JPH08505627A - C10タキサン誘導体および薬剤組成物 - Google Patents
C10タキサン誘導体および薬剤組成物Info
- Publication number
- JPH08505627A JPH08505627A JP6516328A JP51632894A JPH08505627A JP H08505627 A JPH08505627 A JP H08505627A JP 6516328 A JP6516328 A JP 6516328A JP 51632894 A JP51632894 A JP 51632894A JP H08505627 A JPH08505627 A JP H08505627A
- Authority
- JP
- Japan
- Prior art keywords
- hydrogen
- hydroxy
- oxo
- alkenyl
- heteroaryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 34
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 113
- 239000001257 hydrogen Substances 0.000 claims description 106
- -1 cyano, hydroxy Chemical group 0.000 claims description 86
- 150000002431 hydrogen Chemical class 0.000 claims description 83
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 125000003342 alkenyl group Chemical group 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 40
- 125000000304 alkynyl group Chemical group 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004043 oxo group Chemical group O=* 0.000 claims description 23
- 125000006239 protecting group Chemical group 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004423 acyloxy group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 9
- 125000003566 oxetanyl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 7
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 34
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- 125000005336 allyloxy group Chemical group 0.000 claims 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 claims 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 abstract description 7
- 230000000719 anti-leukaemic effect Effects 0.000 abstract description 5
- 239000000063 antileukemic agent Substances 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 96
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
- 239000000203 mixture Substances 0.000 description 82
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 58
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 44
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
- 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 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 125000001424 substituent group Chemical group 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 229940123237 Taxane Drugs 0.000 description 21
- 238000001704 evaporation Methods 0.000 description 21
- 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 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
- 229930014667 baccatin III Natural products 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 229960001592 paclitaxel Drugs 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 125000001544 thienyl group Chemical group 0.000 description 11
- 229930012538 Paclitaxel Natural products 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000004703 alkoxides Chemical class 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000002541 furyl group Chemical group 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 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 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 150000003952 β-lactams Chemical class 0.000 description 6
- 150000000180 1,2-diols Chemical class 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 125000000468 ketone group Chemical group 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 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
- 229960003668 docetaxel Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229930190007 Baccatin Natural products 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 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 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 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 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 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
- 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 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 241000694440 Colpidium aqueous Species 0.000 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 description 2
- 229930194542 Keto Natural products 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
- 206010028980 Neoplasm Diseases 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- HQCVEGNPQFRFPC-UHFFFAOYSA-N carboxy acetate Chemical compound CC(=O)OC(O)=O HQCVEGNPQFRFPC-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 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
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 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
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 150000003512 tertiary amines Chemical class 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
- 238000010792 warming Methods 0.000 description 2
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D409/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (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
Description
Claims (1)
- 【特許請求の範囲】 1.式(3)で示されるタキサン誘導体: [式中、 X1は−OX6、−SX7または−NX8X9; X2は水素、アルキル、アルケニル、アルキニル、アリールまたはヘテロアリ ール; X3およびX4はそれぞれ、水素、アルキル、アルケニル、アルキニル、アリー ルまたはヘテロアリール; X5は−COX10、−COOX10、−COSX10、−CONX8X10または−S O2X11; X6は水素、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール 、ヒドロキシ保護基、またはタキサン誘導体の水溶性を高める官能基; X7はアルキル、アルケニル、アルキニル、アリール、ヘテロアリールまたは スルフヒドリル保護基; X8は水素、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール 、またはヘテロ置換アルキル、アルケニル、アルキニル、アリールもしくはヘテ ロアリール; X9はアミノ保護基; X10はアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、また はヘテロ置換アルキル、アルケニル、アルキニル、アリールもしくはヘテロアリ ール; X11はアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、−O X10または−NX8X14; X14は水素、アルキル、アルケニル、アルキニル、アリールまたはヘテロアリ ール; R1は水素、ヒドロキシ、保護ヒドロキシ、またはR14と共にカーボネートを 形成; R2は水素、ヒドロキシ、−OCOR31、またはR2aと共にオキソを形成; R2aは水素、またはR2と共にオキソを形成; R4は水素、R4aと共にオキソ、オキシランもしくはメチレンを形成、または R5aおよびそれらが結合する炭素原子と共にオキセタン環を形成; R4aは水素、アルキル、アルケニル、アルキニル、アリール、ヘテロアリール 、シアノ、ヒドロキシ、−OCOR30、またはR4と共にオキソ、オキシランも しくはメチレンを形成; R5は水素、またはR5aと共にオキソを形成; R5aは水素、ヒドロキシ、保護ヒドロキシ、アシルオキシ、R5と共にオキソ を形成、またはR4およびそれらが結合する炭素原子と共にオキセタン環を形成 ; R6は水素、アルキル、アルケニル、アルキニル、アリールもしくはヘテロア リール、ヒドロキシ、保護ヒドロキシ、またはR6aと共にオキソを形成; R6aは水素、アルキル、アルケニル、アルキニル、アリールもしくはヘテロア リール、ヒドロキシ、保護ヒドロキシ、またはR6と共にオキソを形成; R7は水素、またはR7aと共にオキソを形成; R7aは水素、ハロゲン、保護ヒドロキシ、−OR28、またはR7と共にオキソ を形成; R9は水素、またはR9aと共にオキソを形成; R9aは水素、ヒドロキシ、保護ヒドロキシ、アシルオキシ、またはR9と共に オキソを形成; R10は水素、またはR10aと共にオキソを形成; R10aは水素、またはR10と共にオキソを形成; R14は水素、アルキル、アルケニル、アルキニル、アリールもしくはヘテロア リール、ヒドロキシ、保護ヒドロキシ、またはR1と共にカーボネートを形成; R14aは水素、アルキル、アルケニル、アルキニル、アリールまたはヘテロア リール; R28は水素、アシル、ヒドロキシ保譜基、またはタキサン誘導体の溶解性を高 める官能基; R29、R30およびR31はそれぞれ水素、アルキル、アルケニル、アルキニル、 単環アリールまたは単環ヘテロアリール; ただし、R10およびR10aが水素である場合、(a)R14は水素以外、(b) R9およびR9aはオキソ以外、(c)R7aは水素、(d)R4aはアセトキシ以外 、(e)R2はベンゾイルオキシ以外、(f)R1はヒドロキシ以外、(g)X3 またはX4はシクロアルキル、アルケニルまたはヘテロアリール、(h)X5は− COSX10または−CONX8X10、または(i)X5は−COX10または−CO OX10(X10はヘテロアリール)。]。 2.R10およびR10aが水素であり、(a)R9aが水素、ヒドロキシまたはア シルオキシ、または(b)X3またはX4がシクロアルキル、アルケニルまたはヘ テロアリールである請求項1記載のタキサン誘導体。 3.R10およびR10aが共同でオキソを形成する請求項1記載のタキサン誘導 体。 4.R9aがヒドロキシまたはアセトキシである請求項1記載のタキサン誘導体 。 5.R14およびR14aが水素、R10およびR10aが水素、R9aが水素、ヒドロキ シまたはアシルオキシ、R7が水素、R7aがヒドロキシ、R5が水素であり、R5a およびR4およびそれらの結合する炭素がオキセタン環を形成し、R4aがアセト キシ、R2aが水素、R2がベンゾイルオキシ、R1がヒドロキシ、X1が−OH、 X2が水素、X3がフェニル、X4が水素、X5が−COX10、X10がフェニルまた はt−ブトキシであり、2’R,3’S配置を有する請求項1記載のタキサン誘 導体。 6.R14およびR14aが水素、R10およびR10aが水素であり、R9aが水素、ヒ ドロキシ、アシルオキシであるか、またはR9と共にオキソを形成し、R7が水素 、R7a、がヒドロキシ、R5が水素であり、R5aおよびR4およびそれらの結合す る炭素がオキセタン環を形成し、R4aがアセトキシ以外またはR2がベンゾイル オキシ以外、R2aが水素、R1がヒドロキシ、X1が−OH、X2が水素、X3がフ ェニル、X4が水素、X5が−COX10、X10がフェニルまたはt−ブトキシであ り、2’R,3’S配置を有する請求項1記載のタキサン誘導体。 7.R14およびR14aが水素、R10およびR10aが水素であり、R9aが水素、ヒ ドロキシであるか、またはR9と共にオキソを形成し、R7が水素、R7aがヒドロ キシ、R5が水素であり、R5aおよびR4およびそれらの結合する炭素がオキセタ ン環を形成し、R4aがアセトキシ、R1がヒドロキシ、X1が−OH、X2が水素 、X3がシクロアルキル、アルケニルまたはヘテロアリール、X4が水素、X5が −COX10、X10がフェニル、t−、イソ−もしくはn−ブトキシ、エトキシ、イ ソ−もしくはn−プロポキシ、シクロヘキシルオキシ、アリルオキシ、クロチル オキシ、1,3−ジエトキシ−2−プロポキシ、2−メトキシエトキシ、アミル オキシ、ネオペンチルオキシ、PhCH2O−、−NPh2、−NHnPr、−NHP hおよび−NHEtである請求項1記載のタキサン誘導体。 8.R14およびR14aが水素であり、R10およびR10aが共同でオキソを形成し 、R9aが水素、ヒドロキシであるか、またはR9と共にオキソを形成し、R7が水 素、R7aがヒドロキシ、R5が水素であり、R5aおよびR4およびそれらの結合す る炭素がオキセタン環を形成し、R4aがアセトキシ、R2aが水素、R2がベンゾ イルオキシ、R1がヒドロキシ、X1が−OH、X2が水素、X3がフェニル、X4 が水素、X5が−COX10、X10がフェニルまたはt−ブトキシであり、2’R, 3’S配置を有する請求項1記載のタキサン誘導体。 9.R14およびR14aが水素であり、R10およびR10aが共同でオキソを形成し 、R9aが水素、ヒドロキシであるか、またはR9と共にオキソを形成し、R7が水 素、R7aがヒドロキシ、R5が水素であり、R5aおよびR4およびそれらの結合す る炭素がオキセタン環を形成し、R4aアセトキシ、R1がヒドロキシ、X1が−O H、X2が水素、X3がアルキルまたはアルケニル、X4が水素、X5が−COX10 、 X10がフェニル、t−、イソ−もしくはn−ブトキシ、エトキシ、イソ−もしくは n−プロポキシ、シクロヘキシルオキシ、アリルオキシ、クロチルオキシ、1,3 −ジエトキシ−2−プロポキシ、2−メトキシエトキシ、アミルオキシ、ネオペ ンチルオキシ、PhCH2O−、−NPh2、−NHnPr、−NHPhおよび−NH Etである請求項1記載のタキサン誘導体。 10.請求項1記載のタキサン誘導体と、薬理学的に許容し得る、不活性な、 または生理学的に活性な希釈剤または佐剤1種またはそれ以上とを含有する薬剤 組成物。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/005,229 | 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 | |
US08/034,852 | 1993-03-22 | ||
US9454593A | 1993-07-20 | 1993-07-20 | |
US08/094,545 | 1993-07-20 | ||
PCT/US1994/000479 WO1994015599A1 (en) | 1993-01-15 | 1994-01-14 | C10 taxane derivatives and pharmaceutical compositions |
Publications (2)
Publication Number | Publication Date |
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JPH08505627A true JPH08505627A (ja) | 1996-06-18 |
JP3917173B2 JP3917173B2 (ja) | 2007-05-23 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP51632894A Expired - Fee Related JP3917173B2 (ja) | 1993-01-15 | 1994-01-14 | C10タキサン誘導体 |
Country Status (12)
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EP (2) | EP0679082B1 (ja) |
JP (1) | JP3917173B2 (ja) |
CN (2) | CN1244569C (ja) |
AT (2) | ATE225656T1 (ja) |
AU (1) | AU682852B2 (ja) |
CA (1) | CA2153805C (ja) |
DE (2) | DE69431514T2 (ja) |
DK (2) | DK1211250T3 (ja) |
ES (2) | ES2184761T3 (ja) |
IL (1) | IL108316A (ja) |
PT (2) | PT679082E (ja) |
WO (1) | WO1994015599A1 (ja) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
HU226325B1 (en) * | 1995-09-12 | 2008-08-28 | Cephalon Ltd | Hydrolysis-promoting hydrophobic taxane derivatives, medicaments comprising them and the use of medicaments |
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 |
US8785669B2 (en) * | 2010-06-30 | 2014-07-22 | Gfv, Llc | Taxane compounds, compositions and methods |
Family Cites Families (8)
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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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1994
- 1994-01-11 IL IL108316A patent/IL108316A/en not_active IP Right Cessation
- 1994-01-14 DK DK02005075T patent/DK1211250T3/da active
- 1994-01-14 EP EP94909453A patent/EP0679082B1/en not_active Expired - Lifetime
- 1994-01-14 CA CA002153805A patent/CA2153805C/en not_active Expired - Fee Related
- 1994-01-14 ES ES94909453T patent/ES2184761T3/es not_active Expired - Lifetime
- 1994-01-14 JP JP51632894A patent/JP3917173B2/ja not_active Expired - Fee Related
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- 1994-01-14 WO PCT/US1994/000479 patent/WO1994015599A1/en active IP Right Grant
- 1994-01-14 AU AU62295/94A patent/AU682852B2/en not_active Ceased
- 1994-01-14 ES ES02005075T patent/ES2225671T3/es not_active Expired - Lifetime
- 1994-01-14 DE DE69433856T patent/DE69433856T2/de not_active Expired - Fee Related
- 1994-01-14 PT PT02005075T patent/PT1211250E/pt unknown
- 1994-01-14 AT AT94909453T patent/ATE225656T1/de not_active IP Right Cessation
- 1994-01-14 DK DK94909453T patent/DK0679082T3/da active
- 1994-01-14 EP EP02005075A patent/EP1211250B1/en not_active Expired - Lifetime
- 1994-01-14 AT AT02005075T patent/ATE269315T1/de not_active IP Right Cessation
- 1994-01-15 CN CNB031579078A patent/CN1244569C/zh not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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CN1125060C (zh) | 2003-10-22 |
DK0679082T3 (da) | 2003-02-17 |
WO1994015599A1 (en) | 1994-07-21 |
DE69433856D1 (de) | 2004-07-22 |
DK1211250T3 (da) | 2004-10-25 |
ATE269315T1 (de) | 2004-07-15 |
DE69433856T2 (de) | 2004-11-04 |
IL108316A (en) | 2006-10-31 |
DE69431514T2 (de) | 2003-02-13 |
JP3917173B2 (ja) | 2007-05-23 |
PT679082E (pt) | 2003-02-28 |
CN1495177A (zh) | 2004-05-12 |
EP0679082A4 (en) | 1995-12-20 |
DE69431514D1 (de) | 2002-11-14 |
CN1244569C (zh) | 2006-03-08 |
PT1211250E (pt) | 2004-10-29 |
ES2184761T3 (es) | 2003-04-16 |
IL108316A0 (en) | 1994-04-12 |
EP0679082B1 (en) | 2002-10-09 |
AU682852B2 (en) | 1997-10-23 |
CN1097746A (zh) | 1995-01-25 |
ATE225656T1 (de) | 2002-10-15 |
EP1211250B1 (en) | 2004-06-16 |
CA2153805C (en) | 2006-03-28 |
EP0679082A1 (en) | 1995-11-02 |
AU6229594A (en) | 1994-08-15 |
ES2225671T3 (es) | 2005-03-16 |
EP1211250A1 (en) | 2002-06-05 |
CA2153805A1 (en) | 1994-07-21 |
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