CN1073105C - 具有抗肿瘤活性的半合成紫杉烷 - Google Patents
具有抗肿瘤活性的半合成紫杉烷 Download PDFInfo
- Publication number
- CN1073105C CN1073105C CN95194333A CN95194333A CN1073105C CN 1073105 C CN1073105 C CN 1073105C CN 95194333 A CN95194333 A CN 95194333A CN 95194333 A CN95194333 A CN 95194333A CN 1073105 C CN1073105 C CN 1073105C
- Authority
- CN
- China
- Prior art keywords
- hydroxyl
- phenyl
- acyloxy
- general formula
- 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.)
- Expired - Fee Related
Links
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 9
- 229940123237 Taxane Drugs 0.000 title description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical group NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000032050 esterification Effects 0.000 claims abstract description 4
- 238000005886 esterification reaction Methods 0.000 claims abstract description 4
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 17
- 229930014667 baccatin III Natural products 0.000 claims description 14
- 238000003381 deacetylation reaction Methods 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- -1 4Be hydrogen Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- GBEVOZLAFNMTKL-UHFFFAOYSA-N [O]C(=O)OCC(Cl)(Cl)Cl Chemical compound [O]C(=O)OCC(Cl)(Cl)Cl GBEVOZLAFNMTKL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 230000000747 cardiac effect Effects 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical class O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 abstract description 15
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 231100000433 cytotoxic Toxicity 0.000 abstract description 2
- 230000001472 cytotoxic effect Effects 0.000 abstract description 2
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 abstract 1
- 238000002347 injection Methods 0.000 abstract 1
- 239000007924 injection Substances 0.000 abstract 1
- 230000000707 stereoselective effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 19
- 229930012538 Paclitaxel Natural products 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 229960001592 paclitaxel Drugs 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 10
- 238000003810 ethyl acetate extraction Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 125000004423 acyloxy group Chemical group 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- XQCKXOKBWVXUJH-UHFFFAOYSA-N CCOC([O])=O Chemical compound CCOC([O])=O XQCKXOKBWVXUJH-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- XQTIWNLDFPPCIU-UHFFFAOYSA-N cerium(3+) Chemical class [Ce+3] XQTIWNLDFPPCIU-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AQOXAQNPPJHPAD-JKSUJKDBSA-N (4s,5r)-3-benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-5-carboxylic acid Chemical compound N1([C@H]([C@@H](OC1(C)C)C(O)=O)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 AQOXAQNPPJHPAD-JKSUJKDBSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YMHOBZXQZVXHBM-UHFFFAOYSA-N 2,5-dimethoxy-4-bromophenethylamine Chemical compound COC1=CC(CCN)=C(OC)C=C1Br YMHOBZXQZVXHBM-UHFFFAOYSA-N 0.000 description 1
- QZFUOWJOSKVGAZ-UHFFFAOYSA-N 4-(2-methylpropyl)-1,3-oxazolidine-5-carboxylic acid Chemical compound CC(C)CC1NCOC1C(O)=O QZFUOWJOSKVGAZ-UHFFFAOYSA-N 0.000 description 1
- OJHMZGCNWLTEMV-UHFFFAOYSA-N 4-phenyl-1,3-oxazolidine-5-carboxylic acid Chemical compound OC(=O)C1OCNC1C1=CC=CC=C1 OJHMZGCNWLTEMV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 229930190007 Baccatin Natural products 0.000 description 1
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 1
- IUZZBBDOBLXCAB-UHFFFAOYSA-N CCOC(Cl(Cl)(Cl)Cl)=O Chemical compound CCOC(Cl(Cl)(Cl)Cl)=O IUZZBBDOBLXCAB-UHFFFAOYSA-N 0.000 description 1
- 241001092054 Cercocarpus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241000545067 Venus Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000002622 anti-tumorigenesis Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 208000012549 congenital acardia Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 229940063179 platinol Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000004819 silanols Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
本发明涉及新的衍生物，它通过氧化和立体选择性还原10-脱乙酰基浆果赤霉素Ⅲ，然后用不同取代的异丝氨酸链酯化制备紫杉醇类似物而得到。本发明的产物具有细胞毒性和抗肿瘤活性，且在适当配制时可通过注射和/或口服给药。
Description
具有紫杉烷(taxane)骨架的双萜，特别是紫杉醇，已知对人类许多肿瘤有抗肿瘤活性。但是，在使用这些药物时，特别是紫杉醇，由于产生不希望的副作用而导致使用上的缺点，而且由于这些抗肿瘤疗法很快引起耐受性，因此，开发新的能减少这类临床问题的分子是人们研究的热点。WO93/02067(Nippon Steel,1993年2月4日)公开了例如10-α-乙酰基紫杉醇，它从紫杉属的白蛋白组织培养物中提取出来，具有显著的细胞毒性。
本发明涉及半合成得到的新的紫杉烷骨架的衍生物，它们具有很强的抗肿瘤活性。本发明的衍生物具有通式(1)：
它们可分成两个系列：a)在11,12位之间含有烯属双键和在10α-位为羟基或酰氧基的紫杉烷衍生物(式1a的紫杉烷)。(1a)(R3=H；R4=OH或酰氧基)b)在11和12位的碳原子之间含有单键，在12位的甲基为α-取向的，且在10β位为羟基或酰氧基的紫杉烷衍生物(式1b的紫杉烷)。
(1b)(R3=OH或酰氧基；R4=H)
在通式(1)的紫杉烷中，R1和R2可相同或不同，可以是C1-C8基，C2-C8链烯基，芳基(优选苯基)或杂芳基。R2也可以是叔丁氧基。
在通式(1a)化合物中，R3是氢，R4是羟基或C2-C8酰氧基。
在通式(1b)化合物中，R3是羟基或C2-C8酰氧基，且R4是氢。
通式(1)的紫杉烷可通过使用适当活化的异丝氨酸链作为酰化试剂在通式(2)的新合成子(syntones)的13-位酯化而制备，制备可按照半合成紫杉醇及其类似物的文献中描述的方法进行(参见，例如，EP-A-400971,1992,Fr.Dem.86,10400；E.Didier等，TetrahedronLetters 35,2349,1994；E.Didier等，ibid.35,3063,1994)。
在通式(2)中其中：
当11,12位之间存在烯属双键时，R3是氢原子，R4和R5是羟基，C2-C8酰氧基，烷基甲硅烷氧基或2,2,2-三氯乙氧羰氧基；
当11,12位之间不存在烯属双键时，12-位的甲基是α-取向的，R4是氢原子，R3和R5是羟基，C2-C8酰氧基，烷基甲硅烷氧基或2,2,2-三氯乙氧羰氧基。
具体地讲，通式(2a)的合成子用于合成通式(1a)的新的紫杉烷。另一方面，通式(2b)的合成子用于合成通式(1b)的新的紫杉烷。
在合成子(2a)中，在11和12位之间有烯属双键，在10α-位有C2-C8酰氧基或任意被保护的羟基。因此，在合成子(2a)中，R3是氢，R4和R5是羟基，酰氧基，烷基甲硅烷氧基(如三乙基甲硅烷氧基，O-TES)或2,2,2-三氯乙氧羰基氧基(O-CO-O-CH2CCl3,O-TROC)。
在合成子(2b)中，11-位和12-位的碳原子以单键相连，12-位的甲基是α-取向的，且在10α位有酰氧基或任意保护的羟基。因此，在合成子(2b)中，R4是氢，R3和R5是羟基，酰氧基，烷基甲硅烷氧基(如三乙基甲硅烷氧基，O-TES)或2,2,2-三氯乙氧羰基氧基(O-CO-O-CH2CCl3,O-TROC)。
在合成子(2)的13-位用异丝氨酸链酯化后，使用本领域的常规方法除去保护基，从而得到式(1)的新的紫杉烷。
10-脱乙酰基浆果赤霉素Ⅲ(3)，可从浆果紫杉的叶子中分离得到(G.Chauvière et coll.,C.R.Acad.Sc.Ser.Ⅲ,293；591[1981]),是用于制备合成子(2a)和(2b)的唯一起始物。
文献中未知的合成子(2a)可通过(反应流程1)从(3)得到，它是通过用乙酸铜(Ⅱ)氧化(3)的10-位，得到二酮(4)，然后在铈(Ⅲ)盐存在下用硼氢化钠还原得到。
所得产物(2a,R3=H,R4=R5=OH)，它是(3)的10-位的差向异构体，在7-位和10-位适当进行保护，并用于合成紫杉烷(1a)。
反应流程1
在反应流程1中得到的副产物是新的断紫杉烷(secotaxane)(5)。
断紫杉烷(5)可用于合成具有潜在抗肿瘤活性的其他紫杉烷。
本发明还涉及半合成制备的新的断紫杉烷骨架的衍生物，它具有强的抗肿瘤活性。所述衍生物具有通式(5a)。
其中：
R1和R2，可以相同或不同，可以是C1-C20烷基，C2-C8链烯基，芳基(优选苯基)或杂芳基。R2也可以是叔丁氧基。
通式(5a)的紫杉烷可通过使用适当活化的异丝氨酸链作为酰化试剂在通式(5)化合物的13-位酯化而制备，如在半合成紫杉醇及其类似物的文献中报道的(参见，例如EP-A-400,971；E.Didier等，Tetrahedron Letters 35,2349,1994；E.Didier等，ibid.35,3063,1994)。可按传统方法，用合适的保护基将通式(5)化合物的羟基任意性地保护起来。
在化合物(5)的13-位用异丝氨酸链酯化后，使用文献中的常规方法除去保护基，就可得到通式(5a)的断紫杉烷。
合成子(2b)，在文献中是未知的，也可从10-脱乙酰基浆果赤霉素Ⅲ(3)(反应流程2)得到。已发现可通过用间氯过苯甲酸(MCPBA)氧化(3)，得到相应的13-酮衍生物(6)。用三乙基甲硅烷基氯(TESCl)保护7-位羟基后，在铈(Ⅲ)盐存在下用硼氢化钠还原，由(6)得到合成子(2b)(R3=OH,R4=H,R5=O-TES)，它可用于合成式(1b)的紫杉烷。在合成子(2b)中，12-位α-取向的甲基可通过使用核磁共振的研究推断出来。
反应流程2
根据本发明的产物对不同肿瘤细胞系的细胞毒性效果进行筛选，其作用与紫杉醇相比较。表1显示了IC50数据的比较，即对化合物13-[(2R,3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-10-表-10-脱乙酰基浆果赤霉素Ⅲ(1a,R1=Ph,R2=tBuO,R3=H,R4=OH),13-[(2R,3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-10-脱乙酰基-11,12-二氢浆果赤霉素Ⅲ(1b,R1=Ph,R2=tBuO,R3=OH,R4=H),13-[(2R,3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素Ⅲ(5a,R1=Ph,R2=tBuO)和13-[(2R,3S)-3-异丁基-2-羟基-3-己酰基氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素Ⅲ(5a,R1=异丁基，R2=戊基)的数据与紫杉醇中得到的数据进行比较。
表1-紫杉烷1a(R1=Ph,R2=tBuO,R3=H,R4=OH),1b(R1=Ph,R2=tBuO,R3=OH,R4=H)和紫杉醇对6种细胞系的IC50。
暴露时间 紫杉醇 1a 1b
(h) (R1=Ph,R2=tBuO,(R1=Ph,R2=tBuO,
R3=H,R4=OH) R3=OH,R4=H)L1210(鼠白血病) 48 57.0±3.0 46.0±2.1 32.0±0.1A121(人卵巢) 72 3.7±0.3 2.8±0.3 1.6±0.2A549(人NSCLC) 72 5.4±0.5 6.9±0.3 2.1±0.3HT-29(人结肠) 72 6.0±0.6 3.4±0.1 3.6±0.4HCF7(人乳房) 72 4.3±0.1 2.2±0.2 0.8±0.2HCF7-ADR(抗药性的) 72 395.0±8.7 130.0±2.2 128.0±6.2标准条件：培养基RPMI1640+20mM HEPES+2mM L-谷氨酰胺。
表1-续 紫杉烷5a(R1=Ph,R2=tBuO),5a(R1=异丁基，R2=戊基)和紫杉醇对6种细胞系的IC50。
暴露时间 紫杉醇 5a 5a
(h) (R1=Ph, (R1=异丁基，
R2=tBuO) R2=戊基)L1210(鼠白血病) 48 57.0±3.0 35±1.2 26±1.3A121(人卵巢) 72 3.7±0.3 1.9±0.2 1.3±0.1A549(人NSCLC) 72 5.4±0.5 3.3±0.4 2.6±0.3HT-29(人结肠) 72 6.0±0.6 3.2±0.3 2.7±0.2HCF7(人乳房) 72 4.3±0.1 1.5±0.2 1.1±0.2HCF7-ADR(抗药性的)72 395.0±8.7 31.3±4.2 25.4±3.7标准条件：培养基RPMI 1640+20mM HEPES+2mM L-谷氨酰胺
在异丝氨酸链上有不同取代基的化合物作用相似。这些化合物对于对其它抗肿瘤物质如阿霉素和顺铂(cis-platinum)有抗药性的细胞系的作用比紫杉醇具有惊人的优越性。在体内模型中这些化合物与紫杉醇的不同更为明显，如种植了人肿瘤细胞的无胸腺裸鼠。另外，我们还惊奇的发现，本发明的R2为烷基或链烯基的化合物完全无心脏毒性，不象紫杉醇和其已知的衍生物，因此，它们可有效地用于不能用紫杉醇和其已知衍生物治疗的心脏病患者。
本发明的化合物适于与适当的药用制剂结合用于非肠道和口服给药。对于静脉内给药而言，主要使用聚乙氧基化蓖麻油和乙醇的混合物，或用天然磷脂酰胆碱制成的脂质体制剂或天然磷脂与胆固醇的混合物。
下面的实施例将进一步详述本发明。实施例1 10-脱氢-10-脱乙酰基浆果赤霉素Ⅲ(4)的制备。
将10g10-脱乙酰基浆果赤霉素Ⅲ(3)悬浮于350ml甲醇中，向其中加入Cu(OAc)265g。将悬浮液在室温连续搅拌120小时。滤除盐，溶液用100g硅胶色谱纯化，用6∶4己烷/乙酸乙酯混合物洗脱。用里格罗因(ligroin)结晶，得到9.5g(4)化合物。M+为m/z 542。实施例2制备10-脱乙酰基-10-表浆果赤霉素Ⅲ(2a,R3=H,R4=R5=OH)和C-断-10-脱乙酰基浆果赤霉素Ⅲ(5)。
向300mg(4)的5ml甲醇溶液中加入一当量CeCl3·3H2O，室温搅拌5分钟，然后加入80mg NaBH4。溶液用NH4Cl溶液处理，用乙酸乙酯萃取，并用硅胶色谱纯化，用3∶7己烷/乙酸乙酯混合物洗脱。得到98mg(2a)(M+在m/z 544)和120mg(5)(M+在m/z 546)。10-脱乙酰基-10-表浆果赤霉素Ⅲ具有1H-NMR(CDCl3)如下：H2,d5.68 J6.8；H3,d4.26J6.8；H5,d 5.03 J7.1；H7/13,m 4.76；H10,brs 5.20；10 OH,brs3.44；H16,s1.14；H17,s1.68；H18,s2.22；H19,s1.13；H20a,d4.33；H20b,d4.18；Ac,s2.31；Bnz,br8.12 J8,brt 7.60 J8,brt17.49 J8。实施例3制备10-脱乙酰基-13-脱氢浆果赤霉素Ⅲ(6)。
向1g10-脱乙酰基浆果赤霉素Ⅲ(3)在100mlCH2Cl2中的悬浮液中加入3g间氯过苯甲酸和1g乙酸钠。将此悬浮液在室温连续搅拌120小时，然后用5％Na2CO3水溶液稀释。有机相用5％Na2CO3洗涤并蒸发至干，剩余物用硅胶色谱纯化，用3∶7己烷/乙酸乙酯混合物洗脱。得到789mg(6),M+在m/z 542。实施例4制备10-脱乙酰基-11,12-二氢-7-三乙基甲硅烷基-浆果赤霉素Ⅲ(2b,R3=OH,R4=H,R5=O-TES)。
将1.6g(6)溶于二氯甲烷中并加入370mg4-二甲基氨基吡啶和2.5ml三乙基甲硅烷基氯。室温保持2小时后，将反应混合物用二氯甲烷稀释并用水洗涤。有机相浓缩至干。得到1.72g剩余物，用150ml95％乙醇溶解，并用9gNaBH4处理。3小时后混合物用NH4Cl溶液稀释，产物用乙酸乙酯萃取。用硅胶色谱纯化，使用7∶3己烷/乙酸乙酯洗脱，得到800mg(2b)(R3=OH,R4=H,R5=O-TES)。实施例5制备11,12-二氢-7-TES-浆果赤霉素Ⅲ(2b,R3=OH,R4=H,R5=O-TES)和11,12-二氢浆果赤霉素Ⅲ(2b,R3=OAc,R4=H,R5=OH)
将500mg10-脱乙酰基-11,12-二氢-7-三乙基甲硅烷基浆果赤霉素Ⅲ(2b,R3=OH,R4=H,R5=O-TES)与3当量的乙酰氯在无水吡啶中在0℃反应6小时。反应混合物用水稀释并用二氯甲烷萃取。蒸发溶剂后，剩余物用丙酮/己烷结晶。得到510mg11,12-二氢-7-TES浆果赤霉素Ⅲ,M+为m/z 702Ⅲ。将产物溶于甲醇并用稀HCl处理至完全脱甲硅基化。反应混合物用水稀释，用乙酸乙酯萃取，并用含水甲醇结晶。得到400mg11,12-二氢浆果赤霉素Ⅲ,M+为m/z 588。实施例6制备13-[(2R,3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-11,12-二氢浆果赤霉素Ⅲ(1b,R2=Ph,R2=tBuO,R3=OAc,R4=H)。将500mg11,12-二氢浆果赤霉素Ⅲ(2b,R3=OAc,R4=H,R5=O-TES)溶于20ml甲苯中，与0.45g(4S,5R)-N-叔丁氧羰基-2,2-二甲基-苯基-5-噁唑烷羧酸，二环己基碳化二亚胺(1.03eq)和N,N-二甲基氨基吡啶(0.2eq)在80℃反应2小时。反应混合物用水洗涤直至除去过量的反应试剂，然后浓缩至干。剩余物用含1％甲酸的甲醇在室温处理4小时。甲醇溶液用水稀释，中和，并用乙酸乙酯萃取。有机相浓缩至干，剩余物用含1.5eq碳酸二叔丁基酯和碳酸氢钠在15ml四氢呋喃中的溶液处理。反应混合物用水稀释，用乙酸乙酯萃取，将复合乙酸相(heteroacetic phase)浓缩至干。剩余物用盐酸酸化的甲醇溶解以完成脱甲硅基化。溶液用水稀释，用乙酸乙酯萃取。蒸发复合乙酸相得到的剩余物用硅胶色谱纯化，1∶1丙酮/己烷混合物洗脱以除去反应杂质。得到580mg产物，M+为m/z 851。实施例7制备13-[(2R,3S)-3-苯甲酰氨基-3-苯基-2-羟基丙酰基]-11,12-二氢浆果赤霉素Ⅲ(1b,R1=R2=Ph,R3=OAc,R4=H)。
将500mg11,12-二氢-7-TES-浆果赤霉素(2b,R3=OAc,R4=H,R5=O-TES)溶于20ml甲苯，并与1.5g(4S,5R)-N-苯甲酰基-2,2-二甲基-4-苯基-5-噁唑烷羧酸，二环己基碳化二亚胺(1.03eq)和N,N-二甲基氨基吡啶(0.2eq)在80℃反应2小时。反应混合物用水洗条直至除去过量的反应试剂，然后浓缩至干。剩余物用含1％甲酸的甲醇在室温处理4小时。甲醇溶液用水稀释，中和，并用乙酸乙酯萃取。有机相浓缩至干，剩余物用盐酸酸化的甲醇溶解以完成脱甲硅基化。溶液用水稀释并用乙酸乙酯萃取。蒸发复合乙酸相得到的剩余物用硅胶色谱纯化，1∶1丙酮/己烷混合物洗脱以除去反应杂质。得到530mg产物，M+为m/z 855。实施例8制备13-[(2R,3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-10-表-10-脱乙酰基浆果赤霉素Ⅲ(1a,R2=Ph,R2=tBuO,R3=H,R4=OH)。
将500mg10-脱乙酰基-10-表浆果赤霉素Ⅲ(2a,R3=H,R4=R5=OH)溶于15ml无水吡啶，并用三当量三氯乙氧羰基氯(TROC-Cl)在80℃处理5分钟，然后冷却到室温。加入1ml甲醇分解过量的TROC-Cl。溶液用冰水稀释并用氯仿萃取，用稀盐酸溶液洗涤有机相。有机相蒸发至干，剩余物用含三当量(4S,5R)-N-叔丁氧羰基-2,2-二甲基-4-苯基-5-噁唑烷羰酸，3当量二环己基碳化二亚胺和0.2当量N,N-二甲基氨基吡啶的甲苯溶液在室温处理24小时。反应混合物用水洗涤，有机相在真空下蒸发至干，剩余物溶于甲醇，并用一当量对甲苯磺酸处理48小时，之后用水稀释，并用乙酸乙酯萃取。有机相在真空下蒸发，剩余物溶于1∶1的乙酸/乙酸乙酯混合物200ml中，并用11当量锌粉在30℃处理3小时。滤除固体物质，溶液用水稀释，用乙酸乙酯萃取并用硅胶色谱纯化，用1∶4乙酸乙酯/己烷混合物洗脱。得到512mg产物(1a),M+为m/z 807。实施例9制备7,9-二(三乙基甲硅烷基)-C-断-10-脱乙酰基浆果赤霉素Ⅲ
向(5)(200mg,0.37mmol)在无水二甲基甲酰胺(DMF)(5ml)中的溶液中加入咪唑(75mg,1.11mmol,3eq.mol)和三乙基甲硅烷基氯(TES)(186ml,167.3mg,1.11mmol,3eq.mol)，反应混合物在室温搅拌10分钟。用TLC检测反应(3∶7己烷-乙酸乙酯，起始物的Rf为0.10，产物的Rf为0.80)。加入水和CeliteR终止反应，过滤沉淀并用水洗涤以除去DMF，然后用CHCl3洗涤以取出产物。用柱色谱(9∶1己烷/乙酸乙酯洗脱硅烷醇，6∶4己烷/乙酸乙酯洗脱出产物)纯化，得到146mg标题化合物(51％)。实施例10制备13-[(2R,3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素Ⅲ(5a,R1=Ph,R2=tBuO)。
向实施例9的产物(126mg,0.16mmol)在无水甲苯(5ml)中的溶液中加入67.5mg二环己基碳化二亚胺(0.327mmol,2mol.eq.),105mg(4S,5R)-N-Boc-2-(2,4-二甲氧苯基)-4-苯基-5-噁唑烷羧酸(0.327mmol,2mol.eq.)和5mg4-二甲基氨基吡啶。混合物在60℃加热24小时，然后用饱和NaHCO3水溶液和乙酸乙酯稀释。剩余物用柱色谱纯化(8∶2己烷-乙酸乙酯)得到175mg 13-酯(95％)。剩余物用50ml甲醇/HCl(0.01％)溶解，且反应混合物在室温保留1小时。溶液碱化至pH5，并在真空下浓缩至干。剩余物用硅胶柱色谱纯化，98∶2二氯甲烷-甲醇混合物洗脱。用乙酸乙酯结晶后，得到85mg标题化合物。实施例11制备13-[(2R,3S)-3-异丁基-2-羟基-3-己酰氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素Ⅲ(5a,R1=Ph,R2=戊基)。
向实施例9的产物(126mg,0.16mmol)在无水甲苯(5ml)中的溶液中加入67.5mg二环己基碳化二亚胺(0.327mmol,2mol.eq.),140mg(4S,5R)-N-己酰基-2-(2,4-二甲氧苯基)-4-异丁基-5-噁唑烷羧酸(0.327mmol,2mol.eq)和5mg4-二甲基氨基吡啶。混合物在60℃加热24小时，然后用饱和NaHCO3水溶液和乙酸乙酯稀释。剩余物用柱色谱纯化(8∶2己烷-乙酸乙酯)得到175mg 13-酯(95％)。剩余物用50ml甲醇/HCl(0.01％)溶解，且反应混合物在室温保留1小时。溶液碱化至pH5，并在真空下浓缩至干。剩余物用硅胶柱色谱纯化，用98∶2二氯甲烷-甲醇混合物洗脱，用乙酸乙酯结晶后，得到88mg标题化合物。
Claims (7)
1．通式(1)的半合成紫杉烷其中：
R1和R2可相同或不同，它们是C1-C8烷基，C2-C8链烯基，芳基或杂芳基；
R2也可以是叔丁氧基；
当11,12位之间有烯属双键时，R3是氢原子，R4是羟基或C2-C8酰氧基；
当11,12位之间无烯属双键时，12位的甲基是α-取向的，R3是羟基或C2-C8酰氧基，且R4是氢；条件是R1和R2为苯基且11和12位由双键连接时，R4不为乙酰基。
2．按照权利要求1的化合物，是13-[(2R,3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-10-表-10-脱乙酰基浆果赤霉素Ⅲ，具有通式(1a)其中R1=苯基，R2=叔丁氧基，R3=H,R4=OH。
3．按照权利要求1的化合物，是13-[(2R,3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-11,12-二氢浆果赤霉素Ⅲ，具有通式(1b)
其中R1=苯基，R2=叔丁氧基，R3=乙酰氧基和R4=H。
4．一种制备权利要求1的化合物的方法，其中使合成子(2)其中：
当11,12位之间存在烯属双键时，R3是氢，R4和R5是羟基，C2-C8酰氧基，烷基甲硅烷氧基或2,2,2-三氯乙氧羰基氧基；
当11,12位之间无烯属双键时，12位的甲基是α-取向的，R4是氢，R3和R5是羟基，C2-C8酰氧基，烷基甲硅烷氧基或2,2,2-三氯乙氧羰基氧基；用适当活化的和/或保护的异丝氨酸衍生物按照已知方法进行酯化，从而在13位引入酰基。其中R1和R2定义如权利要求1，和然后按照已知方法除去保护基。
5．含有权利要求1-3中任一项的紫杉烷化合物的具有抗肿瘤作用的药物组合物。
6．权利要求1-3中任一项的紫杉烷用于制备治疗癌症的药物。
7．R2是烷基或链烯基的权利要求1紫杉烷用于制备治疗心脏病患者的癌症的药物。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI94A001592 | 1994-07-26 | ||
| ITMI941592A IT1274356B (it) | 1994-07-26 | 1994-07-26 | Tassani semisintetici odtati di attivita' antitumorale |
| IT95RM000413A IT1278108B1 (it) | 1995-06-19 | 1995-06-19 | Secotassani dotati di attivita' antitumorale. |
| ITRM95A000413 | 1995-06-19 |
Related Child Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00129055A Division CN1130356C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成断紫杉烷 |
| CN00129056A Division CN1128795C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129054A Division CN1120161C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1154109A CN1154109A (zh) | 1997-07-09 |
| CN1073105C true CN1073105C (zh) | 2001-10-17 |
Family
ID=26331178
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95194333A Expired - Fee Related CN1073105C (zh) | 1994-07-26 | 1995-07-21 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129056A Expired - Fee Related CN1128795C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129054A Expired - Fee Related CN1120161C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129055A Expired - Fee Related CN1130356C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成断紫杉烷 |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00129056A Expired - Fee Related CN1128795C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129054A Expired - Fee Related CN1120161C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129055A Expired - Fee Related CN1130356C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成断紫杉烷 |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US5756776A (zh) |
| EP (1) | EP0773938B1 (zh) |
| JP (1) | JP2986550B2 (zh) |
| KR (1) | KR100220490B1 (zh) |
| CN (4) | CN1073105C (zh) |
| AT (1) | ATE176464T1 (zh) |
| AU (1) | AU684218B2 (zh) |
| BG (1) | BG62851B1 (zh) |
| CA (1) | CA2195844C (zh) |
| CZ (1) | CZ293076B6 (zh) |
| DE (1) | DE69507702T2 (zh) |
| DK (1) | DK0773938T3 (zh) |
| ES (1) | ES2126919T3 (zh) |
| FI (1) | FI120398B (zh) |
| GR (1) | GR3029309T3 (zh) |
| HK (1) | HK1011687A1 (zh) |
| HU (1) | HU222496B1 (zh) |
| NO (1) | NO315116B1 (zh) |
| PL (1) | PL187579B1 (zh) |
| RO (2) | RO116549B1 (zh) |
| RU (1) | RU2134688C1 (zh) |
| SI (1) | SI9520078B (zh) |
| SK (1) | SK281526B6 (zh) |
| WO (1) | WO1996003394A1 (zh) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6107332A (en) | 1995-09-12 | 2000-08-22 | The Liposome Company, Inc. | Hydrolysis-promoting hydrophobic taxane derivatives |
| US6395770B1 (en) * | 1995-10-26 | 2002-05-28 | Baker Norton Pharmaceuticals, Inc. | Method and compositions for administering taxanes orally to human patients |
| FR2745814B1 (fr) * | 1996-03-06 | 1998-04-03 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
| WO1998013359A1 (de) * | 1996-09-24 | 1998-04-02 | Marigen S.A. | Ultramikroemulsionen aus spontan dispergierbaren konzentraten mit antitumoral und antiviral wirksamen estern von baccatin-iii-verbindungen |
| US5773464A (en) * | 1996-09-30 | 1998-06-30 | Bristol-Myers Squibb Company | C-10 epoxy taxanes |
| US5977386A (en) * | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
| US5902822A (en) * | 1997-02-28 | 1999-05-11 | Bristol-Myers Squibb Company | 7-methylthiooxomethyl and 7-methylthiodioxomethyl paclitaxels |
| US5912264A (en) * | 1997-03-03 | 1999-06-15 | Bristol-Myers Squibb Company | 6-halo-or nitrate-substituted paclitaxels |
| US6017935A (en) * | 1997-04-24 | 2000-01-25 | Bristol-Myers Squibb Company | 7-sulfur substituted paclitaxels |
| CZ9904244A3 (cs) * | 1997-05-27 | 2001-10-17 | Baker Norton Pharmaceuticals, Inc. | Pouľití taxanů, jejich derivátů, analogů nebo předléků pro přípravu farmaceutického prostředku pro perorální podávání |
| IT1308636B1 (it) * | 1999-03-02 | 2002-01-09 | Indena Spa | Procedimento per la preparazione di tassani da 10-desacetilbaccatinaiii. |
| EP2266607A3 (en) | 1999-10-01 | 2011-04-20 | Immunogen, Inc. | Immunoconjugates for treating cancer |
| IT1317731B1 (it) * | 2000-01-18 | 2003-07-15 | Indena Spa | Tassani semisintetici con attivita' antitumorale ed antiangiogenetica. |
| US6649632B2 (en) * | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
| EP1129991A1 (de) * | 2000-03-02 | 2001-09-05 | Degussa AG | Verfahren zur Herstellung eines titanhaltigen Zeolithen |
| US7064980B2 (en) * | 2003-09-17 | 2006-06-20 | Sandisk Corporation | Non-volatile memory and method with bit line coupled compensation |
| PE20050693A1 (es) * | 2004-02-13 | 2005-09-27 | Univ Florida State Res Found | Taxanos sustituidos con esteres de ciclopentilo en c10 |
| US20060189679A1 (en) * | 2005-02-14 | 2006-08-24 | Florida State University Research Foundation, Inc. | C10 cyclopropyl ester substituted taxane compositions |
| ITMI20050415A1 (it) * | 2005-03-15 | 2006-09-16 | Indena Spa | Derivati tassanici semi-sintetici ad attivita' antitumorale |
| ITMI20062479A1 (it) * | 2006-12-21 | 2008-06-22 | Indena Spa | Processo per la preparazione di secotassani |
| EP2183234A4 (en) * | 2007-08-22 | 2012-02-29 | Canada Inc 6570763 | PROCESS FOR CONVERTING 9-DIHYDRO-13-ACETYLBACCATIN III IN DOCETAXEL OR PACLITAXEL |
| JP2011517455A (ja) * | 2008-03-31 | 2011-06-09 | フロリダ・ステイト・ユニバーシティ・リサーチ・ファウンデイション・インコーポレイテッド | Ｃ（１０）エチルエステルおよびｃ（１０）シクロプロピルエステル置換タキサン |
| EP2331140B1 (en) | 2008-08-11 | 2018-07-04 | Nektar Therapeutics | Multi-arm polymeric alkanoate conjugates |
| US20130338216A1 (en) * | 2010-12-22 | 2013-12-19 | Nektar Therapeutics | Deuterated and/or fluorinated taxane derivatives |
| WO2012088422A1 (en) | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
| WO2012088391A1 (en) * | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Non-ring hydroxy substituted taxanes and methods for synthesizing the same |
| WO2012088445A1 (en) | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0555485A1 (en) * | 1991-07-17 | 1993-08-18 | Nippon Steel Corporation | Antitumor compound nsc-lsc1 and production thereof |
| CN1086512A (zh) * | 1989-05-31 | 1994-05-11 | 佛罗里达州立大学 | 紫杉酚中间体的制备方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5399726A (en) * | 1993-01-29 | 1995-03-21 | Florida State University | Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups |
| FR2688499B1 (fr) * | 1992-03-10 | 1994-05-06 | Rhone Poulenc Rorer Sa | Procede de preparation de la beta-phenylisoserine et de ses analogues. |
| US5200534A (en) * | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
-
1995
- 1995-07-21 DE DE69507702T patent/DE69507702T2/de not_active Expired - Lifetime
- 1995-07-21 DK DK95927699T patent/DK0773938T3/da active
- 1995-07-21 SI SI9520078A patent/SI9520078B/sl not_active IP Right Cessation
- 1995-07-21 RU RU97102722A patent/RU2134688C1/ru not_active IP Right Cessation
- 1995-07-21 CN CN95194333A patent/CN1073105C/zh not_active Expired - Fee Related
- 1995-07-21 CZ CZ1997199A patent/CZ293076B6/cs not_active IP Right Cessation
- 1995-07-21 AU AU31641/95A patent/AU684218B2/en not_active Ceased
- 1995-07-21 AT AT95927699T patent/ATE176464T1/de active
- 1995-07-21 CA CA002195844A patent/CA2195844C/en not_active Expired - Fee Related
- 1995-07-21 KR KR1019970700442A patent/KR100220490B1/ko not_active IP Right Cessation
- 1995-07-21 RO ROA200000502A patent/RO116549B1/ro unknown
- 1995-07-21 SK SK100-97A patent/SK281526B6/sk not_active IP Right Cessation
- 1995-07-21 WO PCT/EP1995/002896 patent/WO1996003394A1/en active IP Right Grant
- 1995-07-21 ES ES95927699T patent/ES2126919T3/es not_active Expired - Lifetime
- 1995-07-21 RO RO97-00125A patent/RO115875B1/ro unknown
- 1995-07-21 HU HU9700206A patent/HU222496B1/hu not_active IP Right Cessation
- 1995-07-21 EP EP95927699A patent/EP0773938B1/en not_active Expired - Lifetime
- 1995-07-21 JP JP8505456A patent/JP2986550B2/ja not_active Ceased
- 1995-07-21 PL PL95318289A patent/PL187579B1/pl not_active IP Right Cessation
- 1995-07-24 US US08/505,924 patent/US5756776A/en not_active Expired - Lifetime
-
1997
- 1997-01-23 BG BG101165A patent/BG62851B1/bg unknown
- 1997-01-23 NO NO19970296A patent/NO315116B1/no not_active IP Right Cessation
- 1997-01-23 FI FI970271A patent/FI120398B/fi not_active IP Right Cessation
-
1998
- 1998-12-07 HK HK98112903A patent/HK1011687A1/xx not_active IP Right Cessation
-
1999
- 1999-02-09 GR GR990400393T patent/GR3029309T3/el unknown
-
2000
- 2000-09-29 CN CN00129056A patent/CN1128795C/zh not_active Expired - Fee Related
- 2000-09-29 CN CN00129054A patent/CN1120161C/zh not_active Expired - Fee Related
- 2000-09-29 CN CN00129055A patent/CN1130356C/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1086512A (zh) * | 1989-05-31 | 1994-05-11 | 佛罗里达州立大学 | 紫杉酚中间体的制备方法 |
| EP0555485A1 (en) * | 1991-07-17 | 1993-08-18 | Nippon Steel Corporation | Antitumor compound nsc-lsc1 and production thereof |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1073105C (zh) | 具有抗肿瘤活性的半合成紫杉烷 | |
| JP2011046744A (ja) | １０−デアセチルバッカチンＩＩＩおよび１０−デアセチル１４β−ヒドロキシバッカチンＩＩＩ誘導体類、それらの調製方法およびそれらを含む医薬製剤 | |
| HU211824A9 (en) | Baccatine iii derivatives | |
| AU706155B2 (en) | 7-deoxy-6-substituted paclitaxels | |
| EP0185740B1 (en) | Epipodophyllotoxinquinone glucoside derivatives method of production and use | |
| RU2161615C2 (ru) | Производные 10-деацетил-14-бета-гидроксибаккатина iii, способ их получения и композиции, содержащие эти соединения | |
| GB2289277A (en) | Taxane derivatives | |
| ITRM950413A1 (it) | Secotassani dotati di attivita' antitumorale. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20011017 Termination date: 20120721 |