CN1097746A - C-10位紫杉烷衍生物及其药组合物 - Google Patents
C-10位紫杉烷衍生物及其药组合物 Download PDFInfo
- Publication number
- CN1097746A CN1097746A CN94100725A CN94100725A CN1097746A CN 1097746 A CN1097746 A CN 1097746A CN 94100725 A CN94100725 A CN 94100725A CN 94100725 A CN94100725 A CN 94100725A CN 1097746 A CN1097746 A CN 1097746A
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- Prior art keywords
- hydrogen
- hydroxyl
- alkenyl
- aryl
- alkyl
- Prior art date
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- 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 title claims abstract description 21
- 239000000203 mixture Substances 0.000 title description 59
- 239000003814 drug Substances 0.000 title description 4
- 229940079593 drug Drugs 0.000 title description 3
- 239000001257 hydrogen Substances 0.000 claims description 94
- 229910052739 hydrogen Inorganic materials 0.000 claims description 94
- -1 4Be hydrogen Chemical class 0.000 claims description 81
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 81
- 150000002431 hydrogen Chemical class 0.000 claims description 64
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 125000003342 alkenyl group Chemical group 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 40
- 125000000304 alkynyl group Chemical group 0.000 claims description 37
- 229910052799 carbon Inorganic materials 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 13
- 125000004423 acyloxy group Chemical group 0.000 claims description 12
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical group C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 9
- 125000000524 functional group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 239000011449 brick Substances 0.000 claims description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- IWDXDWGMUWFIIM-UHFFFAOYSA-N COCCOC(C(C)(C)C)OOCCCCC Chemical compound COCCOC(C(C)(C)C)OOCCCCC IWDXDWGMUWFIIM-UHFFFAOYSA-N 0.000 claims 2
- 125000005336 allyloxy group Chemical group 0.000 claims 2
- DWDAZFJBSZTCCM-UHFFFAOYSA-N [O]C1CCCCC1 Chemical compound [O]C1CCCCC1 DWDAZFJBSZTCCM-UHFFFAOYSA-N 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 79
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 57
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 55
- 229930012538 Paclitaxel Natural products 0.000 description 43
- 229960001592 paclitaxel Drugs 0.000 description 43
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound 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 description 43
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 42
- 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 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- 239000007864 aqueous solution Substances 0.000 description 28
- 239000002585 base Substances 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 23
- 238000001704 evaporation Methods 0.000 description 22
- 230000008020 evaporation Effects 0.000 description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- YWLXLRUDGLRYDR-UHFFFAOYSA-N 10-deacetylbaccatin Chemical compound CC(=O)OC12COC1CC(O)C(C(C(O)C1=C(C)C(O)CC3(O)C1(C)C)=O)(C)C2C3OC(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 125000001544 thienyl group Chemical group 0.000 description 13
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 238000003381 deacetylation reaction Methods 0.000 description 10
- 125000002541 furyl group Chemical group 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 150000004703 alkoxides Chemical class 0.000 description 7
- 150000003952 β-lactams Chemical class 0.000 description 7
- 150000001263 acyl chlorides Chemical class 0.000 description 6
- 229930014667 baccatin III Natural products 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 229910052744 lithium Inorganic materials 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)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 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000005906 dihydroxylation reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 229940063683 taxotere Drugs 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 3
- 229910052772 Samarium Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 244000162450 Taxus cuspidata Species 0.000 description 3
- 235000009065 Taxus cuspidata Nutrition 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 230000033444 hydroxylation Effects 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 125000000468 ketone group Chemical group 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- CDMXXXZRZWQJQE-UHFFFAOYSA-N acetic acid;2-methylprop-2-enoic acid Chemical compound CC(O)=O.CC(=C)C(O)=O CDMXXXZRZWQJQE-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 229960003328 benzoyl peroxide Drugs 0.000 description 2
- 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 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 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 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
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- 238000003786 synthesis reaction Methods 0.000 description 2
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- 150000003512 tertiary amines Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
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- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- ORLCYMQZIPSODD-UHFFFAOYSA-N 1-chloro-2-[chloro(2,2,2-trichloroethoxy)phosphoryl]oxybenzene Chemical compound ClC1=CC=CC=C1OP(Cl)(=O)OCC(Cl)(Cl)Cl ORLCYMQZIPSODD-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 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 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229930190007 Baccatin Natural products 0.000 description 1
- UHBXGHADNVDXMM-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Li] Chemical compound C(C)(C)N(C(C)C)CC[Li] UHBXGHADNVDXMM-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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Abstract
具有可变换的C-10位取代基的紫杉烷衍生
物。
Description
本发明涉及用作抗白血病和抗肿瘤药剂的新的紫杉烷类化合物(taxanes)。萜类化合物中紫杉族的一员,紫杉酚,在生物和化学领域已引起人们很大的兴趣。紫杉酚是一种具有宽谱抗白血病和抑制肿瘤活性的很有前景的癌化学治疗剂。紫杉酚具有2′R,3′S构型,其结构式如下所示:式中Ac为乙酰基。由于这一有前景的活性,在法国和美国现在都对紫杉酚在进行临床试验。
Colin等人在U.S.P.No 4814470中报告,结构式为(2)的紫杉酚衍生物具有比结构式为(1)的紫杉酚大得多的活性。式中R′为氢或乙酰基,R″和R之一为羟基和另一个为叔丁氧羰基氨基和它们的立体异构形或及混合物。R″为羟基,R为叔丁氧羰氨基的具有2′R,3′S构型的通式(2)化合物一般叫做taxotere。
虽然,紫杉酚和taxotere都是有前景的化学治疗剂,但是,它们并非普遍有效,因此,需要研制另外化学治疗剂。
本发明的目的是提供新的紫杉烷衍生物,它们是有价值的抗白血病和抗肿瘤药剂。
X1是-OX6,-SX7或-NX8X9;
X2是氢,烷基,链烯基,炔基,芳基或杂芳基;
X3和X4各自独立地是氢,烷基,链烯基,炔基,芳基或杂芳基;
X5是-COX10,-COOX10,-COSX10,-CONX8X10或-SO2X11;
X6是氢,烷基,链烯基,炔基,芳基,杂芳基,羟基保护基或增加紫杉烷衍生物水溶性的官能团;
X7是烷基,链烯基,炔基,芳基,杂芳基或巯基保护基;
X8是氢,烷基,链烯基,炔基,芳基,杂芳基或者杂取代的烷基,链烯基,炔基,芳基或杂芳基;
X9是氨基保护基;
X10是烷基,链烯基,炔基,芳基,杂芳基或者杂取代的烷基,链烯基,炔基,芳基或杂芳基;
X11是烷基,链烯基,炔基,芳基,杂芳基,-OX10或-NX8X14;
X14是氢,烷基,链烯基,炔基,芳基或杂芳基;
R1是氢,羟基,保护了的羟基或与R14一起形成碳酸酯;
R2是氢,羟基,-OCOR31或与R2a一起形成氧代基;
R2a是氢或与R2一起形成氧代基;
R4是氢,与R4a一起形成氧代基,环氧乙烷或亚甲基,或者与R5a和连接它们的碳原子一起形成氧杂环丁烷环;
R4a是氢,烷基,链烯基,炔基,芳基,杂芳基,氰基,羟基,-OCOR30,或与R4一起形成氧代基,环氧乙烷或亚甲基;
R5是氢或与R5a一起形成氧代基;
R5a是氢,羟基,保护了羟基,酰氧基,与R5一起形成氧代基,或与R4和连接它们的碳原子一起形成氧杂环丁烷环;
R6是氢,烷基,链烯基,炔基,芳基或杂芳基,羟基,保护了的羟基或与R6a一起形成氧代基;
R6a是氢,烷基,链烯基,炔基,芳基或杂芳基,羟基,保护了的羟基或与R6一起形成氧代基;
R7是氢或与R7a一起形成氧代基;
R7a是氢,囟素,保护了的羟基,-OR28,或与R7一起形成氧代基;
R9是氢或与R9a一起形成氧代基;
R9a是氢,羟基,保护了的羟基,酰氧基,或与R9一起形成氧代基;
R10是氢或与R10a一起形成氧代基;
R10a是氢或与R10一起形成氧代基;
R14是氢,烷基,链烯基,炔基,芳基或杂芳基,羟基,保护了的羟基或与R1一起形成碳酸酯;
R14a是氢,烷基,链烯基,炔基,芳基或杂芳基;
R28是氢,酰基,羟基保护基或增加紫杉烷衍生物的溶解性的官能基团;和
R29,R30和R31各自独立地是氢,烷基,链烯基,炔基,单环芳基或单环杂芳基。
本发明的其它目的和特征,部分是明显的,部分将在下文中指出。
文中所用符号和术语的含义是:
“Ar”指芳基;“Ph”指苯基;“Ac”指乙酰基;“Et”指乙基;“R”除另外定义外一般是指烷基;“Bu”指丁基;“Pr”指丙基;“TES”指三乙基甲硅烷基;“TMS”指三甲基硅烷基;“TPAP”指过钉酸四丙基铵;“DMAP”指对二甲氨基吡啶;“DMF”指二甲基甲酰胺;“LDA”指二异丙基氨基化锂;“LHMDS”指六甲基二硅氮化锂;“LAH”指氢化铝锂;“Red-Al”指氢化双(2-甲氧基乙氧基)铝钠;“AIBN”指偶氮-(双)-异丁腈;“10-DAB”指10-脱乙酰基浆果赤霉素III;“FAR”指2-氯-1,1,2-三氰三乙胺;“保护了的羟基”指-OR,其中R是羟基保护基;“巯基保护基”包括但不限于半硫缩醛如1-乙氧基乙基和甲氧基甲基硫酯,或硫代碳酸酯;“氨基保护基”,包括但不限于,氨基甲酸酯如氨基甲酸2,2,2-三氯乙酯或氨基甲酸叔丁酯;和“羟基保护基”包括但不限于,醚如甲基,叔丁基,苄基,对甲氧基苄基,对硝基苄基,烯丙基,三苯甲基,甲氧基甲基,2-甲氧基丙基,甲氧基乙氧基甲基,乙氧基乙基,四氢吡喃基,四氢噻喃基,和三烷基甲硅烷基醚如三甲基甲硅烷基醚,三乙基甲硅烷基醚,二甲基芳基甲硅烷基醚,三异丙基甲硅烷基醚和叔丁基二甲基甲硅烷基醚;酯如苯甲酰基,乙酰基,苯基乙酰基,甲酰基,一、二和三囟乙酰基如氯乙酰基,二氯乙酰基,三氯乙酰基,三氟乙酰基;和碳酸酯包括但不限于有1-6个碳原子的烷基的碳酸酯,如甲基,乙基,正丙基,异丙基,正丁基,叔丁基,异丁基和正戊基的碳酸酯;有1-6个碳原子和一个或多个囟原子取代的烷基的碳酸酯,如2,2,2-三氯乙氧基甲基和2,2,2-三氯乙基的碳酸酯;有2-6个碳原子的链烯基的碳酸酯,如乙烯基和烯丙基;的碳酸酯;有3-6个碳原子的环烷基的碳酸酯,如环丙基,环丁基,环戊基和环己基和在环上任意取代有1个或多个C1-C6烷氧基或硝基的苯基或苄基的碳酸酯。其它的羟基,巯基和氨基保护基可以在“Protective Groups in Organic Synthes is”byT.W.Greene,John Wiley and Sons,1981中找到。
这里所说的烷基,不论是独立的还是有各种取代基,优选主链含1-6个碳原子和至多为15个碳原子的低级烷基。它们可以是取代的。直链的,支链的或环状的,包括甲基,乙基,丙基,异丙基,丁基,己基,环丙基,环戊基,环己基等。
这里所说的链烯基,不论是独立的还是有各种取代基,优选主链含2-6个碳原子和至多为15个碳原子的低级链烯基。它们可以是取代的,直链的或支链的,包括乙烯基,丙烯基,异丙烯基,丁烯基,异丁烯基,己烯基等。
这里所说的炔基,不论是独立的还是有各种取代基,优选主链含2-6个碳原子和至多有15个碳原子的低级炔基。它们可以是取代的,直链的或支链的包括乙炔基,丙炔基,丁炔基,异丁炔基或己炔基等。
这里所说的芳基部分,或者是独立的或者是取代的,含有6-15个碳原子并包括苯基。取代基包括烷氧基,保护了的羟基,囟素,烷基,芳基,链烯基,酰基,酰氧基,硝基,氨基,酰胺基等。苯基是最优选的芳基。
这里所说的杂芳基部分,或者是独立的或者是取代的,含有5-15个碳原子和包括呋喃基,噻吩基,吡啶基等。取代基包括烷氧基,保护了的羟基,囟素,烷基,芳基,链烯基,酰基,酰氧基,硝基,氨基和酰胺基。
这里所说的酰氧基含有烷基,链烯基,炔基,芳基或杂芳基。
这里所说的取代的烷基,链烯基,炔基,芳基和杂芳基的取代基部分可以是烷基,链烯基,炔基,芳基,杂芳基和/或可以含有氮,氧,硫,囟素,包括例如甲氧基,乙氧基,丁氧基这样的低级烷氧基,囟素如氯或氟,硝基,氨基和酮基。
按照本发明,发现通式(3)化合物在试管内显示显著的性质,是有价值的抗白血病和抗肿瘤剂。它们的生物活性已经在试管内,按照Parness等人在J.Cell Biology,91:479-487(1981)中发表的方法,用微管蛋白试验和人的癌细胞系测定,并可与紫杉酚和taxotere的活性比较。
在本发明的优选的具体实施方案中,紫杉烷的结构与紫杉酚或taxotere相似,只是在C-10位的取代基是两个氢。即,R2a是氢,R2是苯甲酰氧基,R14和R14a是氢,R9和R9a形成氧代基,R7是氢,R7a是羟基,R5是氢,R5a和R4和它们所连的碳原子一起形成氧杂环丁烷环,R4a是乙酰氧基,R1是羟基,X1是-OH,X2是氢,X3是苯基,X4是氢,X5是-COX10,X10是苯基或叔丁氧基,该紫杉烷具有2′R,3′S构型。
在本发明的其它具体实施方案中,就C-10位取代基和至少一个另个的取代基而言,紫杉烷的结构与紫杉酚或taxotere不同。例如,R2可以是羟基或-OCOR31,其中R31是氢,烷基或选自如下的基团and
Z是烷基,羟基,烷氧基,囟素或三氟甲基。R9a可以是氢和R9可以是氢或羟基,R7可以是氢,乙酰氧基及其它的酰氧基或囱素,X3可以是选自异丁烯基,异丙基,环丙基,正丁基,叔丁基,环丁基,环己基,呋喃基,噻吩基,吡啶基或它们的取代衍生物,X5可以是,-COX10或-COOX10和X10可选自呋喃基,噻吩基,吡啶基,烷基取代的呋喃基或噻吩基,叔丁基,异丁基,正丁基,乙基,异丙基,正丙基,环丙基,环己基,烯丙基,2-丁烯基,1,3-二乙氧基-2-丙基,2-甲氧基乙基,戊基,新戊基,PhCH2O-,NPh2,-NHnPr,-NHPh和-NHEt。
试剂:(a)三乙胺,CH2Cl2,25℃,18小时;(b)4当量硝酸铈铵,CH3CN,-10℃,10分钟;(c)KOH,THF,H2O,0℃,30分钟,或吡咯烷,吡啶,25℃,3小时;(d)TESCl,吡啶,25℃,30分钟或2-甲氧基丙烯甲苯磺酸(cat.),THF,0℃,2小时;(e)正丁基锂,THF,-78℃,30分钟;和酰氯或氯甲酸酯(X5=-COX10),磺酰氯(X5=-COSX10)或异氰酸酯(X5=-CONX8X10);(f)二异丙基氨基锂,THF,-78℃至-50℃;(g)六甲基二硅氮化锂;THF,-78℃-0℃;(h)THF,-78℃至25℃,12小时。
原料容易获得。在流程A中,α-乙酰氧基乙酰基氯从羟基乙酸制得,并在叔胺存在下,与从醛和对甲氧基苯胺制得的亚胺环缩合,得到1-对甲氧基苯基-3-酰氧基-4-芳基氮杂环丁烷-2-酮。对甲氧基苯基通过硝酸铈铵氧化可容易地除去,和酰氧基可在本技术领域技术人员熟悉的一般条件下水解,得到3-羟基-4-芳基氮杂环丁烷-2-酮。在流程B中,α-三乙基甲硅烷氧乙酸乙酯容易从羟基乙酸制备。
在反应流程A和B中,X1最好是-OX和X6是羟基保护基。优选保护基如2-甲氧基丙基(“MOP”),1-乙氧基乙基(“EE”)等,但可以使用各种其它标准保护基如三乙基甲硅炕基或其它三烷基(或芳基)甲硅烷基。如上所指出,另外的羟基保护基及其合成可参见“Protcctive groups in organic Synthesis”by T.W.Greene,JohnWiley & Sons,1981。
外消旋β-内酰胺可在保护之前通过相应的2-甲氧基-2-(三氟甲基)苯基乙酸酯重结晶拆分为纯的对映体。然而,下文所述的连接β-氨基酯侧链的反应具有高度非立体选择性的优点,这允许使用侧链前体的外消旋混合物。
具有三环或四环紫杉烷核并在C-13位有金属氧化物或铵氧化物取代基的醇盐的结构式如下:
式中R1-R14a的定义同前,M是铵或选自IA族,IIA族和过渡金属的任意一种金属,优选Li,Mg,Na,K或Ti。最优选的醇盐具有四环紫杉烷核并相应于下式结构下:式中M,R2,R4a,R7,R7a,R9,R9a,R10和R10a的定义同前。
醇盐可由具有紫杉烷核并在C-13位有羟基的醇与有机金属化合物在适合的溶剂中反应来制备。最可取的,该醇是保护了浆果赤霉素III,特别是7-o-三乙基甲硅烷基浆果赤霉素III(可由Greene等人在JACS 110:5917(1988)中所叙的方法或其它方法制得)或7,10-双-o-三乙基甲硅烷基浆果赤霉素III。
在据报是仔细优选的条件下,10-脱乙酰基浆果赤霉素III与20当量(C2H5)3SiCl在氩气氛下和在50ml吡啶/mmol 10-脱乙酰基浆果赤霉素III存在下,23℃反应20小时,得到反应产物7-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素III(4a),提纯后的收率为84-86%。反应产物然后可任意地以5当量CH3COCl3和25ml吡啶/mmol 4a反应脱乙酰基,条件是在氩气氛下在0℃反应48小时,得到86%的7-O-三乙基甲硅烷基浆果赤霉素III(4b)。参见Greene等人在JACS 110,5917至5918(1988)中的方法。
如以下流程所示,13-O-锂-7-O-三乙基甲硅烷基浆果赤霉素III与β-内酰胺(其中X1优选为-OX6,X6是羟基保护基,X2-X5的定义同前)反应,得到C-7和C-2′位羟基被保护的中间体。然后,在温和条件下水解保护基以使不影响酯链或紫杉烷取代基。
醇转化为醇盐和紫杉烷衍生物的最终合成可以在同一反应容器中进行。最好是,在反应容器中形成醇盐后再加入β-内酰胺。
本发明的通式3化合物可用于抑制包括人在内的动物体内肿瘤的生长。优选的给药形式是含有效抗肿瘤量的本发明化合物和药学上可接受的载体或稀释剂的药物组合物。
这种抗肿瘤组合物可制成适于所要求用途例如口服、胃肠外或局部给药的任何适宜形式。胃肠外给药的例子是肌内,静脉内,腹膜内,直肠和皮下给药。
稀释剂或载体组分不应该是减弱抗肿瘤化合物治疗效果的物质。
适宜口服的剂量形式包括片剂、可分散粉剂、粒剂、胶囊剂,悬浮液,糖浆剂和酏剂。片剂用的惰性稀释剂和载体包括例如,碳酸钙,碳酸钠,乳糖和滑石粉。片剂也可含有成粒剂和分散剂如淀粉和藻酸,粘结剂如淀粉,明胶和***树胶,润滑剂如硬脂酸镁,硬脂酸和滑石粉。片剂可以不包衣,也可以用各种已知技术包衣以便例如延迟崩解和吸收。在胶囊剂中所用的惰性稀释剂和载体包括例如,碳酸钙,磷酸钙和高岭土。悬浮液,糖浆剂和酏剂可以含常规的赋形剂如,甲基纤维素,黄蓍胶,藻酸钠;湿润剂如,卵磷脂和硬脂酸聚氧乙烯酯;和防腐剂如,对羟基苯甲酸乙酯。
适宜胃肠外给药的剂量形式包括溶液,悬浮液,分散液,乳液等。它们也可制成无菌固体组合物形式,在使用前溶解或悬浮于无菌注射介质中。它们可含有本技术领域已知的悬浮剂或分散剂。
通式(3)化合物的水溶性可以通过C-2′和/或C-7位取代基的修饰而得到改进。例如,以下取代基可增加水溶性:
X1为-OX6和R7a是-OR28,X6和R28各自独立地是氢或-COGCOR1,
其中G是亚乙基,亚丙基,-CH=CH-,1,2-环己基或1,2-亚苯基,
R1=OH碱,NR2R3,OR3,SR3,OCH2CONR4R5,OH,
R2=氢,甲基,
R3=(CH2)nNR6R7,(CH2)nNR6R7R8X
n=1-3,
R4=氢,C1-4低级烷基,
R5=氢,C1-4低级烷基,苄基,羟乙基,CH2CO2H,二甲基氨基乙基,
R6,R7=甲基,乙基,苄基或R6和R7与NR6R7的氮原子一起形成如下环:
R8=甲基,乙基或苄基,
X=囱素
碱=NH3,(HOC2H4)3N,N(CH3)3,CH3N(C2H4OH)2,
NH2(CH2)6NH2,N-甲基葡糖胺,NaOH,KOH。
X1或X2是-COGCOR1的化合物的制备在Haugwitz的U.S.4942184中已说明,合并在这里作参考。
当X1是-OX6和X6是-COCX=CHX或-COX-CHX-CHX-SO2O-M,其中X是氢,烷基或芳基和M是氢,碱金属或铵时,溶解性可增加,如在Kingston等人的U.S.5059699中所述(合并于这里作参考)。
具有除酮基外的C-9位取代基的紫杉烷可通过10-DAB,浆果赤霉素III或者10-DAB或浆果赤霉素III的衍生物的C9酮基取代基的选择性还原得到相应的C-9位β-羟基衍生物来制备。还原剂优选硼氢化物,更可选的硼氢化四丁铵(Bu4NBH4)或三乙酰氧基硼氢化物。
正如反应流程1中阐明的,浆果赤霉素III与Bu4NBH4在二氯甲烷中反应,得到9-脱氧-9β-羟基浆果赤霉素III5。在C-7位羟基用三乙基甲硅烷基保护基保护后,例如,适宜的侧链可接到7-位保护的-9β-羟基衍生物6,如本文别处所述。除去剩余的保护基,得到具有C-13位侧链的9β-羟基-脱氧紫杉酚或其它9β-羟基四环紫杉烷。
或者,7-位保护的-9β-羟基衍生物6的C-13位羟基可用三甲基甲硅烷基或其它保护基保护,该保护基相对于C-7位羟基保护基可被选择性地除去,如在反应流程2中阐明的,因此,能够进一步的选择性控制紫杉烷的各种取代基。例如,7,13-保护的-9β-羟基衍生物7与KH反应,引起乙酰基从C-10位迁移到C-9位和羟基从C-9位迁移到C-10位,因此,得到10-位脱乙酰基衍生物8。10-位脱乙酰衍生物的C-10位羟基用三乙基甲硅烷基保护,得到衍生物9。从衍生物9选择性除去C-13位羟基保护基,得到可以如上述连接适宜侧链的衍生物10。
如反应流程3所示,10-脱乙酰基衍生物8经氧化可得到10-氧代衍生物11。然后,如上述,C-13位羟基保护基被选择性除去后,得到具有C-13位侧链的9-乙酰氧基-10-氧代-紫杉酚或其它9-乙酰氧基-10-氧代四环紫杉烷。用还原剂如二磺化钐还原10-氧化衍生物11,选择性除去C-9位乙酰基,得到9-脱氧-10-氧代衍生物12,C-13位羟基保护在选择性除去后,以上述方法连接侧连,可由衍生物12得到具有C-13位侧链的9-脱氧-10-氧代-紫杉酚或其它9-脱氧-10-氧代四环紫杉烷。
反应流程3
反应流程4说明10-DAB还原成五元醇13的反应。五元醇13的C-7位和C-10位羟基然后用三乙基甲硅烷基或其它保护基选择性保护得到三元醇14,该三元醇可按上述方法连接C-13位侧链,或者也可在进一步四环取代基修饰后再接C-13位侧链。
C-9位和/或C-10位有除乙酸根以外的酰氧基取代基的紫杉烷可以如反应流程5说明的用10-DAB作原料来制备。10-DAB与氯化三乙基甲硅烷在吡啶中反应,得到7-位保护的10-DAB 15。7-位保护的10-DAB 15的C-10位羟基然后用任何标准酰化剂很容易地酰化为具有新的C-10位酰氧取代基的衍生物16。衍生物16的C-9位酮取代基选择还原成9β-羟基衍生物17,然后,可连接C-13位侧链。或者也可如上面反应流程2阐述的那样,发生C-10位和C-9位基团的迁移。
反应流程5
具有C-2和/或C-4位酯的紫杉烷可以用浆果赤霉素III和10-DAB作原料制备。浆果赤霉素III和10-DAB的C-2位和/或C-4位酯,可用还原剂如LAH或Red-A1选择性还原为相应的醇,然后,新酯可用标准酰化剂如酸酐和酰氯与胺如吡啶,三乙胺,DMAP或二异丙基乙基胺结合进行取代。C-2位和/或C-4位醇也可以转化为新的C-2位和/或C-4位酯,方法是该醇用适宜的碱如LDA处理,形成相应的醇盐然后再用酰化剂如酰氯处理。
在C-2位和/或C-4位具有不同取代基的浆果赤霉素III和10-DAB类似物,可按反应流程6-10制备。为简化叙述,以10-DAB作为原料。不过,应该明白,浆果赤霉素III衍生物或类似物可用同样的反应系列产生(除C-10位羟基保护外),只是简单地用浆果赤霉素III作原料而代替10-DAB。
在C-10位和至少另外一个位置,例如C-1,C-2,C-7,C-4,C-9和C-13位,具有不同取代基的浆果赤霉素III和10-DAB类似物的衍生物,可通过这里所述的任何其它反应和本技术领域熟悉的其它任何反应来制备。
在反应流程6中,保护了的10-DAB 3用氢化铝锂转化为三元醇18。三元醇18然后用Cl2CO在吡啶中然后用亲核试剂(如格氏试剂或烷基锂试剂)转化为相应的C-4酯。
反应流程6
三元醇18用LDA脱保护,接着加入酰氯,选择性地得到C-4位酯。例如,当用乙酰氯时,三元醇18转化为1,2-二元醇4,如流程7所述。
三元醇18也可容易地转化为1,2-碳酸酯19。在强力的标准条件下,如反应流程8所述,碳酸酯19乙酰化为碳酸酯21。将烷基锂或格氏试剂加到碳酸酯19上,得到在C-4位有游离羟基的C-2位酯,如反应流程6所述。
如反应流程9所阐明的,通过碳酸酯19与酰氯和叔胺反应得到碳酸酯22,可以制备其它C-4位取代的化合物,然后与烷基锂或格氏试剂反应,得到在C-2位有新的取代基的10-DAB衍生物。
反应流程9
浆果赤霉素III也可用作原料进行反应,如反应流程10所述。在C-7和C-3位保护后,用LAH还原浆果赤霉素III得到1,2,4,10-四元醇24。四元醇24用Cl2CO和吡啶转化为碳酸酯25,碳酸酯25用酰氯和吡啶酰化C-10位,得到碳酸酯26(流程中所示),用乙酸酐和吡啶酰化也可以(未示出)。碳酸酯26在强力标准条件下乙酰化,得到碳酸酯27,该碳酸酯27然后与烷基锂反应,得到在C-2和C-10位有新取代基的浆果赤霉素III衍生物。
反应流程10
浆果赤霉素III的10-脱乙酰氧基衍生物和10-DAB的10-脱氧衍生物可通过浆果赤霉素III或10-DAB(或它们的衍生物)与二碘化钐反应制备。C-10位有离去基团的四环紫杉烷和二碘化钐之间的反应,可在溶剂如四氢呋喃中于0℃下进行。更有利地是,二碘化钐选择性地移去C-10位离去基团;,四环核的C-13位侧链和其它取代基不受影响。然后,如本文别外所述,C-9位酮取代基可被还原,得到相应的9-脱氧-9-羟基-10-脱乙酰氧基或10-脱氧衍生物。
C-7二氢和其它C-7取代的紫杉炕可以如反应流程11,12和12a所述的那样制备。
如反应流程12所示,浆果赤霉素III在THF溶液中于室温下用FAR处理,可转化为7-氟浆果赤霉素III。基它具有游离的C-7羟基的浆果赤霉素衍生物行为类似。7-氯浆果赤霉素III可通过在含过量三乙胺盐酸盐的二氯甲烷溶液中,用甲磺酰氯和三乙胺处理浆果赤霉素III来制备。
具有C-7位酰氧基取代基的紫杉烷可按反应流程12a阐述的方法制备,7,13-保护的10-氧代衍生物11可通过选择性除去C-13位保护基并用金属如锂代替,转化为其相应的C-13位醇盐。该醇盐然后与β-内酰胺或其它侧体前体化合物反应。接着,水解C-7位保护基,引起C-7位羟基取代基迁移到C-10位,而C-10位的氧代基迁移到C-9位和C-9位的酰氧基迁移到C-7位。
天然存在多种三环紫杉烷,而通过类似本文所述的处理,一个适当的侧链可连接到这些物质的C-13位氧上。或者,如反应流程13所示,7-o-三乙基甲硅烷基浆果赤霉素III在二氯甲烷溶液中与四氟硼酸三甲基反应,转化为三环紫杉烷。然后,产物二元醇与四乙酸铅反应,得到相应的C-4酮。
新近,一种羟基化紫杉烷(14-羟基-10-脱乙酰基浆果赤霉素III)已在紫杉针的提取物中发现(C&EN,P36-37,April 12,1993)。上述具有各种C-2位,C-4位等官能基的羟基化紫杉烷的衍生物也可用这种羟基化紫杉烷制备。另外,如C&EN所述,10-DAB的C-14位羟基与C-1位羟基一起可转化为1,2-碳酸酯,或如本文别处所述的它可就C-2,C-4,C-7,C-9,C-10和C-13取代基转化为各种各样的酯或,其它官能团。
下列实施例对本发明提供了更详细的说明。
3′-脱苯基-3′-(2-噻吩基)-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚的制备
向0.7ml THF中的7-O-三乙基甲硅烷基-10-脱乙酰氧基浆果赤霉素lll(47.5mg,0.073mmol)的溶液中,在-45℃下滴加0.08ml 0.98M LiN(SiMe3)2的己烷溶液。-45℃下0.5小时后,问此混合物中滴加在0.7ml THF中的顺-1-t-丁氧羰基-3-三乙基甲硅烷氧基-4-(2-噻吩基)-氮杂环丁烷-2-酮(70.0mg,0.182mmol)溶液。温热该溶液至0℃并保持此温度1小时,然后,加在THF中的1ml10%AcOH溶液。该混合物在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷之间分配。蒸发有机相所得残留物用硅胶过滤提纯,得到64.3mg含(2′R,3′S)-2′,7-双-O-三乙基甲硅烷基-3′-脱苯基-3′-(2-噻吩基)-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚和小量(2′S,3′R)异构体的混合物。
向64.3mg(0.056mmol)上述反应所得混合物与3.2ml乙腈和0.15ml吡啶的溶液中,在0℃下加0.50ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配反应产物。蒸发乙酸乙酯层,得到46.3mg物质,经快速色谱提纯,得到40.1mg(91%)3′-脱苯基-3′-(2-噻吩)-N-脱苯基甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚,再经甲醇/水重结晶。m.p.158-160℃;[α]25 Na -58.4°(c 0.0028,CHCl3) .1H NMR(CDCl3,300MHz)δ8.11(d,J=6.9Hz,2H,benzoateortho),7.61(m,1H,benzoate para),7.50(m,2H,benzoatemeta),7.27(dd,J=5.5,1.2Hz,1H,thienyl),7.06(d,J=3.3Hz,1H,thienyl),7.01(dd,J=5.7,3.9Hz,1H,thienyl),6.13(td,J=6.3,0.9Hz,1H,H13),5.70(d,J=6.9Hz,1H,H2),5.49(d,J=9.2Hz,1H,NH),5.34(d,J=9.9Hz,1H,H3′),4.62(dd,J=5.4 2.1Hz,1H,H5),4.30(d,J=8.1Hz,1H,H20α),4.29(s,1H,H2′),4.17(d,J=8.1Hz,1H,H20β),4.06(d,J=6.9Hz,1H,H7),3.81(d,J=15.3Hz,H10α),3.51(d,J=6.6Hz,1H,H3),3.41(m,1H,2′OH),2.61(m,1H,H6α),2.36(s,3H,4Ac),2.30(m,1H,H10β),2.17(br s,1H,7 OH),2.06(m,1H,H14α),1.81(m,1H,H14β),1.76(br s,3H,Me18),1.66(s,1H,1 OH),1.62(m,1H, H6β),1.35(s,9H,3Me t-buthoxy),1.25(s,3H,Me17),1.19(s,3H,Me19),1.17(s,3H,Me16).
3′-脱苯基-3′-(异丁烯基)-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚的制备
于-45℃下,向在0.8ml THF中的7-O-三乙基甲硅烷基-10-脱乙酰氧基浆果赤霉素lll(50.0mg,0.077mmol)溶液中,滴加0.09ml 0.98M LiN(SiMe3)2的己烷溶液。-45℃下0.5小时后,向此混合物中滴加在0.7ml THF中的顺-1-t-丁氧羰基-3-(2-甲氧基异丙氧基)-4-(异丁烯基)氮杂环丁烷-2-酮(58.0mg,0.193mmol)的溶液。温热此溶液至0℃并在此温下保持1小时,然后,加1ml 10%AcOH的THF溶液。反应混合物在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷间分配。蒸发有机层得到的残留物经硅胶过滤提纯,得到62.7mg含(2′R,3′S)-2′-O-(2-甲氧基异丙基)-7-O-三乙基甲硅烷基-3′-脱苯基-3′-(异丁烯基)-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚和小量(2′S,3′R)异构体的混合物。
于0℃下,向上述反应所得混合物62.7mg(0.059mmol)与3.5ml乙腈和0.16ml啶的溶液中,加0.55ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯层得到51.5mg物质,经快速色谱提纯得到43.0mg(95%)3′-脱苯基-3′-(异丁烯基)-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚,再经甲醇/水重结晶。m.p.153-155℃;[α]25 Na-56.3°(c 0.003,CHCl3).1H NMR(CDCl3,300MHz)δ8.10(d,J=7.3Hz,2H,benzoateortho),7.60(m,1H,benzoate para),7.47(m,2H,benzoatemeta),6.15(td,J=8.5,1.8Hz,1H,H13),5.69(d,J=6.9Hz,1H,H2),5.32(d,J=9.2Hz,1H,NH),4.93(dd,J=9.6,1.8Hz,1H,H5),4.82(d,J=8.7Hz,1H,Me2C=C
H-),4.76(td,J=8.7,2.7Hz,1H,H3′),4.37(d,J=8.7Hz,1H,H20α),4.22(d,J=8.7Hz,1H,H20β),4.18(d,J=2.7Hz,1H,H2′),4.03(d,J=7.3Hz,1H,H7),3.82(d,J=15.2Hz,1H,H10α),3.47(m,1H,2′OH),3.41(d,J=6.6Hz,1H,H3),2.60(m,1H,H6α),2.39(m,1H,H10β),2.37(s,3H,4Ac),2.18(s,1H,7OH),2.08(m,1H,H14α),1.78(m,1H,H14β),1.76(s,3H,Me18),1.74(s,6H,2Me from isobuthenyl),1.63(m,1H,H6β),1.36(s,9H,3Me t-buthoxy)1.26(s,3H,Me17),1.18(s,3H,Me19),1.15(s,3H,Me16).
N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰
氧基紫杉酚的制备
于45℃下,向在0.8ml THF中的7-O-三乙基甲硅烷基-10-脱乙酰氧基浆果赤霉素lll(50.0mg,0.077mmol)溶液,滴加0.09ml 0.98M LiN(SiMe3)2的己烷溶液。-45℃下0.5小时后,向此混合物中滴加在0.8ml THF中的顺-1-t-丁氧羰基-3-三乙基甲硅烷氧基-4-苯基氮杂环丁烷-2-酮(67.5mg,0.193mmol)溶液。温热该溶液至0℃并在此温下保持1小时,然后,加1ml 10%AcOH的THF溶液。此混合物在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷间分配。蒸发有机层所得的残留物经硅胶过滤提纯,得到72.0mg含(2′R,3′S)-2′7-双-O-三乙基甲硅烷基-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向在3.8ml乙腈和0.17ml吡啶中的上述反应所得混合物(72.0mg,0.071mmol)的溶液中,加0.60ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得57.4mg物质,经快速色谱提纯得39.4mg(71%)N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚,再经甲醇/水重结晶。
m.p.145-147℃;[α]25 Na-54.4°(c 0.0027,CHCl3).1H NMR(CDCl3,300MHz)δ8.11(d,J=7.1Hz,2H,benzoateortho),7.61-7.23(m,8H,benzoate,phenyl),6.13(td,J=6.3,0.9Hz,1H,H13),5.68(d,J=6.9Hz,1H,H2),5.43(d,J=9.2Hz,1H,NH),5.26(d,J=9.9Hz,1H,H3′),4.96(dd,J=5.42.1Hz,1H,H5),4.31(d,J=8.1Hz,1H,H20α),4.22(s,1H,H2′),4.18(d,J=8.1Hz,1H,H20β),4.03(d,J=6.9Hz,1H,H7),3.81(d,J=15.1Hz,H10α),3.43(m,1H,2′OH),3.40(d,J=6.6Hz,1H,H3),2.60(m,1H,H6α),2.38(s,3H,4Ac),2.32(m,1H,H10β),2.15(br s,1H,7 OH),2.09(m,1H,H14α),1.83(m,1H,H14β),1.78(br s,3H,Me18),1.66(s,1H,1 OH),1.63(m,1H,H6β),1.36(s,9H,3Me t-butoxy),1.25(s,3H,Me17),1.18(s,3H,Me19),1.16(s,3H,Me16).
实施例4
3′-脱苯基-3′-(2-呋喃基)-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚的制备
于-45℃下,向在0.8ml THF中的7-O-三乙基甲硅烷基-10-脱乙酰氧基浆果赤霉素lll(50.0mg,0.077mmol)溶液中,滴加0.09ml 0.98M LiN(SiMe3)2的己烷溶液。-45℃,0.5小时后,向此混合物中滴加,在0.8ml THF中的顺-1-t-丁氧羰基-3-三乙基甲硅烷氧基-4-(2-呋喃基)氮杂环丁烷-2-酮(72.8mg,0.195mmol)溶液,温热此溶液至0℃并保持此温度1小时,然后,加1ml 10%AcOH的THF溶液。在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷间分配此混合物。蒸发有机层所得残留物经硅胶过滤提纯,得到69.4mg含(2′R,3′S)-2′,7-双-O-三乙基甲硅烷基-3′-脱苯基-3′-(2-呋喃基)-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向在3.8ml乙腈和0.17ml吡啶中的(69.4mg,0.068mmol)上述反应所得混合物的溶液中,加0.60ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得59.0mg物质经快速色谱提纯得41.0mg(76%)3′-脱苯基-3′-(2-呋喃基)-N-脱苯甲酰基-N-(t-丁氧羰基)-10-脱乙酰氧基紫杉酚,再经甲醇/水重结晶。m.p.151-153℃;[α]25 Na-56.5°(c 0.0025,CHCl3).1H NMR(CDCl3,300MHz)δ8.11(d,J=7.3Hz,2H,benzoateortho),7.60(m,1H,benzoate para),7.49(m,2H,benzoatemeta),7.41(m,1H,furyl),6.37(m,1H,furyl),6.34(m,1H,furyl),6.13(dd,J=6.3,0.9Hz,1H,H13),5.69(d,J=6.6Hz,1H,H2),5.49(d,J=9.2Hz,1H,NH),5.34(d,J=9.9Hz,1H,H3′),4.62(dd,J=5.4,2.1Hz,1H,H5),4.30(d,J=8.1Hz,1H,H20α),4.29(s,1H,H2′),4.17(d,J=8.1Hz,1H,H20β),4.06(d,J=6.9,1H,H7),3.81(d,J=15.3Hz,1H,H10α),3.51(d,J=6.6Hz,1H,H3),3.41(m,1H,2′OH),2.61(m,1H,H6α),2.36(s,3H,4Ac),2.32(m,2H,H14α),2.28(m,1H,H10β),2.17(br s,1H,7 OH),2.14(m,1H,H14α),1.82(m,1H,H14β),1.76(br s,3H,Me18),1.66(s,1H,1 OH),1.62(m,1H,H6β),1.35(s,9H,3Me t-butoxy),1.25(s,3H,Me17),1.19(s,3H,Me19),1.16(s,3H,Me16).
实施例5
3′-脱苯基-3′-(2-噻吩基)-N-脱苯甲酰基-N-(t-丁氧羰基)-9-脱氧-10-脱乙酰氧基-10-酮紫杉酚的制备
于-45℃下,向在0.5ml THF中的7-O-三乙基甲硅烷基-9-脱氧-10-脱乙酰氧基-10-酮浆果赤霉素lll(25.0mg,0.039mmol)溶液中,滴加0.05ml 0.98M LiN(SiMe3)2的己烷溶液。-45℃,0.5小时后,向此混合物中滴加在0.5ml THF中的顺-1-t-丁氧羰基-3-三乙基甲硅烷氧基-4-(2-噻吩基)氮杂环丁烷-2-酮(45.0mg,0.117mmol)溶液,温热此溶液至0℃并保持此温度1小时,然后,加1ml 10%AcOH的THF溶液。此混合物在饱和NaHCO3和60/40乙酸乙酯/己烷间分配。蒸发有机层所得残留物经硅胶过滤提纯,得到36.2mg含(2′R,3′S)-2′,7-双-O-三乙基甲硅烷基-3′-脱苯基-3′-(2-噻吩基)-N-脱苯甲酰基-N-(t-丁氧羰基)-9-脱氧-10-脱乙酰氧基-10-酮紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向在3.0ml乙腈和0.15ml吡啶中的36.2mg(0.035mmol)上述反应所得混合物的溶液中,加0.45ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得29.4mg物质,经快速色谱提纯,得24.3mg(87%)3′-脱苯基-3′-(2-噻吩基)-N-脱苯甲酰基-N-(t-丁氧羰基)-9-脱氧-10-脱乙酰氧基-10-酮紫杉酚,再经甲醇/水重结晶。m.p.163-169℃;[α]25 Na-54.2°(c 0.0023,CHCl3).1H NMR(CDCl3,300MHz)δ8.12(d,J=7.3Hz,2H,benzoateortho),7.64(m,1H,benzoate para),7.51(m,2H,benzoatemeta),7.26(m,1H,thienyl),7.10(d,J=3.4Hz,1H,thienyl),6.99(dd,J=5.1,3.4Hz,1H,thienyl),6.12(td,J=6.1,1.0Hz,1H,H13),5.95(d,J=5.9Hz,1H,H2),5.50(d,J=4.4Hz,1H,NH),5.42(d,J=9.8Hz,1H,H3′),4.94(d,J=8.3Hz,1H,H5),4.64(dd,J=4.2,2.0Hz,1H,2′),4.33(d,J=7.8Hz,1H,H20α),4.18(d,J=7.8Hz,1H,H20β),3.90(br s,1H,2′OH),3.73(m,1H,H7),3.11(d,J=15.8Hz,H9α),3.09(d,J=5.1Hz,1H,H3),2.90(d,J=15.6Hz,1H,H9β),2.54(m,1H,H6α),2.45(m,1H,H14β),2.31(s,3H,4Ac),2.28(m,1H,H14α),2.01(br s,1H,7OH),1.88(s,1H,1 OH),1.83(m,1H,H6β),1.69(s,3H,Me18),1.56(s,3H,Me16),1.46(s,3H,Me19),1.40(s,9H,3Me t-buthoxy),1.29(s,3H,Me17) .
于-45℃下,向在0.5ml THF中的7-O-三乙基甲硅烷基-9-脱氧-10-脱乙酰氧基-10-酮浆果赤霉素lll(30.0mg,0.047mmol)溶液中,滴加0.5ml 0.98M LiN(SiMe3)2的己烷溶液。-45℃,0.5小时后,将在0.5ml THF中的顺-1-t-丁氧羰基-3-(-2甲氧基异丙氧基)-4-(异丁烯基)氮杂环丁烷-2-酮(44.1mg,0.141mmol)溶液,滴加入该混合物。温热此溶液至0℃并保持此温度1小时,然后,加1ml 10%AcOH的THF溶液。此混合物在饱和NaHCO3和60/40乙酸乙酯/己烷间分配。蒸发有机层所得残留物经硅胶过滤提纯,得到40.8mg含(2′R,3′S)-O-(2-甲氧基异丙基)-7-O-三乙基甲硅烷基-3′-脱苯基-3′-(异丁烯基)-N-脱苯甲酰基-N-(t-丁氧羰基)-9-脱氧-10-脱乙酰氧基-10-酮紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向在4ml乙腈和0.2ml吡啶中的40.8mg(0.043mmol)上述反应所得混合物的溶液中,加0.5ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得34.4mg物质,经快速色谱提纯,得23.0mg(70%)3′-脱苯基-3′-(异丁烯基)-N-脱苯甲酰基-N-(t-丁氧羰基)-9-脱氧-10-脱乙酰氧基-10-酮紫杉酚,再经甲醇/水重结晶。m.p.149-153℃;[α]25 Na-56.3°(c 0.0025,CHCl3).1H NMR(CDCl3,300MHz)δ8.12(d,J=7.2Hz,2H,benzoateortho),7.64(m,1H,benzoate para),7.51(m,2H,benzoatemeta),6.12(t,J=7.5Hz,1H,H13),5.95(d,J=6.2Hz,1H,H2),5.30(d,J=8.9Hz,1H,NH),4.94(d,J=8.2Hz,1H,H5),4.88(d,J=8.9Hz,1H,Me2C=C
H-),4.79(td,J=8.9,2.4Hz,1H,H3′),4.34(d,J=8.2Hz,1H,H20α),4.27(dd,J=5.5,2.7Hz,1H,H2),4.19(d,J=8.2Hz,1H,H20β),3.73(m,1H,H7),3.67(br s,1H,2′OH),3.13(d,J=5.1Hz,1H,H3),3.12(d,J=15.7Hz,1H,H9α),2.90(d,J=15.7Hz,1H,H9β),2.55(m,1H,H6α),2.47(m,1H,H14β),2.32(s,3H,4Ac),2.28(m,1H,H14α),2.04(br s,1H,7 OH),1.88(s,1H,1 OH),1.82(m,1H,H6β),1.79(s,3H,Me18),1.76(s,6H,2Me from isobuthenyl),1.57(s,3H,Me16),1.47(s,3H,Me19),1.40(s,9H,3Me t-buthoxy)1.30(s,3H,Me17).
N-(脱苯甲酰基)-N-(t-丁氧羰基)-9-脱氧-10-脱乙酰氧基-10-酮紫杉酚的制备
于-45℃下,向在0.5ml THF中的7-O-三乙基甲硅烷基-10-脱乙酰氧基-10-酮浆果赤霉素lll(30.0mg,0.047mmol)溶液中,滴加0.05ml 0.98M LiN(SiMe3)2的己烷溶液。-45℃,0.5小时后,向此混合物中滴加在0.5ml THF中的顺-1-t-丁氧羰基-3-三乙基甲硅烷氧基-4-苯基氮杂环丁烷-2-酮(53.1mg,0.14mmol)溶液。温热此溶液至0℃并保持此温度1小时,然后,加1ml 10%AcOH的THF溶液。在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷间分配此混合物。蒸发有机层所得残留物经硅胶过滤提纯,得到43.7mg含(2′R,3′S)-2′7-双-O-三乙基甲硅烷基-N-脱苯甲酰基-N-(t-丁氧羰基)-9-脱氧-10-脱乙酰氧基-10-酮紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向下4.0ml乙腈和0.20ml吡啶中的43.7mg(0.042mmol)上述反应所得混合物的溶液中,加0.5ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得33.2mg物质经快速色谱提纯,得24.1mg(73%)-N-脱苯甲酰基-N-(t-丁氧羰基)-9-脱氧-10-脱乙酰氧基-10-酮紫杉酚,再经甲醇/水重结晶。m.p.162-165℃;[α]25 Na-58.7°(c 0.0025,CHCl3).1H NMR(CDCl3,300MHz)δ8.11(d,J=7.1Hz,2H,benzoateortho),7.63(m,1H,benzoate para),7.50(m,2H,benzoatemeta),7.40-7.29(m,5H,benzoate,phenyl),6.11(td,J=7.8,1.0Hz,1H,H13),5.94(d,J=6.4Hz,1H,H2),5.52(d,J=9.8Hz,1H,H3′),5.27(d,J=9.3Hz,1H,NH),4.93(dd,J=8.8Hz,1H,H5),4.64(br s,1H,H2′),4.32(d,J=8.3Hz,1H,H20α),4.18(d,J=8.3Hz,1H,H20β),3.88(brs,1H,2′OH),3.71(m,1H,H7),3.11(d,J=5.1Hz,1H,H3),3.10(d,J=15.7Hz,H9α),2.88(d,J=16.1,1H,H9β),2.54(m,1H,H6α),2.44(m,1H,H14β),2.29(s,3H,4Ac),2.26(m,1H,H14α),2.02(br s,1H,7 OH),1.88(s,1H,1 OH),1.80(m,1H,H6β),1.65(s,3H,Me18),1.55(s,3H,Me16),1.46(s,3H,Me19),1.35(s,9H,3Me t-butoxy),1.29(s,3H,Me17).
3′-脱苯基-3′-(异丙烯基)-N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基紫杉酚的制备
于-45℃下,向在0.7ml THF中的7-脱羟基-10-脱乙酰氧基浆果赤霉素lll(28.7mg,0.051mmol)溶液中,滴加0.09ml0.98M LiN(SiMe3)2的己烷溶液。-45℃,0.5小时后,向此混合物中滴加在0.7ml THF中的顺-1-t-丁氧羰基-3-(2-甲氧基异丙氧基)-4-(异丁烯基)氮杂环丁烷-2-酮(47.3mg,0.15mmol)溶液,温热此溶液至0℃并保持此温度1小时,然后,加1ml10%AcOH的THF溶液。此混合物在饱和NaHCO3和60/40乙酸乙酯/己烷间分配。蒸发有机层所得残留物经硅胶过滤提纯,得到40.3mg含(2′R,3′S)-2′-O-(2-甲氧异丙基)基-3′-(异丁烯基)-N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向在3.2ml乙腈和0.15ml吡啶中的40.3mg(0.046mmol)上述反应所得混合物的溶液中,加0.47ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得35.2mg物质,经快速色谱提纯,得24.0mg(70%)3′-脱苯基-3′-(异丁烯基)-N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚,再经甲醇/水重结晶。
m.p.122-125℃;[α]25 Na-64.3°(c 0.0025,CHCl3).1H NMR(CDCl3,300MHz)δ8.12(d,J=7.1Hz,2H,benzoateortho),7.60(m,1H,benzoate para),7.48(m,2H,benzoatemeta),6.11(td,J=8.1,1.8Hz,1H,H13),5.68(d,J=6.9Hz,1H,H2),5.23(d,J=9.9Hz,1H,NH),5.12(d,J=9.9Hz,1H,H3′),4.96(dd,J=9.1,2.7Hz,1H,H5),4.80(d,J=8.7Hz,1H,Me2C=C
H-),4.58(dd,J=5.7,2.1Hz,1H,H2′),4.30(d,J=8.1,1H,H20α),4.19(d,J=8.1Hz,1H,H20β),3.97(d,J=6.9Hz,H3),3.83(d,J=16.5,1H,H10α),3.33(m,1H,H10β),3.30(m,1H,2′OH),2.39(m,1H,H14α),2.35(s,3H,4Ac),2.26(m,1H,H14β),2.19(m,1H,H6α),2.10(m,1H,H7α),1.95(m,1H,H6β),1.73(s,3H,Me18),1.69(s,6H,2Me from isobuthenyl),1.63(s,3H,Me19),1.44(m,1H,H7β),1.39(br.s,1H,1 OH),1.35(s,9H,3Me t-buthoxy),1.25(s,3H,Me16),1.15(s,3H,Me17) .
于-45℃下,向在0.7ml THF中的7-脱羟基-10-脱乙酰氧基浆果赤霉素lll(25.0mg,0.044mmol)溶液中,滴加0.05ml0.98M LiN(SiMe3)2的己烷溶液。-45℃,0.5小时后,向此混合物中滴加,在0.7ml THF中的顺-1-t-丁氧羰基-3-三乙氧基用硅烷氧基-4-(2-噻吩基)氮杂环丁烷-2-酮(50.0mg,0.13mmol)溶液。温热此溶液至0℃并保持此温度1小时,然后,加1ml10%AcOH的THF溶液。此混合物在饱和NaHCO3和60/40乙酸乙酯/己烷间分配。蒸发有机层所得残留物经硅胶过滤提纯,得到35.4mg含(2′R,3′S)-2′-O-三乙基甲硅烷基-3′-脱苯基-3′-(2-噻吩基)-N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向在3.2ml乙腈和0.15ml吡啶中的35.4mg(0.037mmol)上述反应所得混合物的溶液中,加0.47ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得32.4mg物质,经快速色谱提纯,得20.5mg(71%)3′-脱苯基-3′-(2-噻吩基)-N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚,再经甲醇/水重结晶。m.p.132-134℃;[α]25 Na-61.3°(c 0.0025,CHCl3).1H NMR(CDCl3,300MHz)δ8.14(d,J=7.1Hz,2H,benzoateortho),7.61(m,1H,benzoate para),7.51(m,2H,benzoatemeta),7.29(dd,J=5.4,1.2Hz,1H,thienyl),7.09(d,J=3.3Hz,1H,thienyl),7.01(dd,J=5.4,3.3Hz,1H,thienyl),6.14(td,J=8.4,1.8Hz,1H,H13),5.69(d,J=6.9Hz,1H,H2),5.24(d,J=9.9Hz,1H,NH),5.19(d,J=9.9Hz,1H,H3′),4.93(dd,J=9.3,2.7Hz,1H,H5),4.62(dd,J=5.7,2.1Hz,1H,H2′),4.31(d,J=8.1,1H,H20α),4.21(d,J=8.1Hz,1H,H20β),3.98(d,J=6.9Hz,H3),3.84(d,J=16.5,1H,H10α),3.38(m,1H,H10β),3.33(m,1H,2′OH),2.40(m,1H,H14α),2.37(s,3H,4Ac),2.27(m,1H,H14β),2.20(m,1H,H6α),2.11(m,1H,H7α),1.95(m,1H,H6β),1.74(s,3H,Me18),1.71(s,3H,Me19),1.46(m,1H,H7β),1.40(br.s,1H,1 OH),1.34(s,9H,3Me t-buthoxy),1.24(s,3H,Me16),1.13(s,3H,Me17).
3′-脱苯基-3′-(2-呋喃基)-N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚的制备
于-45℃下,向在0.8ml THF中的7-脱羟基-10-脱乙酰氧基浆果赤霉素lll(35.0mg,0.061mmol)溶液中,滴加0.07ml0.98M LiN(SiMe3)2的己烷溶液。-45℃,0.5小时后,向此混合物中滴加在0.7ml THF中的顺-1-t-丁氧羰基-3-三乙基甲硅氧基-4-(2-呋喃基)氮杂环丁烷-2-酮(68.0mg,0.18mmol)溶液。温热此溶液至0℃并保持此温度1小时,然后,加1ml10%AcOH的THF溶液。此混合物在饱和NaHCO3和60/40乙酸乙酯/己烷间分配。蒸发有机层所得残留物经硅胶过滤提纯,得到56.3mg含(2′R,3′S)-2′-O-三乙基甲硅烷基-3′-脱苯基-3′-(2-呋喃基)-N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱氧羟基-10-脱酰氧基紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向在4.6ml乙腈和0.22ml吡啶中的56.3mg(0.06mmol)上述反应所得混合物的溶液中,加0.68ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得48.3mg物质经快速色谱提纯,得31.7mg(69%)3′-脱苯基-3′-(2-呋喃基)-N-苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚,再经甲醇/水重结晶。m.p.128-131℃;[α]25 Na-66.9°(c 0.0028,CHCl3).1H NMR(CDCl3,300MHz)δ8.13(d,J=6.9Hz,2H,benzoateortho),7.60(m,1H,benzoate para),7.48(m,2H,benzoatemeta),7.40(m,1H,furyl),6.38(m,1H,furyl),6.32(m,1H,furyl),6.12(td,J=8.1,1.8Hz,1H,H13),5.67(d,J=6.9Hz,1H,H2),5.22(d,J=9.9Hz,1H,NH),5.17(d,J=9.9Hz,1H,H3′),4.91(dd,J=9.1,2.7Hz,1H,H5),4.60(dd,J=5.7,2.1Hz,1H,H2′),4.28(d,J=8.1,1H,H20α),4.21(d,J=8.1Hz,1H,H20β),3.95(d,J=6.9Hz,H3),3.82(d,J=16.5,1H,H10α),3.33(m,1H,H10β),3.31(m,1H,2′OH),2.38(m,1H,H14α),2.35(s,3H,4Ac),2.23(m,1H,H14β),2.20(m,1H,H6α),2.11(m,1H,H7α),1.94(m,1H,H6β),1.73(s,3H,Me18),1.71(s,3H,Me19),1.43(m,1H,H7β),1.38(br.s,1H,1 OH),1.32(s,9H,3Me t-buthoxy),1.23(s,3H,Me16),1.12(s,3H,Me17)。
(72-4)
N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚的制备
于-45℃下,向在0.7ml THF中的7-脱羟基-10-脱乙酰氧基浆果赤霉素lll(28.0mg,0.049mmol)溶液中,滴加0.06ml0.98M LiN(SiMe3)2的己烷溶液。-45℃,0.5小时后,向此混合物中滴加,在0.7ml THF中的顺-1-t-丁氧羰基-3-三乙基甲硅烷氧基-4-(苯基)氮杂环丁烷-2-酮(56mg,0.15mmol)溶液,温热此溶液至0℃并保持此温度1小时,然后,加1ml 10%AcOH的THF溶液。在饱和NaHCO3水溶液和60/40乙酸乙酯/己烷间分酚此混合物。蒸发有机层所得残留物经硅胶过滤提纯,得到38.4mg含(2′R,3′S)-2′-O-三乙基甲硅烷基-N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚和小量(2′S,3′R)异构体的混合物。
在0℃下,向在3.2ml乙腈和0.15ml吡啶中的(38.4mg,0.041mmol)上述反应所得混合物的溶液中,加0.46ml 48%HF水溶液。于0℃下搅拌此混合物3小时,然后,于25℃下搅拌13小时,在饱和NaHCO3水溶液和乙酸乙酯间分配。蒸发乙酸乙酯溶液得33.8mg物质经快速色谱提纯得27.4mg(71%)N-脱苯甲酰基-N-(t-丁氧羰基)-7-脱羟基-10-脱乙酰氧基紫杉酚,再经甲醇/水重结晶。m.p.135-138℃;[α]25 Na-65.2°(c 0.0025,CHCl3).1H NMR(CDCl3,300MHz)δ8.12(d,J=7.1Hz,2H,benzoateortho),7.60(m,1H,benzoate para),7.51(m,2H,benzoatemeta),7.42-7.29(m,5H,phenyl),6.12(td,J=8.1,1.8Hz,1H,H13),5.66(d,J=6.9Hz,1H,H2),5.21(d,J=9.9Hz,1H,NH),5.16(d,J=9.9Hz,1H,H3′),4.92(dd,J=9.1,2.7Hz,1H,H5),4.58(dd,J=5.7,2.1Hz,1H,H2′),4.30(d,J=8.1,1H,H20α),4.21(d,J=8.1Hz,1H,H20β),3.97(d,J=6.9Hz,H3),3.82(d,J=16.5,1H,H10α),3.41(m,1H,H10β),3.36(m,1H,2′OH),2.40(m,1H,H14α),2.38(s,3H,4Ac),2.26(m,1H,H14β),2.20(m,1H,H6α),2.13(m,1H,H7α),1.93(m,1H,H6β),.73(s,3H,Me18),1.70(s,3H,Me19),1.43(m,1H,H7β),1.38(br. s,1H,1 OH),1.32(s,9H,3Me t-buthoxy),1.25(s,3H,Me16),1.15(s,3H,Me17) .
实施例12
在试管中评价实施例1-11的紫杉烷68-3,68-4,69-1,69-2,75-1,74-4,74-3,72-1,72-2,72-3和72-4对人结肠癌细胞HCT-116的细胞毒性活性。对HCT-116细胞的细胞毒性以XTT(2,3-双(2-甲氧基-4-硝基-5-磺苯基)-5-[(苯氨基)羰基]-2H-四唑鎓氢氧化物)检验(Scudiero等人“Evaluationof a soluble tetrazolium/formazan assay for cell growth and drugsensitivity in culture using human and other tumor cell lines”,Cancer Res.48;4827-4833,1988)。以4000细胞/孔将细胞涂于96孔微滴板中,24小时后加药剂并连续稀释。于37℃下培养细胞72小时,并在此期间加四唑鎓染料,XTT。活细胞中的脱氢酶还原XTT为在450nm处吸收光的形式,并可以分光光度法测定。吸收值越大活细胞数越大。IC50表示的结果是抑制细胞增殖(即在450nm处的吸收)到未处理对照细胞的50%所需的药剂浓度。
所有化合物的IC50小于0.1表明它们都具有细胞毒性活性。
Claims (10)
X1是-OX6,-SX7或-NX8X9;
X2是氢,烷基,链烯基,炔基,芳基或杂芳基;
X3和X4各自独立地是氢,烷基,链烯基,炔基,芳基或杂芳基;
X5是-COX10,-COOX10,-COSX10,-CONX8X10或-SO2X11;
X6是氢,烷基,链烯基,炔基,芳基,杂芳基,羟基保护基或增加紫杉烷衍生物水溶性的官能团;
X7是烷基,链烯基,炔基,芳基,杂芳基或巯基保护基;
X8是氢,烷基,链烯基,炔基,芳基,杂芳基或者杂取代的烷基,链烯基,炔基,芳基或杂芳基;
X9是氨基保护基;
X10是烷基,链烯基,炔基,芳基,杂芳基或者杂取代的烷基,链烯基,炔基,芳基或杂芳基;
X11是炕基,链烯基,炔基,芳基,杂芳基,-OX10或-NX8X14;
X14是氢,烷基,链烯基,炔基,芳基或杂芳基;
R1是氢,羟基,保护了的羟基或与R14一起形成碳酸酯;
R2是氢,羟基,-OCOR31或与R2a一起形成氧代基;
R2a是氢或与R2一起形成氧代基;
R4是氢,与R4a一起形成氧代基,环氧乙烷或亚甲基,或者与R5a和连接它们的碳原子一起形成氧杂环丁烷环;
R4a是氢,烷基,链烯基,炔基,芳基,杂芳基,氰基,羟基,-OCOR30,或与R4一起形成氧代基,环氧乙烷或亚甲基;
R5是氢或与R5a一起形成氧代基;
R5a是氢,羟基,保护了的羟基,酰氧基,与R5一起形成氧代基,或与R4和连接它们的碳原子一起形成氧杂环丁烷环;
R6是氢,炕基,链烯基,炔基,芳基或杂芳基,羟基,保护了的羟基或与R6a一起形成氧代基;
R6a是氧,烷基,链烯基,炔基,芳基或杂芳基,羟基,保护了的羟基或与R6一起形成氧代基;
R7是氢或与R7a一起形成氧代基;
R7a是氢,囟素,保护了的羟基,-OR28,或与R7一起形成氧代基;
R9是氢或与R9a一起形成氧代基;
R9a是氢,羟基,保护了的羟基,酰氧基,或与R9一起形成氧代基;
R10是氢或与R10a一起形成氧代基;
R10a是氢或与R10一起形成氧代;
R14是氢,烷基,链烯基,炔基,芳基或杂芳基,羟基,保护了的羟基或与R1一起形成碳酸酯;
R14a是氢,烷基,链烯基,炔基,芳基或杂芳基;
R28是氢,酰基,羟基保护基或增加紫杉烷衍生物的溶解性的官能基团;和
R29,R30和R31各自独立地是氢,烷基,链烯基,炔基,单环芳基或单环杂芳基。
2.权利要求1的紫杉烷衍生物,其中R10和R10a为氢。
3.权利要求1的紫杉烷衍生物,其中R10和R10a一起为氧代基。
4.权利要求1的紫杉烷衍生物,其中R9a为羟基。
5.权利要求1的紫杉烷衍生物,其中R9a为乙酰氧基。
6.权利要求1的紫杉烷衍生物,其中R14和R14a为氢,R10和R10a为氢,R9a为氢,羟基或与R9一起形成氧代基,R7为氢,R7a为羟基,R5为氢,R5a和R4及连接它们的碳原子一起形成氧杂环丁烷环,R4a为乙酰氧基,R2a为氢,R2为苯甲酰氧基,R1为羟基,X1为-OH,X2为氢,X3为苯基,X4为氢,X5为-COX10,X10为苯基或t-丁氧基,该紫杉烷为(2′R,3′S)构型。
7.权利要求1的紫杉烷衍生物,其中R14和R14a为氢,R10和R10a为氢,R9a为氢,羟基或与R9一起形成氧代基,R7为氢,R7a为羟基,R5为氢,R5a和R4及连接它们的碳原子一起形成氧杂环丁烷环,R4a为乙酰氧基,R1为羟基,X1为-OH,X2为氢,X3为烷基或链烯基,X4为氢,X5为-COX10,X10为苯基,叔-、异-或正-丁氧基,乙氧基,异-或正丙氧基,环己氧基,烯丙氧基,丁烯氧基,1,3-二乙氧基-2-丙氧基,2-甲氧乙氧基,戊氧基,新戊氧基,PhCH2O-,-NPh2,-NHnPr,-NHPh,和-NHEt。
8.权利要求1的紫杉烷衍生物,其中R14和R14a为氢,R10和R10a一起形成氧代基,R9a为氢,羟基或与R9一起形成氧代基,R7为氢,R7a为羟基,R5为氢,R5a和R4及连接它们的碳原子一起形成氧杂环丁烷环,R4a为乙酰氧基,R2a为氢,R2为苯甲酰氧基,R1为羟基,X1为-OH,X2为氢,X3为苯基,X4为氢,X5为-COX10,X10为苯基或t-丁氧基,该紫杉烷为(2′R,3′S)构型。
9.权利要求1的紫杉烷衍生物,其中R14和R14a为氢,R10和R10a一起形成氧代基,R9a为氢,羟基或与R9一起形成氧代基,R7为氢,R7a为羟基,R5为氢,R5a和R4及连接它们的碳原子一起形成氧杂环丁烷环,R4a为乙酰氧基,R1为羟基,X1为-OH,X2为氢,X3为烷基或链烯基,X4为氢,X5为-COX10,X10为苯基,叔-、异-或正-丁氧基,乙氧基,异-或正-丙氧基,环己基氧基,烯丙氧基,丁烯氧基,1,3-二乙氧基-2-丙氧基,2-甲氧乙氧基,戊氧基,新戊氧基,PhCH2O-,-NPh2,-NHnPr,-NHPh,和-NHEt。
10.一种药物组合物,含有权利要求1的紫杉烷衍生物和一种或多种药学上可接受的,惰性的或生理活性的稀释剂或佐剂。
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US005229 | 1993-01-15 | ||
US005,229 | 1993-01-15 | ||
US08/005,229 US5338872A (en) | 1993-01-15 | 1993-01-15 | Process for the preparation of 10-desacetoxybaccatin III and 10-desacetoxytaxol and derivatives thereof |
US3485293A | 1993-03-22 | 1993-03-22 | |
US034852 | 1993-03-22 | ||
US034,852 | 1993-03-22 | ||
US9454593A | 1993-07-20 | 1993-07-20 | |
US094545 | 1993-07-20 | ||
US094,545 | 1993-07-20 |
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CN1100770C (zh) * | 1995-09-12 | 2003-02-05 | 利普索姆公司 | 促进水解的紫杉烷疏水性衍生物 |
CN103025739A (zh) * | 2010-06-30 | 2013-04-03 | 真塔公司 | 替司他赛和相关化合物以及对应合成中间体的制备 |
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US5710287A (en) | 1991-09-23 | 1998-01-20 | Florida State University | Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them |
US5440056A (en) * | 1992-04-17 | 1995-08-08 | Abbott Laboratories | 9-deoxotaxane compounds |
CA2153903C (en) * | 1993-01-15 | 2004-11-02 | Robert A. Holton | Process for the preparation of 10-desacetoxybaccatin iii |
IL108443A0 (en) * | 1993-01-29 | 1994-04-12 | Univ Florida State | C7 taxane derivatives and pharmaceutical compositions containing them |
US5677470A (en) * | 1994-06-28 | 1997-10-14 | Tanabe Seiyaku Co., Ltd. | Baccatin derivatives and processes for preparing the same |
CA2162759A1 (en) * | 1994-11-17 | 1996-05-18 | Kenji Tsujihara | Baccatin derivatives and processes for preparing the same |
US5773464A (en) * | 1996-09-30 | 1998-06-30 | Bristol-Myers Squibb Company | C-10 epoxy taxanes |
CA2410632A1 (en) | 2000-06-22 | 2001-12-27 | David S. Garvey | Nitrosated and nitrosylated taxanes, compositions and methods of use |
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US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
US5250683A (en) * | 1991-09-23 | 1993-10-05 | Florida State University | Certain substituted taxanes and pharmaceutical compositions containing them |
US5243045A (en) * | 1991-09-23 | 1993-09-07 | Florida State University | Certain alkoxy substituted taxanes and pharmaceutical compositions containing them |
US5200534A (en) * | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
US5248796A (en) * | 1992-06-18 | 1993-09-28 | Bristol-Myers Squibb Company | Taxol derivatives |
CA2109861C (en) * | 1992-12-04 | 1999-03-16 | Shu-Hui Chen | 6,7-modified paclitaxels |
FR2707293A1 (fr) * | 1993-07-08 | 1995-01-13 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur préparation et les compositions pharmaceutiques qui les contiennent. |
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CN1100770C (zh) * | 1995-09-12 | 2003-02-05 | 利普索姆公司 | 促进水解的紫杉烷疏水性衍生物 |
CN103025739A (zh) * | 2010-06-30 | 2013-04-03 | 真塔公司 | 替司他赛和相关化合物以及对应合成中间体的制备 |
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WO1994015599A1 (en) | 1994-07-21 |
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DK1211250T3 (da) | 2004-10-25 |
ATE269315T1 (de) | 2004-07-15 |
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CN1244569C (zh) | 2006-03-08 |
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CA2153805C (en) | 2006-03-28 |
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