CN1042032C - 蒽环二糖类、其制备方法和含有它们的药物组合物 - Google Patents
蒽环二糖类、其制备方法和含有它们的药物组合物 Download PDFInfo
- Publication number
- CN1042032C CN1042032C CN94194276A CN94194276A CN1042032C CN 1042032 C CN1042032 C CN 1042032C CN 94194276 A CN94194276 A CN 94194276A CN 94194276 A CN94194276 A CN 94194276A CN 1042032 C CN1042032 C CN 1042032C
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- China
- Prior art keywords
- formula
- compound
- extension
- amino
- lysol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 5
- 229940045799 anthracyclines and related substance Drugs 0.000 title description 4
- 150000002016 disaccharides Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- -1 dimethyl tertiary butyl Chemical group 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- ZLWULWWXACZTPR-UHFFFAOYSA-N [ClH]=O Chemical compound [ClH]=O ZLWULWWXACZTPR-UHFFFAOYSA-N 0.000 claims description 15
- 229960000975 daunorubicin Drugs 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 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 claims description 8
- 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 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical group [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 239000002808 molecular sieve Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229920001429 chelating resin Polymers 0.000 claims description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000003456 ion exchange resin Substances 0.000 claims description 2
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- NGYIMTKLQULBOO-UHFFFAOYSA-L mercury dibromide Chemical compound Br[Hg]Br NGYIMTKLQULBOO-UHFFFAOYSA-L 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 238000011275 oncology therapy Methods 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- SDLBJIZEEMKQKY-UHFFFAOYSA-M silver chlorate Chemical compound [Ag+].[O-]Cl(=O)=O SDLBJIZEEMKQKY-UHFFFAOYSA-M 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims 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 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 4
- 238000006482 condensation reaction Methods 0.000 claims 2
- 150000007524 organic acids Chemical class 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims 1
- 239000003005 anticarcinogenic agent Substances 0.000 claims 1
- 230000002508 compound effect Effects 0.000 claims 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims 1
- 150000002338 glycosides Chemical class 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 4
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 229940029575 guanosine Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 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 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 150000008131 glucosides Chemical class 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000004880 oxines Chemical class 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- DORPKYRPJIIARM-UHFFFAOYSA-N Decaffeoylacteoside Natural products OC1C(O)C(O)C(C)OC1OC1C(O)C(OCCC=2C=C(O)C(O)=CC=2)OC(CO)C1O DORPKYRPJIIARM-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- DORPKYRPJIIARM-GYAWPQPFSA-N Verbasoside Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](O)[C@H](OCCC=2C=C(O)C(O)=CC=2)O[C@H](CO)[C@H]1O DORPKYRPJIIARM-GYAWPQPFSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001454 anthracenes Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002905 metal composite material Substances 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin 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)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
Abstract
本发明涉及通式(I)和(II)的化合物及其药用的盐类,以及它们的制备方法和含有它们的药物组合物。
Description
其中:
R是H、OH或OR7基,其中R7=CHO或COCH3或者是含有至多个6个碳原子的羧酸的酰基;
R1是H、OH或OCH3;
R2是H或F;
R3是H或OH;
R4和R5,相同或不同,分别是H、OH或NH2;
本发明还涉及所述化合物的制备方法,其药用的盐类和含有它们的药物组合物。
柔红霉素和阿霉素是已知的抗生素,目前已被用于临床治疗各种固性肿瘤和白血病(F.Arcamone in“Doxombicin:Anticancer Antibiotics”,A.C.Sartorelli,Ed.,Academic Press,N.Y.,1981)。
具有类似于本申请但只有一个糖苷的化合物描述于EP-457215、WO80/00305和WO90/07519。具有两个或多个糖部分的化合物,其中直接连结到糖苷配基部分的糖是氨基取代的,这类化合物描述于,例如Journal ofAntibiotics P.1720-1730 Nov 93;Tetrahedron vol.37,No.24,4219-4228(1981);DE 2751395;Carbohydrate Research,228,171-90(1992)和ED-3641833。
具有3个苷部分的化合物描述于WO92/07862,但未报导活性数据。
但是,众所周知,目前使用的抗癌药物因其严重的副作用而限制了许多患者的使用,其中包括某些可能会从中获益的患者。在治疗某些重要固性肿瘤,如肺癌和卵巢癌方面需要显著的进展,这些疾病对现有的治疗方案均不理想。
因此,急需一些药物面市,这些药物对肿瘤细胞增殖的抑制作用比正常细胞增殖的抑制具有高的选择性。
本发明的目的之一是提供新的抗癌化合物,特别是蒽环类似物,其中的烃部分含有一个二糖基。
令人惊异的是,本发明申请的蒽环二糖,其中与直接连结到糖苷配基的糖不含有氨基,该蒽环化合物具有更高的抗癌活性和选择性。值得注意的是,在已知的蒽环化合物中,它含有两个烃基,连结到糖苷配基上的糖总是含有自由的或取代的氨基。
根据本发明的化合物是如上所述的式(I)和(II)的化合物及其药用的盐类,其中R、R1、R2、R3、R4和R5如上所定义。
本发明还涉及药物组合物,该组合物含有所述的化合物及其与药用的酸优选是盐酸,所形成的盐。
特别优选的化合物包括:
a)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-来苏-挂-吡喃糖基]柔红霉素酮盐酸盐;
b)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-阿拉伯-挂-吡喃糖基]柔红霉素酮盐酸盐;
c)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-来苏-挂-吡喃糖基]阿霉素酮盐酸盐;
d)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-阿拉伯-挂-吡喃糖基]阿霉素酮盐酸盐;
e)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-阿拉伯-挂-吡喃糖基]-4-脱甲氧基-柔红霉素酮盐酸盐;
f)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-来苏-挂吡喃糖基]-4-脱甲氧基-柔红霉素酮盐酸盐;
g)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-来苏-挂-吡喃糖基]-4-脱甲氧基-阿霉素酮盐酸盐;
h)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-阿拉伯-挂-吡喃糖基]-4-脱甲氧基-阿霉素酮盐酸盐;
i)7-O-[2,6-二脱氧-4-O-(2,3,4,6-四脱氧-4-氨基-α-L-赤藓-挂-吡喃糖基(erythroexopyransyl))-α-L-来苏-挂-吡喃糖基]柔红霉素酮盐酸盐;
j)7-O-[2,6-二脱氧-4-O-(2,3,4,6-四脱氧-4-氨基-α-L-赤藓-挂-吡喃糖基)-α-L-来苏-挂-吡喃糖基]-4-脱甲氧基-柔红霉素酮盐酸盐;
k)7-O-[2,6-二脱氧-4-O-(2,3,4,6-四脱氧-4-氨基-α-L-赤藓-挂-吡喃糖基)-α-L-来苏-挂-吡喃糖基]阿霉素酮盐酸盐;
l)7-O-[2,6-二脱氧-4-O-(2,3,4,6-四脱氧-4-氨基-α-L-赤藓-挂-吡喃糖基)-α-L-来苏-挂-吡喃糖基]-4-脱甲氧基-阿霉素酮盐酸盐;
m)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-来苏-挂-吡喃糖基]-4-脱甲氧基-8-氟-柔红霉素酮盐酸盐;
n)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-来苏-挂-吡喃糖基]-4-脱甲氧基-8-氟-阿霉素酮盐酸盐;
通式(I)和(II)的化合物可以通过下述方法制备:
a)使式(III)的化合物与式(IV)或(V)的化合物缩合,得到式(VI)或(VII)的化合物:
式(IV)(V)中,R8是H或被保护的羟基,优选是对硝基苯甲酸酯;R9和R10可以相同或不同,各自是H或被保护的羟基,优选是对硝基苯甲酸酯或被保护的氨基,优选三氟乙酰胺或烯丙基羧基酰胺,X是在缩合条件下可以产生的一个稳定的碳-阳离子的基,它本身可以与式(III)化合物C-7位的羟基结合,所述的基团X易于选自苷化反应中常见的基团,例如卤素诸如氯或溴,优选氯,或者是对硝基苯甲酰氧基。 式(VI)或式(VII)中,R1、R2、R6、R8、R9、R10和符号(
)都如上所定义;
c)转化反应,如果必要,将前述的式(I)和(II)糖苷转化成药用的盐,优选的是盐酸盐。
使式(III)的化合物与式(IV)或(V)的化合物进行苷化反应而得到式(VI)或(VII)的化合物,其反应条件取决于式(IV)和(V)化合物中存在的取代基类型。
苷化反应是在缩合剂存在下于惰性有机溶剂中进行。
所用的缩合剂包括,例如三氟甲基磺酸银、过氯酸银、氧化汞和溴化汞的混合物、卤化硼、四氯化钛或锡、或离子交换树脂,如Amberlite、三氟甲基磺酸银、三甲基硅基三氟甲基磺酸银、对甲苯磺酸、三氟乙酸。
苷化反应优选的是以1∶1至1∶3的摩尔比,在下述惰性有机溶剂中进行,如苯、甲苯、乙醚、四氢呋喃、二噁烷、氯仿、二氯甲烷或二氯乙烷和其混合物。
反应温度可从-40℃至40℃,优选的是-20℃至20℃,反应时间从15分钟至3小时。
所述反应混合物中可以包括脱水物质,如活化的分子筛。
在反应过程中或在反应结束时,可以向反应混合物中加入有机碱,如,吡啶、可力丁、N,N-二甲氨基吡啶、三乙胺或1,8-双-(二甲氨基)萘。
根据本发明,从式(VI)和(VII)的化合物中除去羟基和/或胺基的保护基而得到式(I)的化合物,该反应是在依赖所使用的保护基类型的不同条件下而进行的。
当R9和/或R10相同或不同,各自是被保护的胺基如三氰乙酰胺或被保护的羟基如对硝基苯甲酸酯,和/或R8是被保护的羟基如对硝基苯甲酸酯;和/或R6是被保护的羟基如乙酸酯时,脱保护反应是在极性溶剂如水、甲醇、乙醇、吡啶、二甲基甲酰胺或其混合物中且在化学计算量的或过量的无机碱如钠、钾、锂或钡的氢氧化物或碳酸盐的存在下而进行。
反应温度从0℃至50℃,反应时间从3小时至48小时。
当R9和/或R10各自是被保护的胺基如烯丙基羧基酰胺时,则脱保护反应是在惰性溶剂中且在有金属复合物存在下进行,如在Tetrahedron Letters,30,3773(1989)中所公开的四(三苯基膦)钯或J.Org.,Chem.,38,3233(1973)中所公开的四羰基镍存在下进行。
当R6是被保护羟基如二甲基叔丁基甲硅烷基醚时,脱保护反应是在惰性溶剂中且在有四丁基铵氟化物存在下进行,如在J of Antibiot.,37,853(1984)中公开的。
当R6是被保护的羟基如对甲氧基苯基二苯基甲基醚时,脱保护反应,按在J.Org.,Chem.,42,3653(1977)中所公开的,在酸性介质例如在醋酸水溶液中进行。
式(III)的化合物是已知的或可以通过有机化学中已知工艺和方法进行制备,例如Gazz.Chim.Ital.,114,517(1984),Bull.Chem.Soc.Jpn.,59,423(1986)以及前面提及的意大利专利申请,其中所公开的内容一并作为参考。
式(IV)或(V)的化合物是已知的,也可以是根据有机化学中已知的二糖合成方法制备(J.Carbohydr.Chem.,10,833(1991);Carbohydr.Res.,74,199(1979);Carbohydr.Res.,208,111(1980);Tetrahedron,46,103(1990)。
任选地,如果需要,式(I)和(II)的蒽环苷,其中R1、R2、R3、R4、R5如上所定义且R是羟基,可以由式(I)和(II)的苷或其药用的盐类(其中R1、R2、R3、R4、R5和符号( )如上所定义的且R是H),通过在氯仿用溴将14位的碳溴化接着将所得到的14-溴代衍生物用甲酸钠在室温下水解48小时。
如果需要,式(I)和(II)的苷可以转化其药用的盐类,例如在甲醇中用盐酸处理生成盐酸盐。
本发明还涉及一些药用组合物,该组合物包括式(I)或(II)的化合物或其药用的盐作为活性成分并与药用的载体或稀释剂组合。
根据本发明,治疗有效剂量的式(I)或(II)的化合物与惰性载体组合。
该组合物可以使用常用载体按常规方法配制。
所申请的化合物可用于治疗人及其它哺乳动物。特别是,所述的化合物以治疗有效剂量施用时是较好的抗癌药物。
下述实施例将详细描述本发明。实施例1
7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂-吡喃糖基)-α-L-来苏-挂-吡喃糖基]-4-脱甲氧基柔红霉素酮盐酸盐(式II的化合物;R=R1=R2=H,R3=R5=OH,R4=NH2)
将4-脱甲氧柔红霉素酮(式III的化合物,R1=R2=R6=H)(300mg,0.81mmol)和2,6-二脱氧-4-O-(2,3,6-三脱氧-4-O-对硝基苯甲酰基-3-三氟乙酰氨基-α-L-来苏-挂吡喃糖基-3-O-对硝基苯甲酰基-α-L-来苏-挂吡喃糖基-对硝基甲酸酯(式IV的化合物,R3=R5=对硝基苯甲酰氧基、R4=三氟乙酰氨基、X=对硝基苯甲酰氧基)(600mg,0.72mmol)于氯代甲烷(72ml)和乙醚(24ml)中的混合物,在分子筛(A4)存在下于-20℃用三甲基硅基甲基三氟甲基磺酸盐(trimethyl silylflate)(266mg,1.44mmol)处理。将该反应混合物搅拌1小时,然后用二氯甲烷稀释,饱和碳酸氢钠溶液洗涤,并蒸发至干。所得残留物用硅胶柱层析纯化(洗脱剂CH2Cl2-EtOH,99/1)得到360mg的7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-4-O-对硝基苯甲酰基-3-氟乙酰氨基-α-L-来苏-挂吡喃糖基)-3-O-对硝基苯甲酰基-α-L-来苏-挂吡喃糖基]-4-脱甲氧基柔红霉素酮(式VII的化合物,R1=R2=R6=H,R8=R10=对硝基苯甲酰氧基,R9=三氟乙酰氨基)。
将式(VII)化合物(R1=R2=R6=H,R8=R10=对硝基苯甲酰氧基,R9=三氟乙酰氧基)的被保护的二糖苷(120mg;0.117mmol)于17.6ml的0.1MBa(OH)2于H2O/MeOH 1∶1中的悬浮液,在室温下搅拌3小时,将该反应混合物用0.2M的硫酸氢钾溶液进行中和,并用氯仿抽提,合并有机提取液并用无水硫酸钠干燥,蒸发至干,再溶解于0.002M HCl溶液中,用氯仿洗涤该酸性水溶液,冷冻干燥,得到62mg的所需产物(式II的化合物,R=R1=R2=H,R3=R5=OH,R4=NH2),产率39%。
所得物的NMR数据如下:1H-NMR(DMSO-d6),δ1.05(d,3H),1.15(d,3H),1.5-1.95(m,4H),2.1(m,2H),2.25(s,3H),2.95(dd,2H),3.55(s,2H),3.8(m,1H),3.95(m,1H),4.15(q,1H),4.35(q,1H),4.6(d,1H),4.9(bs,2H),5.25(bs,1H),5.35(d,1H),5.55(s,1H),7.95(bs,2H),8.25(bs,2H).
按照类似的方法,可以制得下述的式(I)和(II)的化合物:
7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-来苏-挂吡喃糖基]柔红霉素酮盐酸盐(式II的化合物,R=R2=H,R1=OCH3,R3=R5=OH,R4=NH2)1H-NMR (DMSO-d6),δ1.05(d,3H),1.15(d,3H),1.35-2.15(m,6H),2.25(s,3H),2.95(dd,2H),3.55(bs,2H),3.8(m,1H),3.95(s,3H),4.05-4.2(m+q,2H),4.35(q,1H),4.9(bs,2H),5.25(bs,1H),7.65(m,1H),7.9(b,2H).
7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-阿拉伯-挂吡喃糖基]柔红霉素酮盐酸盐(式I的化合物,R=R2=H,R1=OCH3,R3=R5=OH,R4=NH2)1H-NMR(DMSO-d6),δ1.13(d,3H),1.15(d,3H),1.45-1.85(m,4H),2.05(m,2H),2.15(s,3H),2.87(dd,2H),2.98(m,1H),3.5(m,1H),3.6(m,1H),3.85(q,1H),3.9(q,1H),3.9(s,3H),4.84(m,2H),5.13(bs,1H),5.28(s,1H),5.32(d,1H),5.55(s,1H),7.55(m,1H),7.8(m,2H).
7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-阿拉伯-挂吡喃糖基]-4-脱甲氧基柔红霉素酮盐酸盐(式I的化合物,R=R1=R2=H,R3=R5=OH,R4=NH2)1H-NMR(DMSO-d6),δ1.1(d,3H),1.2(d,3H),1.5-1.95(m,4H),2.05-2.2(m,2H),2.25(s,3H),2.95(dd,2H),3.1(t,1H),3.4(m,1H),3.6(bs,1H),3.65(m,1H),3.85-4.00(q+q,2H),3.9(m,1H),4.95(d,1H),5.25(d,1H),5.4(bs,2H),5.7(s,1H),7.95(m,2H),8.25(m,2H)。
Claims (15)
2、根据权利要求1的式(I)或(II)的化合物有:
a)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-来苏-挂吡喃糖基]柔红霉素酮盐酸盐;
b)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-阿拉伯-挂吡喃糖基]柔红霉素酮盐酸盐;
e)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-阿拉伯-挂吡喃糖基]-4-脱甲氧基-柔红霉素酮盐酸盐;
f)7-O-[2,6-二脱氧-4-O-(2,3,6-三脱氧-3-氨基-α-L-来苏-挂吡喃糖基)-α-L-来苏-挂吡喃糖基]-4-脱甲氧基-柔红霉素酮盐酸盐。
R1是H或OH或OCH3;
R2是H;
R3是H或OH;
该方法包括:
i)在缩合剂存在的条件下,该缩合剂选自三氟甲基磺酸银(silvertriflate)、过氯酸银、氧化汞和溴化汞的混合物、三甲基硅基三氟甲基磺酸银、对甲苯磺酸、三氟乙酸、卤化硼、四氯化锡、四氯化钛或离子交换树脂Amberlite,使式(III)化合物与式(IV)或式(V)的化合物进行缩合,得到式(VI)或式(VII)的化合物,在缩合反应过程中,向反应混合物中加入选自吡啶、可力丁、N,N-二甲基氨基吡啶、三乙胺或1,8-双-(二甲氨基)萘的有机碱:
式(IV)和式(V)中,R8是H或被保护的羟基;R9和R10,相同或不同,各自是H或被保护的羟基或被保护的氨基,X是选自卤素或对硝基苯甲酰氧基的基团,式(VI)或式(VII)中,R1、R2、R6、R8、R9、R10和符号(
)如上所定义;
(ii)由式(VI)和(VII)的化合物除去羟基和/或氨基保护基的一个或多个反应,而得到式(I)和(II)的化合物,其中R、R1、R2、R3、R4、R5和符号(
)如上所定义;其中,R为羟基的式(I)和(II)的化合物如下制备:ii-a)将其中R1、R2、R3、R4、R5和符号(
)如上所定义,R是H的式(I)和(II)的化合物的14位上的碳进行溴化,溴化反应是在氯仿中用溴进行的;ii-b)将所得的14-溴代衍生物进行水解,水解反应是用甲酸钠进行的,得到式(I)和(II)的化合物,其中R1、R2、R3、R4、R5定义如上,R是羟基;
III)采用转化反应可将式(I)和式(II)的化合物转化成药用的盐。
4.根据权利要求3的方法,其中步骤i中的式(IV)或(V)化合物中,R8是H或被保护羟基,R9和R10,相同或不同,各自是H或被保护羟基或被三氧乙酰基或烯丙氧羰基保护的氨基。
5.根据权利要求4的方法,其中步骤i中的式(IV)或(V)化合物中,R8是对硝基苯甲酸酯,或者,R9和R10独立为对硝基苯甲酰基。
6.根据权利要求3的方法,其中式(III)的化合物溶于惰性有机溶剂中,而缩合反应是在分子筛作为脱水剂存在的情况下进行的。
7.根据权利要求3的方法,其中步骤i中所述的卤素是氯或溴。
8.根据权利要求3的方法,其中,步骤ii中保护氨基的三氟乙酰基和/或保护羟基的对硝基苯甲酰基和/或乙酰基,是通过选自钠、钾、锂或钯的氢氧化物或碳酸盐的无机碱的作用而除去的。
9.根据权利要求3的方法,其中,步骤ii中保护氨基的烯丙氧羰基是通过与镍或钯的有机配合物作用而除去。
10.根据权利要求3的方法,其中,步骤ii中保护羟基的甲氧基苯基二苯基甲基是通过与有机酸进行反应而除去。
11、根据权利要求10的方法,其中所述的有机酸是乙酸。
12、根据权利要求3的方法,其中步骤ii中保护羟基的二甲基叔丁基硅基是在氟化四丁基铵存在下而被脱去的。
13、根据权利要求3的方法,步骤iii中式(I)和(II)的化合物被转化成可药用的盐酸盐。
14、根据权利要求1或2的化合物或其可药用的盐类在制备抗癌药中的应用。
15、一种作为抗癌药物的药用组合物,该组合物包括至少一种根据权利要求1或2的化合物或其可药用的盐类作为活性成分,以及可药用的载体或稀释剂。
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ITFI930187A IT1262565B (it) | 1993-09-30 | 1993-09-30 | Disaccaridi di antracicline, loro processi di preparazione e composizioni farmaceutiche che li contengono. |
ITFI93A000187 | 1993-09-30 |
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EP (1) | EP0721456B1 (zh) |
JP (1) | JP3836503B2 (zh) |
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CN (1) | CN1042032C (zh) |
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RO (1) | RO115525B1 (zh) |
RU (1) | RU2144540C1 (zh) |
SK (1) | SK281797B6 (zh) |
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IT1271689B (it) * | 1994-08-04 | 1997-06-04 | Menarini Farma Ind | 8-fluoro-antracicline, loro processi di preparazione e composizioni farmaceutiche che le contengono |
IT1307846B1 (it) * | 1999-03-09 | 2001-11-19 | Menarini Ricerche Spa | L-arabino disaccaridi di antracicline, loro processi di preparazione ecomposizioni farmaceutiche che li contengono. |
CN112010913B (zh) * | 2019-05-31 | 2022-06-21 | 南京正大天晴制药有限公司 | 4-脱氧柔红霉素的制备方法 |
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EP0457215A1 (en) * | 1990-05-14 | 1991-11-21 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | 3'-deamino-4'-deoxy-4'-amino-8-fluoroanthracyclines and processes for their preparation |
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US4918172A (en) * | 1987-10-06 | 1990-04-17 | Sanraku Incorporated | Anthracycline antibiotics |
WO1990007519A1 (en) * | 1988-12-28 | 1990-07-12 | Board Of Regents, The University Of Texas System | 3'-deamino analogs of esorubicin and methods for their use |
WO1992007862A1 (en) * | 1990-10-30 | 1992-05-14 | Yale University | Antibiotics improved by conjugation with stereospecific carbohydrtes and methods for carbohydrate stereoselectivity |
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