製造Example 3 (7S,9S)-7-O-(
Production of 2,6-dideoxy-2-fluoro-α-L-talopyranosyl)-4-demethoxy-11-deoxydaunomycinone [V]
【００４７】実施例１で得られたジアセチル化合物〔Ｉ
ＩＩ ′〕２１ｍｇを０．２Ｎ−ＮａＯＨ水溶液２．３
ｍｌ中０℃で３時間攪拌した。次いでこの溶液に０℃で
１Ｎ−ＨＣｌを０．３ｍｌ加え、クロロホルムで抽出し
、抽出液をＭｇＳＯ４ で乾燥し、溶媒を留去した。残
留物をシリカゲルプレート（ＣＨＣｌ３ ：ＭｅＯＨ＝
９５：５）で展開し、精製した。得られた精製物をベン
ゼン−ｎ−ヘキサンより結晶化させて１２ｍｇの目的物
〔Ｖ〕を得た。収率６７％Diacetyl compound [I] obtained in Example 1
II'] 21 mg in 0.2N-NaOH aqueous solution 2.3
The mixture was stirred at 0° C. for 3 hours. Next, 0.3 ml of 1N-HCl was added to this solution at 0°C, extracted with chloroform, the extract was dried over MgSO4, and the solvent was distilled off. The residue was transferred to a silica gel plate (CHCl3:MeOH=
95:5) and purified. The obtained purified product was crystallized from benzene-n-hexane to obtain 12 mg of the target product [V]. Yield 67%
【００４８】ｍ．ｐ．１６７−１７０℃〔α〕（２４，
Ｄ）＋４０．５°（Ｃ＝０．１０，ＣＨＣｌ３ ）m. p. 167-170℃ [α] (24,
D) +40.5° (C=0.10, CHCl3)
【００４９】ＩＲν（ＣＨＣｌ３ ，ｍａｘ）ｃｍ−１
：１７１０，１６７０，１６３０，１５９０．IRν(CHCl3,max)cm-1
:1710,1670,1630,1590.
【００５
０】 １Ｈ−ＮＭＲ（ＣＤＣｌ３ ）δ：１．３９（ｄ
，３Ｈ，５′Ｍｅ，Ｊ＝７Ｈｚ）２．２１（ｄｄ，１Ｈ
，８ａｘＨ，Ｊ＝３０，８Ｈｚ）２．３９（ｓ，３Ｈ，
１４Ｍｅ）
２．３６−２．４５（ｍ，１Ｈ，８ｅｑＨ）３．０８（
ｄｄ，１Ｈ，１０ａｘＨ，Ｊ＝１７，１Ｈｚ）
３．２８（ｄ，１Ｈ，１０ｅｑＨ，Ｊ＝１７Ｈｚ）３．
６０−３．７３（ｍ，２Ｈ，３′ａｎｄ４′Ｈ）３．９
８（ｓ，１Ｈ，９０Ｈ）
４．２０（ｑ，１Ｈ，５′Ｈ，Ｊ＝６Ｈｚ）４．６３（
ｄ，１Ｈ，２′Ｈ，Ｊ＝４８Ｈｚ）５．３２（ｄ，１Ｈ
，７Ｈ，Ｊ＝２Ｈｚ）５．５８（ｄ，１Ｈ，１′Ｈ，Ｊ
＝９Ｈｚ）７．６３（ｓ，１Ｈ，１１Ｈ）
７．８０−７．８６（ｍ，２Ｈ，２ ａｎｄ ３Ｈ）
８．２８−８．３５（ｍ，２Ｈ，１ ａｎｄ ４Ｈ）
１３．３２（ｓ，１Ｈ，６０Ｈ）005
0] 1H-NMR (CDCl3) δ: 1.39 (d
, 3H, 5′Me, J=7Hz) 2.21(dd, 1H
,8axH,J=30,8Hz)2.39(s,3H,
14Me) 2.36-2.45(m, 1H, 8eqH) 3.08(
dd, 1H, 10axH, J = 17, 1Hz) 3.28 (d, 1H, 10eqH, J = 17Hz) 3.
60-3.73 (m, 2H, 3'and4'H) 3.9
8 (s, 1H, 90H) 4.20 (q, 1H, 5'H, J = 6Hz) 4.63 (
d, 1H, 2'H, J = 48Hz) 5.32 (d, 1H
,7H,J=2Hz)5.58(d,1H,1'H,J
=9Hz) 7.63 (s, 1H, 11H) 7.80-7.86 (m, 2H, 2 and 3H)
8.28-8.35 (m, 2H, 1 and 4H)
13.32 (s, 1H, 60H)
【００５１】ＦＡＢ−ＭＳ（ｎｅｇａｔｉｖｅ）ｍ／ｚ
：５００（Ｍ− ）[0051] FAB-MS (negative) m/z
:500(M-)
【００５２】実施例４ （７Ｓ，９Ｓ）−７−Ｏ−（
２，６−ジデオキシ−２−フルオロ−α−Ｌ−タロピラ
ノシル）−４−デメトキシ−１１−デオキシアドリアマ
イシノンの〔ＶＩ〕の製造Example 4 (7S,9S)-7-O-(
Production of 2,6-dideoxy-2-fluoro-α-L-talopyranosyl)-4-demethoxy-11-deoxyadriamycinone [VI]
【００５３】実施例３で得られた化合物〔Ｖ〕の１０ｍ
ｇ（０．０２ｍ ｍｏｌ）を無水メタノール０．５ｍ
ｌ、無水ジオキサン０．７ｍｌの混液に懸濁させ、オル
トギ酸メチル０．０１７ｍｌを加えて反応させ、１３位
カルボニル基をケタール化により保護した。次いで反応
混合物を０℃に冷却し、これに臭素５ｍｇを無水ジクロ
ロメタン０．０５ｍｌに溶解した溶液を加え、同温度で
１時間攪拌し、続いて室温で１．５時間攪拌した。この
反応により１４位のメチル基を臭素化した。生じた均一
溶液から溶媒を留去し、残渣〔Ｘ〕をアセトン１ｍｌに
懸濁させ、室温で４０分間攪拌した（脱ケタール反応）
。その後溶媒を留去し、残渣をアセトン１ｍｌ、水０．
３ｍｌの混液に溶解させ、ギ酸ナトリウム２０ｍｇを加
え室温で１７時間激しく攪拌した。この反応溶液を少量
にまで濃縮し、クロロホルムにて抽出し、抽出液を乾燥
したのち溶媒を留去して残渣を得た。これをクロロホル
ム−メタノール（１：１）の混液１ｍｌに溶かし、アン
モニア水０．１５ｍｌを加え、０℃にて４０分間攪拌し
た。これによって１４位のブロモメチル基はヒドロキシ
メチル基に変換した。反応混合物から溶媒を留去しプレ
ートにて精製し化合物〔ＶＩ〕５ｍｇを得た。収率４８
％10 m of compound [V] obtained in Example 3
g (0.02 m mol) in anhydrous methanol 0.5 m
The suspension was suspended in a mixed solution of 0.7 ml of anhydrous dioxane, and 0.017 ml of methyl orthoformate was added to react, and the carbonyl group at position 13 was protected by ketalization. The reaction mixture was then cooled to 0° C., and a solution of 5 mg of bromine dissolved in 0.05 ml of anhydrous dichloromethane was added thereto, stirred at the same temperature for 1 hour, and then stirred at room temperature for 1.5 hours. This reaction brominated the methyl group at position 14. The solvent was distilled off from the resulting homogeneous solution, and the residue [X] was suspended in 1 ml of acetone and stirred at room temperature for 40 minutes (deketalization reaction).
. Thereafter, the solvent was distilled off, and the residue was mixed with 1 ml of acetone and 0.0 ml of water.
The mixture was dissolved in 3 ml of the mixed solution, 20 mg of sodium formate was added, and the mixture was vigorously stirred at room temperature for 17 hours. This reaction solution was concentrated to a small amount and extracted with chloroform. After drying the extract, the solvent was distilled off to obtain a residue. This was dissolved in 1 ml of a mixture of chloroform and methanol (1:1), 0.15 ml of aqueous ammonia was added, and the mixture was stirred at 0° C. for 40 minutes. As a result, the bromomethyl group at position 14 was converted to a hydroxymethyl group. The solvent was distilled off from the reaction mixture and purified on a plate to obtain 5 mg of compound [VI]. Yield 48
%
【００５４】ｍ．ｐ．２２０−２２４℃（ベンゼン−ｎ
−ヘキサン）
〔α〕（２４，Ｄ）＋７５．５°（Ｃ＝０．１０５，Ｃ
ＨＣｌ３ −ＭｅＯＨ１：１）m. p. 220-224℃ (benzene-n
-hexane) [α] (24, D) + 75.5° (C = 0.105, C
HCl3-MeOH1:1)
【００５５】ＩＲν（ＫＢｒ，ｍａｘ）ｃｍ−１：１７
２０，１６２５IRν(KBr,max)cm-1:17
20,1625
【００５６】 １Ｈ−ＮＭＲ（Ｃ５ Ｄ５ Ｎ）δ：１
．５５（ｄ，３Ｈ，５′Ｍｅ，Ｊ＝７Ｈｚ）２．６６（
ｄｄ，１Ｈ，８ａｘＨ，Ｊ＝１５，６Ｈｚ）２．８５（
ｄｔ，１Ｈ，８ｅｑＨ，Ｊ＝１５，１Ｈｚ）３．３８（
ｄ，１Ｈ，１０ａｘＨ，Ｊ＝１７Ｈｚ）３．５８（ｄ，
１Ｈ，１０ｅｑＨ，Ｊ＝１７Ｈｚ）３．９８（ｍ，１Ｈ
，４′Ｈ）
４．２２（ｄｔ，１Ｈ，３′Ｈ，Ｊ＝３２，３Ｈｚ）４
．６８（ｑ，１Ｈ，５′Ｈ，Ｊ＝６Ｈｚ）５．１３（ｄ
，１Ｈ，２′Ｈ，Ｊ＝４９Ｈｚ）５．３５，５．３８（
２ｄ，２Ｈ，１４Ｈｚ，Ｊ＝１９Ｈｚ）
５．５２（ｍ，１Ｈ，７Ｈ）
５．９９（ｄ，１Ｈ，１′Ｈ，Ｊ＝１０Ｈｚ）７．７１
（ｓ，１Ｈ，１１Ｈ）
７．６８５，７．７８（ｍ，２Ｈ，２ ａｎｄ ３Ｈ
）８．３０−８．３８（ｍ，２Ｈ，１ ａｎｄ ４Ｈ
）1H-NMR (C5D5N) δ:1
．． 55(d,3H,5′Me,J=7Hz)2.66(
dd, 1H, 8axH, J=15,6Hz) 2.85(
dt, 1H, 8eqH, J = 15, 1Hz) 3.38 (
d, 1H, 10axH, J=17Hz) 3.58(d,
1H, 10eqH, J=17Hz) 3.98(m, 1H
, 4'H) 4.22 (dt, 1H, 3'H, J=32,3Hz) 4
．． 68 (q, 1H, 5'H, J = 6Hz) 5.13 (d
, 1H, 2'H, J=49Hz) 5.35, 5.38 (
2d, 2H, 14Hz, J = 19Hz) 5.52 (m, 1H, 7H) 5.99 (d, 1H, 1'H, J = 10Hz) 7.71
(s, 1H, 11H) 7.685, 7.78 (m, 2H, 2 and 3H
) 8.30-8.38 (m, 2H, 1 and 4H
)
【００５７】ＣＤ（Ｃ＝１．０×１０−４，ＭｅＯＨ
）〔θ〕（２４，ｍａｘ）（ｎｍ）：−１．２６×１０
４ （２８３），＋１．４４×１０４ （３１３）CD (C=1.0×10-4, MeOH
) [θ] (24, max) (nm): -1.26×10
4 (283), +1.44×104 (313)
【０
０５８】ＦＡＢ−ＭＳ（ｎｅｇａｔｉｖｅ）：５１６（
Ｍ− ）0
058] FAB-MS (negative): 516 (
M-)
【００５９】[0059]
【発明の効果】本発明によれば、新規なアンスラサイク
リン系抗生物質が提供され、同物質は強い抗癌活性を示
す。[Effects of the Invention] According to the present invention, a novel anthracycline antibiotic is provided, and the same substance exhibits strong anticancer activity.
【化１８】[Chemical formula 18]
Claims (8)
れない水酸基、ＯＲ２ は保護されまたはされない水酸
基を表す〕で表わされる新規なアンスラサイクリン系化
合物。1. A novel anthracycline compound represented by the following formula [I] [wherein R1 represents hydrogen or an esterified or unesterified hydroxyl group, and OR2 represents a protected or unprotected hydroxyl group].
される請求項１記載の化合物。2. The compound according to claim 1, represented by the following formula [II]: [In the formula, OR2 is protected or represents a hydrogen group].
す〕で表される請求項１記載の化合物。3. The compound according to claim 1, which is represented by the formula [III]: [In the formula, OR2 represents a protected or unprotected hydroxyl group].
れない水酸基、ＯＲ２ は保護されまたはされない水酸
基を表す〕で表される化合物をが含有する抗腫瘍剤。7. An antiseptic compound containing a compound represented by the following formula [I] [wherein R1 represents hydrogen or an esterified or unesterified hydroxyl group, and OR2 represents a protected or unprotected hydroxyl group] Tumor agents.
式〔ＶＩＩＩ〕 【化９】 〔式中、ＯＲ３ は保護された水酸基、Ｘは臭素、沃素
または塩素を表す〕で表わされる３，４位の水酸基の保
護された２，−６−ジデオキシ−２−フルオロ−ａ−Ｌ
−タロピラノシル・ハライドと反応させて式〔ＩＸ〕【
化１０】 〔式中、ＯＲ３ は前記と同義〕で表されるアンスラサ
イクリン系化合物を生成させるか、続いて１４位のメチ
ル基をヒドロキシメチル基に変換させるかし、またはさ
らにそのヒドロキシメチル基の水酸基をエステル化し、
残存する保護基があれば必要に応じて離脱させることを
特徴とする式〔Ｉ〕 【化１１】 〔式中、Ｒ１ は水素または水酸基、ＯＲ２ は保護さ
れまたはされない水酸基を表す〕で表わされるアンスラ
サイクリン系化合物の製造法。[Claim 8] 4-demethoxy-11-deoxydaunomycinone of the following formula [VII] [Chemical formula 8] is converted to 4-demethoxy-11-deoxydaunomycinone of the formula [VIII] [Chemical formula 9] [wherein, OR3 is a protected hydroxyl group, and X is a bromine , iodine or chlorine] 2,-6-dideoxy-2-fluoro-a-L with protected hydroxyl groups at the 3 and 4 positions
-By reacting with talopyranosyl halide, the formula [IX] [
Either an anthracycline compound represented by the formula [wherein OR3 has the same meaning as above] is produced, or the methyl group at position 14 is subsequently converted to a hydroxymethyl group, or the hydroxymethyl group is further converted to a hydroxymethyl group. Esterifies the hydroxyl group,
The anthrax compound represented by the formula [I] [Chemical formula 11] [wherein R1 represents hydrogen or a hydroxyl group, and OR2 represents a protected or unprotected hydroxyl group] is characterized in that any remaining protective groups are removed as necessary. Method for producing cycline compounds.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8149491A JPH04290891A (en) | 1991-03-19 | 1991-03-19 | New anthracycline-based compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8149491A JPH04290891A (en) | 1991-03-19 | 1991-03-19 | New anthracycline-based compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04290891A true JPH04290891A (en) | 1992-10-15 |
Family
ID=13747945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8149491A Pending JPH04290891A (en) | 1991-03-19 | 1991-03-19 | New anthracycline-based compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04290891A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11401339B2 (en) | 2018-08-23 | 2022-08-02 | Seagen Inc. | Anti-TIGIT antibodies |
-
1991
- 1991-03-19 JP JP8149491A patent/JPH04290891A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11401339B2 (en) | 2018-08-23 | 2022-08-02 | Seagen Inc. | Anti-TIGIT antibodies |
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