AP784A - Novel taxoids, preparation thereof and pharmaceutiacl compositions containing same. - Google Patents
Novel taxoids, preparation thereof and pharmaceutiacl compositions containing same. Download PDFInfo
- Publication number
- AP784A AP784A APAP/P/1997/001094A AP9701094A AP784A AP 784 A AP784 A AP 784A AP 9701094 A AP9701094 A AP 9701094A AP 784 A AP784 A AP 784A
- Authority
- AP
- ARIPO
- Prior art keywords
- radical
- carbon atoms
- radicals
- atoms
- alkyl
- Prior art date
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- 239000000203 mixture Substances 0.000 title description 18
- 238000002360 preparation method Methods 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 55
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 40
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 7
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 6
- -1 alkyl radical Chemical class 0.000 claims description 227
- 125000004432 carbon atom Chemical group C* 0.000 claims description 142
- 150000003254 radicals Chemical class 0.000 claims description 64
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 46
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 150000008064 anhydrides Chemical class 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 230000032050 esterification Effects 0.000 claims description 14
- 238000005886 esterification reaction Methods 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 239000005864 Sulphur Substances 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 150000004820 halides Chemical class 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 150000005840 aryl radicals Chemical class 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 8
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical group O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 7
- 125000004442 acylamino group Chemical group 0.000 claims description 7
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- KKFDJZZADQONDE-UHFFFAOYSA-N (hydridonitrato)hydroxidocarbon(.) Chemical compound O[C]=N KKFDJZZADQONDE-UHFFFAOYSA-N 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 230000003213 activating effect Effects 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 claims description 4
- IIVWHGMLFGNMOW-UHFFFAOYSA-N 2-methylpropane Chemical compound C[C](C)C IIVWHGMLFGNMOW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005239 aroylamino group Chemical group 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 3
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 claims description 3
- OFTKFKYVSBNYEC-UHFFFAOYSA-N 2-furoyl chloride Chemical compound ClC(=O)C1=CC=CO1 OFTKFKYVSBNYEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 150000004200 baccatin III derivatives Chemical class 0.000 claims description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 150000001602 bicycloalkyls Chemical group 0.000 abstract 1
- 125000000392 cycloalkenyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 239000000047 product Substances 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- 239000006260 foam Substances 0.000 description 43
- 239000000243 solution Substances 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 230000008878 coupling Effects 0.000 description 17
- 238000010168 coupling process Methods 0.000 description 17
- 238000005859 coupling reaction Methods 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 230000003287 optical effect Effects 0.000 description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- 239000011521 glass Substances 0.000 description 13
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000012153 distilled water Substances 0.000 description 10
- ZVAFCKLQJCZGAP-WDEREUQCSA-N (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-WDEREUQCSA-N 0.000 description 9
- MSVWUXLRSKRKFZ-IPMKNSEASA-N (2r,4s,5r)-2-(4-methoxyphenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-4-phenyl-1,3-oxazolidine-5-carboxylic acid Chemical compound C1=CC(OC)=CC=C1[C@@H]1N(C(=O)OC(C)(C)C)[C@@H](C=2C=CC=CC=2)[C@H](C(O)=O)O1 MSVWUXLRSKRKFZ-IPMKNSEASA-N 0.000 description 9
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 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 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- 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 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- POALUPLKPJWUJR-UHFFFAOYSA-N phenyl 1,3-oxazolidine-5-carboxylate Chemical compound O=C(Oc1ccccc1)C1CNCO1 POALUPLKPJWUJR-UHFFFAOYSA-N 0.000 description 4
- 239000012429 reaction media Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229930014667 baccatin III Natural products 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- OZQBDSLJTSETCK-UHFFFAOYSA-N but-3-enoyl but-3-enoate Chemical compound C=CCC(=O)OC(=O)CC=C OZQBDSLJTSETCK-UHFFFAOYSA-N 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- PLRPKVNZGONHKD-UHFFFAOYSA-N 1,3-oxazolidine-5-carboxylic acid Chemical compound OC(=O)C1CNCO1 PLRPKVNZGONHKD-UHFFFAOYSA-N 0.000 description 2
- UXTFKIJKRJJXNV-UHFFFAOYSA-N 1-$l^{1}-oxidanylethanone Chemical group CC([O])=O UXTFKIJKRJJXNV-UHFFFAOYSA-N 0.000 description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- IHCCAYCGZOLTEU-UHFFFAOYSA-N 3-furoic acid Chemical compound OC(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-N 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
- WHXLTBRGUWTBQP-UZBMNOCMSA-N 7-o-(triethylsilyl) baccatin iii Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC(C)=O)C2=C(C)[C@@H](O)C[C@]1(O)C2(C)C)C)O[Si](CC)(CC)CC)C(=O)C1=CC=CC=C1 WHXLTBRGUWTBQP-UZBMNOCMSA-N 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010048723 Multiple-drug resistance Diseases 0.000 description 2
- 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 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N Picolinic acid Natural products OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
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- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Natural products OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004216 mammary stem cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229940109615 oxy 10 Drugs 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229940070891 pyridium Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 210000005227 renal system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 210000004999 sex organ Anatomy 0.000 description 1
- OLRJXMHANKMLTD-UHFFFAOYSA-N silyl Chemical compound [SiH3] OLRJXMHANKMLTD-UHFFFAOYSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 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 1
- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)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-XAZOAEDWSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Novel taxoids of general formula (I), wherein R is a substituted alkyl radical or an alkenyl, alkynyl. cycloalfcyl. optionally substituted cycloalkcnyl or phenyi radical, or an optionally aromatic 5- or 6-membered heterocyclic radical; and Z is a hydrogen atom or a radical of general formula (II). wherein RI is an optionally substituted benzoyl. thenoy! or furoyl radical or a radical Rs-O-CO-. where R: is an alkyl, alkenyL alkynyl. cycloalkyl, cycloalkenyl. bicycloalkyl, optionally substituted phcnyl. or hetcrocyclyl radical, and Rj is an aromatic heterocyclic, alkyl. alkcnyl. alkynyl, cycloalkyl, phenyi or naphthy! radical. The novel products of general formula (I), wherein Z is a radical of general formula (II), have remarkablc antimoral activity.
Description
NEW TAXOIDS, THEIR PREPARATION AND PHARMACEUTICAL
COMPOSITIONS CONTAINING THEM
The present invention relates to new taxoids of general formula:
in which:
. R represents an unbranched or branched alkyl radical containing 1 to 8 carbon atoms, substituted with a halogen atom chosen from fluorine, chlorine, bromine and iodine atoms or with an amino radical, an alkylamino radical in which the alkyl portion contains 1 to 4 carbon atoms, a dialkylamino radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur and nitrogen atoms (and optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms) , a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or
0 I 0 / Z 6 /d/dV
AP. Ο Ο 7 8 4 carbamoyl radical, an N-alkylcarbamoyl radical in which the alkyl portion contains 1 to 4 carbon atoms or an N,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the ' 5 nitrogen atom to which it is linked, forms a saturated
5- or 6-membered heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur and nitrogen atoms (and optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the
f.'f‘“· ‘ ' v!' alkyl portion contains 1 to 4 carbon atoms), an alkenyl radical containing 2 to 8 carbon atoms in an unbranched or branched chain, an alkynyl radical containing 2 to 8 carbon atoms in an urbranched or branched chain, a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 3 to 6 carbon atoms, these radicals being optionally substituted with a halogen atom chosen from fluorine, chlorine, bromine and iodine atoms or with an amino radical, an alkylamino radical in which the alkyl portion contains 1 to 4 carbon atoms, a dialkylamino radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or S-membered heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur and nitrogen atoms (and optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a
AP/P/ S7 / 0 10 9 4
AP. Ο Ο 7 8 4 phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical, an Ν'-alkyl carbamoyl radical in which the alkyl portion contains 1 to 4 carbon atoms or an N,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered 10 heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur and nitrogen 'atoms (and optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains
1 to 4 carbon atoms), or a phenyl radical or a 5- or 6-membered aromatic heterocyclic radical containing an oxygen, sulphur or nitrogen atom as hetero atom, and
Z represents a hydrogen atom or a radical of general formula:
R,NH O
OH in which:
Rx represents a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms and alkyl
AP/P/ 9 7 / 0 1 09 4 •ν
AP.00784 ' 4 radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl radicals, a thenoyl or furoyl radical or a radical Rj-O-CO- in which R2 represents:
- an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or
L; 10 a bicycioalkyl radical containing 7 to 10 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkoxy radicals containing 1 to 4 carl—. aL.-j, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals (optionally substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl (· radical in which the alkyl portion contains 1 to 4 carbon atoms) , cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals (optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms), cyano or carboxyl radicals or alkoxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon
AP/P/ 9 7 / 0 1 0 9 4 atoms,
AP. Ο Ο 7 8 4
- a phenyl or a- or jS-naphthyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms, or a 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals,
- or a saturated heterocyclic radical containing 4 to 6 carbon atoms, optionally substituted with one or more alkyl·’ radicals containing 1 to 4 carbon atoms, •V
R3 represents an unbranched or branched alkyl 'radical containing 1 to 8 carbon atoms, an unbranched or branched alkenyl radical containing 2 to 8 carbon atoms, an unbranched or branched alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl or a- or /3-naphthyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and
(. alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl
5 radicals, or a 5- or 6-membered aromatic heterocycle containing one or more identical or different hetero atoms chosen from nitrogen, oxygen and sulphur atoms and optionally substituted with one or more identical
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4 or different substituents chosen from halogen atoms and alkyl, alkoxy, aryl, aryloxy, amino, alkylaminn, dialkylamino, acylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkoxycarbonyl radicals, on the understanding that, in the substituents of the phenyl, a- or 0-naphthyl and aromatic heterocyclic radicals, the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, and that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and that the aryl radicals -are phenyl or oc- or 0-naphthyl radicals.
Preferably, the aryl radicals which can be represented by R3 are phenyl or a- or 0-naphthyl radicals optionally substituted with one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl,
0 acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, on the understanding that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or cc- or 0-naph.thyl radicals.
AP. Ο Ο 7 8 4
Preferably, the heterocyclic radicals which can be represented by R3 are 5- or 6-membered aromatic heterocyclic radicals containing one or more identical or different atoms chosen from nitrogen, oxygen and sulphur atoms, optionally substituted with one or more identical or different substituents chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, aryloxy radicals containing 6 to 10 carbon atoms, amino radicals,
-alkylamino radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, acylamino radicals in which the acyl portion contains 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbon atoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion contains 6 to 10 carbon atoms, cyano, carboxyl or carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains 1 to 4 carbon atoms or alkoxycarbonyl radicals in which the alkoxy portion contains 1 to 4 carbon atoms.
Preferably, R represents an alkyl radical containing 1 to 8 carbon atoms, substituted with a halogen atom or with a dimethylamino or diethylamino,
AP/P/ 97/01094
AP. ο Ο 7 8 4 carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl, Ν,Ν-dimethylcarbamoyl, pyrrolidinocarbonyl or piperidinocarbonyl radical, an alkenyl radical containing 2 to 8 carbon atoms, an %
alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyi radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 3 to 6 carbon atoms, optionally substituted with a halogen atom or with a dimethylamino, diethylamino, carboxyl, methoxycarbonyl, j ' 10 ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl,
Ν,Ν-dimethylcarbamoyl, pyrrolidinocarbonyl or -piperidinocarbonyl radical, or a phenyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-furyl,
3-furyl or 2-, 4- or 5-thiazolyl radical.
More especially, the invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which Rx represents a benzoyl radical or a radical R2-O( CO- in which R2 represents a tert-butyl radical and R3 represents an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, a cycloalkyi radical containing 3 to 6 carbon atoms, a phenyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms (fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino) , acylamino (acetylamino) , alkoxycarbonylamino (tert-butoxycarbonylamino) or
P** a»
CL
CL <
AP.00784 trifluoromethyl radicals, or a 2- or 3-furyl, 2- or
3-thienyl or 2-, 4- or 5-thiazolyl radical, and R represents a cycloalkyl radical containing 3 to 6 carbon atoms or a phenyl, 2-, 3- or 4-pyridyl, 2- or
3-furyl and 2- or 3-thienyl radical.
Still more especially, the invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which Rx represents a benzoyl radical or a radical R2-O-CO- in which Rj represents a tert-butyl . radical and R3 represents an isobutyl, isobutenyl, butenyl,. cyclohexyl, phenyl, 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, and R represents a cyclopropyl,, cyclopentyl, phenyl, 2-pyridyl, 2-thienyl or 2-furyl radical. ·.. ·
The products of general formula (I) in which Z represents a radical of general formula (II) display noteworthy antitumour and antileukaemic properties.
According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II) may be obtained by esterification of a product of general formula:
AP/P/ 97 / 0 1 0 9 4
AP. Ο Ο 7 8 4
(ΠΙ) in which Rx and R3 are defined as above, and either Rg represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or Rs and R7 together form-a saturated 5- or 6-membered heterocycle, by means of an acid of general formula:
R-CO-OH (IV) in which R is defined as above, or by means of a derivative of this acid, such as a halide, the symmetrical anhydride or a mixed anhydrida, to obtaii, a product of general formula:
t 6 (B 0 /16 /d/dV in which Rx, R3, Rs and R7 are defined as above, followed by replacement of the protective groups R7 or Rs and R7 by hydrogen atoms.
The esterification by means of an acid of 15 general formula (IV) may be performed in the presence of a condensing agent (carbodiimide, reactive
AP. ο ο 7 8 4 carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between -10 and 90°C.
The esterification may also be carried out using the acid of general formula (IV) in the form of the symmetrical anhydride, working in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, • aromatic hydrocarbons) at a temperature of between 0 and 90°C.
The esterification may also be carried out 15 using the acid of general formula (IV) in halide form or in the form of a mixed anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base (tertiary aliphatic amine), working in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between 0 and 80°C.
When Rs represents a hydrogen atom, R7 preferably represents a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, /5-trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydropyranyl radical.
AP/P/ 97 / 0 1 0 9 4
AP. Ο Ο 7 8 4
When Re and R, together form a heterocycle, the latter is preferably an oxazolidine ring optionally monosubstituted or gem-disubstituted at position 2.
Replacement of the protective groups R7 and/or 5 Rs and R, by hydrogen atoms may be performed, depending on their nature, in the following manner:
1) when Rs represents a hydrogen atom and R, represents a group protecting the hydroxyl function, replacement of the protective groups by hydrogen atoms is performed by means of an inorganic acid (hydrochloric acid, sulphuric acid, hydrofluoric acid) or organic acid -(acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid) ui.ad alone or mixed, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature of between -10 and 60°C,
2) when Rs and R, together form a saturated 5- or 620 membered heterocycle, and more especially an oxazolidine ring of general formula:
in which Rx is defined as above and Ra and Rs, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an
Rg Rg
AP.00784 ί,/' aralkyl radical in which the alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively Ra represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted with a trihalomethyl radical such as trichioromethyl and R9
-represents a hydrogen atom, or alternatively Ra and R9, together with the carbon atom to which they are linked, form a 4- to 7-membered ring, replacement of the protective group formed by Rs and R, by hydrogen atoms may be performed, depending on the meanings of Rx, Ra and R9, in the following manner:
a) when Rx represents a tert-butoxycarbonyl radical and Ra and Rs, which may be identical or different, represent a hydrogen atom or an alkyl radical or an aralkyl (benzyl) or aryl (phenyl) radical, or alternatively Ra represents a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and R9 represents a hydrogen atom, or alternatively Ra and R, together form a 4- to
7-membered ring, treatment of the ester of general formula (V) with an inorganic or organic acid, where appropriate in an organic solvent such as an alcohol,
AP/P/ 97 / 0 1 0 94
AP.00784 yields the product of general formula:
in which R3 is defined as above, which is acylated by .means of benzoyl chloride in which the phenyl ring is optionally substituted or by means of thenoyl chloride,
-' .-w/1 chloride or of a product of general formula:
Rj-O-CO-X (VIII) in which R2 is defined as above and X represents a halogen atom (fluorine, chlorine) or a residue -O-R2 or -O-CO-O-R2, to obtain a product of general formula (I) in which Z represents a radical of general formula (II) .
Preferably the product of general formula (V) is treated with formic acid at a temperature in the region of 20°C to yield the product of general formula (VII).
Preferably, the acylation of the product of general formula (VII) by means of a benzoyl chloride in which the phenyl radical is optionally substituted or by means of thenoyl chloride, of furoyl chloride or of
AP/P/ 9 7 / 0 1 0 9,4
AP.00784 a product of general formula (VIII) is performed in an inert organic solvent chosen from esters such as ethyl acetate, isopropyl acetate or n-butyl acetate and halogenated aliphatic hydrocarbons such as dichioromethane or 1,2-dichloroethane, in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. The reaction is performed at a temperature of between 0 and 50°C, and preferably in the region of 20°C.
b) when Rx represents an optionally substituted benzoyl radical, a thenoyl or furoyl radical or a radical R^jO-CO- in which R2 is defined as above, R8 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms and Rs represents a hydrogen atom, replacement of the protective group formed by Rs and R, by hydrogen atoms is performed in the presence of an inorganic acid (hydrochloric acid, sulphuric acid) or organic acid (acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid) used alone or mixed in a stoichiometric or catalytic amount, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature of between -10 and 60eC, and preferably between 15 and
AP/P/ 97 / 0 1 0 9.4
30°C.
AP.00784
The products of general formula (III) may be obtained under the conditions described in
International Application PCT WO 94/13654.
The products of general formula (III) may also be obtained by esterification of a baccatin III derivative of formula:
(IX) by means of an acid of general formula:
AP/P/ S 7 / v 1 0 9 4 in which Rt, R3, Rs and R, are defined as above, or by means of a derivative of this acid such as a halide, the symmetrical anhydride or a mixed anhydride, and then replace the acetoxy radical at position 10 by a hydroxyl radical.
The esterification is performed under conditions similar to those described above for the esterification of a product of general formula (III) by means of an acid of general formula (IV).
Replacement of the acetoxy radical at position 10 by a hydroxyl radical is generally
AP . 0 0 7 8 4 performed by means of zinc iodide.
The product of formula (IX) may be obtained binder the conditions described in International
Application PCT WO 94/13654, by the action of an alkali 5 metal halide (sodium iodide, potassium fluoride) or an alkali metal azide (sodium azide) or a quaternary ammonium salt or an alkali metal phosphate on 2a-benzoyloxy-4a, lO/S-diacetoxy-10,13a-dihydroxy-5/S, 20epoxy- Ίβ-trif luoromethylsulphonyloxy- 9 - oxo -11 - taxene.
The products of general formula (I) in which
Z represents a radical of general formula (II) may also
-be obtained by esterification of a product of general formula:
AP/P/ 9 7 / 0 1 0 9 4 c
in which R is defined as above, by means of an acid of 15 general formula (X) or of a derivative of this acid such as a halide, the symmetrical anhydride or a mixed anhydride, to obtain a product of general formula (V) in which the protective groups R, or Rs and R, are replaced by hydrogen atoms under the conditions described above.
The products of general formula (XI), that is to say the products of general formula (I) in which Z
AP. Ο Ο 7 8 4 represents a hydrogen atom, may be obtained by esterification of a product of formula:
in which Zx represents a group protecting the hydroxyl function, such as a silyl radical, for ''Tanea a triethylsilyl radical, by means of an acid of general formula (IV) or cf a derivative of this acid such as a halide or the symmetrical anhydride or a mixed anhydride, under the conditions described above for the esterification of a product of general formula (III) by means of an acid of general formula (IV) or of a derivative of this acid, followed by replacement of the protective group Z, by a hydrogen atom under conditions which do not affect the remainder of the molecule.
The product of general formula (XII) may be obtained under the conditions described in International Application PCT WO 94/13654.
The new products of general formula (I) obtained by carrying out the processes according to the invention may be purified according to known methods
AP/P/ 9 7 / 0 1 0 9 4
ΑΡ. ο Ο 7 8 4 such as crystallization or chromatography.
The products of general formula (I) in which
Z represents a radical of general formula (II) display noteworthy biological properties.
In vitro, measurement of the biological activity is performed on tubulin extracted from pig's brain by the method of M.L. Shelanski et al., Proc. Natl. Acad. Sci. USA, 70,, 765-768 (1973). Study of the depolymerization of microtubules to tubulin is performed according to the method of G. Chauviere et al., C.R. Acad. Sci., 293, series II, 501-503 .(1981). In this study, the products of general formula (I) in which Z represents a radical of general formula (II) were shown to be at least as active as taxol and
Taxotere.
In vivo, the products of general formula (I) in which Z represents a radical of general formula (II) were shown to be active in mice grafted with B16 melanoma at doses of between 1 and 10 mg/kg administered intraperitoneally, as well as on other liquid or solid tumours.
The new products have antitumour properties, and more especially activity against tumours which are resistant to Taxol® or to Taxotere®. Such tumours comprise colon tumours which have a high expression of the mdr 1 gene (multiple drug resistance gene). Multiple drug resistance is a customary term relating to the resistance of a tumour to different products
AP/P/ 97 / 0 1 0 9 4
(..
AP. Ο ο 7 8 4 having different structures and mechanisms of action. Taxoids are generally known to be strongly recognized by experimental tumours such as P388/DOX, a cell line selected for its resistance to doxorubicin (DOX) which overexpresses mdr 1.
The examples which follow illustrate the present invention.
EXAMPLE 1
380 mg of 4a-acetoxy-2a-benzoyloxy-10,10010 dihydroxy-50,20-epoxy-70,80-methylene-9-oxo-19-nor-lltaxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate, 25 mg of 4-(dimethylamino)pyridine, 0.5 g of 4 A molecular sieve and 151 mg of N,N' -dicyclohexylcarbo15 diimide are added at a temperature in the region of 20°C to a solution, maintained under an argon atmosphere and kept stirring, of 62 mg of 2-pyridinecarboxylic acid in 25 cm3 of anhydrous ethyl acetate. The reaction mixture is kept stirring for 16 hours at a temperature in the region of 20°C, and 20 mg of
2-pyridinecarboxylic acid, 8 mg of 4-(dimethylamino) pyridine, 100 mg of 4 A molecular sieve and 50 mg of Ν,Ν' -dicyclohexylcarbodiimide are then added and the mixture is kept stirring again for 4 hours. The reaction mixture is filtered through sintered glass lined with Celite. The sintered glass is washed with 100 cm3 of ethyl acetate, and the filtrates are combined, washed successively with 15 cm3 of saturated
AP/P/ 97/(1094
AP .0 0 7 8 4 aqueous sodium hydrogen carbonate solution and with 5 times 10 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 715 mg of a white foam are obtained, which product is purified by chromatography on 40 g of silica (0.04-0.063 mm) contained in a column 2 cm in diameter [eluent: dichloromethane/methanol (99:1 by volume)], collecting 10-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 297 mg of . 4a-acetoxy-2a-benzoyloxy-50,20-epoxy-l£-hydroxy-7]3,80meth.ylene-9-oxo-10/S- (2-pyridylcarbonyl) oxy-19-nor-11taxen-13a-yl (2R,4S,5R)-3-tart-butoxycarbonyl-2-(4methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate are thereby obtained in the form of a white foam.
290 mg of 4a-acetoxy-2a-benzoyloxy-50,20epoxy-10-hydroxy-7£, 80-methylene-9-oxo-lO0- (2pyr idyl carbonyl) oxy-19-nor-ll-taxen-13a-yl (2R,4S,5R) 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3oxazolidine-5-carboxylate are dissolved in 5.7 cm3 of 0.1N ethanolic hydrochloric acid solution. The solution thereby obtained is stirred for 1 hour at a temperature in the region of 20°C and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residual solid is dissolved in 50 cm3 of dichloromethane, and the solution obtained is washed successively with twice 3 cm3 of saturated
AP/P/ 97 / 0 1 0 9 4
AP. ο Ο 7 8 4 aqueous sodium hydrogen carbonate solution and with 3 times 5 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 270 mg of a white foam are obtained, which product is purified by chromatography on 30 g of silica (0.04-0.063 mm) contained in a column 2 cm in diameter [eluent: dichloromethane/methanol (99:1 by volume)], collecting 10-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 20°C for 16 hours.
. 189 mg of 4a-acetoxy-2a-benzoyloxy-5£, 20-epoxy-l/Shydroxy-7/3, 8/J-methylene-9-oxo-10/5- (2-pyridylcarbonyl) oxy-19-nor-ll-tax ....-iios-yi (2R, 3S) -3-cert15 butoxycarbonylamino-2-hydroxy-3-phenylpropionate are thereby obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [α]°20 = -24 (c = 0.52; methanol)
- LH NMR spectrum (300 MHz; CDC13; chemical shifts δ in 20 ppm; coupling constant J in Hz): 1.28 (s, 9H: -C(CH3)3);
1.41 (s, 3H: -CH3 at position 16 or 17); 1.44 (mt, IH:
-H at position 7) ; 1.57 (s, 3H: -CH3 at position 16 or 17); 1.69 and 2.25 (respectively dd and mt, J = 6 and
5.5, IH each: -CILj- at position 19); 1.89 (s, IH: -OH at position 1); 1.95 (s, 3H: -CH3) ; 2.11 and 2.50 (respectively broad d and dt, J = 16 and J = 16 and 4.5 Hz, IH each: -CH2 at position 6); 2.25 and 2.39 (2 mt,
IH each: -CH2 at position 14); 2.40 (s, 3H: -COCH3) ;
AP/P/ 97 / 0 1 0 9 4
AP. Ο Ο 7 8 4
3.29 (mt, IH: -OH at position 2'); 4.04 and 4.32 (2 d,
J = 9, IH each: -CH, at position 20); 4.15 (d, J = 7.5, IH: -H at position 3); 4.62 (mt, IH: -H at position 2'); 4.74 (d, J « 4.5, 1Ξ: -H at position 5); 5.28 ' 5 (broad d, J = 10, 1Hz -H at position 3·); 5.35 (d, J =
10, IH: -C0NH-); 5.61 (d, J = 7.5, 1Ξ: -H at position
2); 6.28 (broad t, J = 9, IH: -H at position 13); 6.64 (s, 1Ξ: -H at position 10); from 7.25 to 7.45 (mt, 5Ξ: -CsH5 at position 3'); 7.51 [(mt, 3Ξ: -OCOCSHS (-H at ( 10 position 3 and H at position 5) and -C5H4N (-H at position 5)]; 7.60 [(t, J = 7.5, IH: -OCOCSH5 (-Hat position 4)]; 7.85 [(dt, J = 8 and 1.5, 1Ξ: -C5H4N (-H at position 4)]; 8.11 [(d, J = 8, IH: -C5H4N (-H at position 3)]; 8.15 [(d, J = 7.5, 2H: -OCOCSES (-H at position 2 and -H at position 6)]; 8.80 [(broad d, J =
4.5, IH: -C5H4N (-H at position 6)].
4a-Acetoxy-2a-benzoyloxy-l/S, 10/3-dihydroxy 5β, 20-epoxy-7/S, 8/3-methylene-9-oxo-19-nor-11-taxen-13a¢- yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(420 methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate may be prepared in the following manner:
g of powdered 4 A molecular sieve and
9.3 g of zinc iodide are added at a temperature in the region of 20°C to a solution, maintained under an argon atmosphere and kept stirring, of 5.5 g of
2a-benzoyloxy-4a, 10/S-diacetoxy-5/3, 20-epoxy-1/3-hydroxy7/3, 8/3-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl·)-4AP/P/ 97/01094
AP.ο ο 7 8 4 phenyl-1,3-oxazolidine-5-carboxylate in 200 cm3 of anhydrous methanol. The reaction medium is kept stirring for 3 hours at a temperature in the region of 20°C, a further 3.72 g of zinc iodide and 4 g of 4 A molecular sieve are then added and stirring is continued for 24 hours at a temperature in the region of 20°C. The reaction mixture is filtered through sintered glass lined with Celite. The sintered glass is . washed with 100 cm3 of dichloromethane, and the filtrates are combined and poured into 200 cm3 of distilled water. The two-phase mixture is stirred for
-30 minutes, and the agueous phase is then separated after settling has taken place and re-extracted with 3 times 200 cm3 of dichloromethane. The organic phases are combined, washed with 50 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 5.3 g of a white foam are obtained, which product is purified ( , by chromatography on 150 g of silica (0.04-0.063 mm) contained in a column 3.8 cm in diameter [eluent:
dichloromethane/methanol (99:1 by volume)], collecting 100-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 3.7 g of a white foam are thereby obtained, which product is repurified by chromatography on 175 g of silica (0.04-0.063 mm) contained in a column 3.8 cm in diameter [eluent:
dichloromethane/methanol (99.6:0.4 by volume)],
AP/P/ 9 7 / 0 1 0 9 4
AP . ο o 7 8 4 collecting 50-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C.
1.78 g of 4a-acetoxy-2-benzoyloxy-1/3,10/3-dihydroxy 5 5/3,20-epoxy-7/3, 8/3-methylene-9-oxo-19-nor-11-taxen-13ayl (2R,4S,5R) -3-tert-butoxycarbonyl-2-(4methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate are thereby obtained in the form of a white foam.
2a-Benzoyloxy-4a, lO0-diacetoxy-5/3,20-epoxy10 1/3-hydroxy-7/3, 8/3-methylene-9-oxo-19-nor-11-taxen-13o;-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatemay be prepared in the following manner;
4.75 g of 2a-benzoyloxy-4a, 10/J-diacetoxy15 1β, 13a-dihydroxy-5^, 2O-epoxy-70, 8/3-methylene-9-oxo-19nor-ll-taxene, 0.5 g of 4-(dimethylamino) pyridine and 3.01 g of N,N' -dicyclohexylcarbodiimide are added at a temperature in the region of 20°C to a solution, maintained under an argon atmosphere and kept stirring, of 4.01 g of (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylic acid in 19 0 cm3 of anhydrous ethyl acetate. The reaction mixture is kept stirring for 2 hours at a temperature in the region of 20°C and then filtered through sintered glass lined with Celite. The sintered glass is washed with twice 50 cm3 of ethyl acetate, and the filtrates are combined, washed with 5 times 50 cm3 of distilled water, dried over magnesium sulphate,
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4 filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 9.67 g of a yellow foam are obtained, which product is taken up with 70 cm3 of diisopropyl ether. The suspension obtained is stirred for 1 hour at a temperature in the region of 20°C and then filtered through sintered glass. The sintered glass is washed with twice 20 cm3 of diisopropyl ether, and the filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C.
z 7“'^
8.09 g of a yellow foam are obtained, which product is purified by chromatography on 250 g of silica (0.063-0.2 mm) contained in a column 3.8 cm in diameter [eluent: dichloromethane/methanol (99:1 by volume)], collecting 100-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C.
7.23 g of 2a-benzoyloxy-4a, lO/S-diacetoxy-5/S, 20-epoxy1/3-hydroxy-7β, 8/S-methylene-9-oxo-19-nor-ll-taxen-13a-yl
(. (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-420 phenyl-1,3-oxazolidine-5-carboxylate are thereby obtained in the form of a white foam.
(2R,4S,5R)-3-tert-Butoxycarbonyl-2-(4methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid may be prepared in the following manner:
A solution of 10.0 g of methyl (2R,3S)-3-tbutoxycarbonylamino-2-hydroxy-3-phenylpropionate and 0.25 g of pyridium p-toluenesulphonate in 200 cm3 of toluene is dehydrated by distilling off 20 cm3 of
AP/P/ ? ' /01094
AP. Ο Ο 7 8 4 solvent. 6.34 cm3 of p-meth.oxybenzaldeh.yde dimethyl acetal are added over 5 minutes to the reaction mixture heated to boiling. During the addition, 50 cm3 of solvent are distilled off, and a further 100 cm3 of solvent are then distilled off. After cooling to a temperature in the region of 2 0°C, 80 cm3 of cyclohexane are added over 10 minutes. The mixture is cooled to
0-5°C. The slurry obtained is filtered through sintered glass, and tbe filter cake is washed with 40 cm3 of cyclohexane and then dried under reduced pressure at a temperature in the region of 20°C. 10.39 g of .(2R,4S,5R)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4phenyl-5-methoxycarbonyl-1,3-oxazolidine are thereby obtained in a 74 % yield, the characteristics of which product are as follows:
- infrared spectrum (in disk with KBr): characteristic absorption bands at 3100-3000, 2980, 2960, 2930, 2910, 2840, 1740, 1700, 1614, 1514, 1460, 1435, 1390, 1370, 1245, 1175, 1165, 816, 760 and 700 cm'1
- proton nuclear magnetic resonance spectrum (400 MHz;
CDCl-j,- temperature: 323°K; chemical shifts δ in ppm; coupling constants J in Hz): 1.11 (s, 9Ξ); 3.60 (s,
3H); 3.82 (s, 3Ξ); 4.58 (d, J = 5, 1H); 5.42 (broad d,
J = 5,1H); 6.3 8 (broad s, 1H); 6.92 (d, J = 7.5, 2H) ;
7.30 to 7.45 (mt, 7H).
cm3 of an aqueous solution containing
0.31 g of lithium hydroxide monohydrate are added to a solution of 3.0 g of the product obtained above in
AP/P/ 97/010 9 4
AP. Ο Ο 7 8 4 cm3 of methanol. The mixture is stirred for 2 hours at a temperature in the region of 20°C. The methanol is removed by distillation under reduced pressure and 40 cm3 of dichioromethane are then added. With vigorous stirring, the reaction mixture is acidified by adding IN hydrochloric acid to pH 1. After settling has taken place, the aqueous phase is separated and extracted twice with 40 cm3 of dichioromethane. The combined organic phases are dried over sodium sulphate. After filtration and evaporation of the solvent, 2.88 g of (2R,4S,5R)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4.phenyl-1,3-oxazolidine-5-carboxylic acid are obtained in a 94.5 % yield, the characteristics of which product are as follows:
- infrared spectrum (in disk with KBr): characteristic absorption bands at 3325-2S75, 2980, 2955, 2935, 2845,
1755, 1700, 1515, 1590, 1515, 1460, 1250, 1175, 1030, 835, 765 and 705 cm'1
- proton nuclear magnetic resonance spectrum (250 MHz;
CDC13; chemical shifts 5 in ppm; coupling constants J in
Hz): 1.08 (s, 9Ξ) ; 3.82 (s, 3Ξ) ; 4.61 (d, J = 5, 1Ξ) ,δ.42 (broad d, J = 5, IH) ,· 6.38 (broad s, IH) ; 6.92 (d, J = 7.5, 2H); 7.30 to 7.45 (mt, 7H).
2a-Benzoyloxy-4a, lOjS-diacetoxy-10,13a25 dihydroxy-5/3, 20-epoxy-7β, 8/3-methylene-9-oxo-19-nor-lltaxene may be prepared in the following manner;
1.9 g of powdered 4 A molecular sieve and
5.8 g of sodium chloride are added at a temperature in
AP/P/ 9 b / 0 1 0 9 4
AP.00784 the region of 20°C to a solution, maintained under an argon atmosphere and kept stirring, of 3.85 g of 2a-benzoyloxy-4a, 10jS-diacetoxy-ljS, 13a-dihydroxy-5j8,2 0epoxy-9-oxo-70-trif luoromethylsulphonyloxy-11-taxene in a mixture of 75 cm3 of acetonitrile and 7.5 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 30 minutes at a temperature in the region of 20°C, then heated to reflux (75°C) and kept refluxing for 2.5 hours. After cooling to a temperature in the region of 20°C, the reaction mixture is filtered through sintered glass. The sintered glass is washed with 3 times 80 cm3 of dichloromethane, and the filtrates are combined, washed successively with 25 cm3 of saturated aqueous sodium hydrogen carbonate solution and with twice 25 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40“C. 3.5 g of a white foam are obtained, which product is purified by chromatography on 140 g of silica (0.063-0.2 mm) contained in a column 3.5 cm in diameter [eluent:
dichloromethane/methanol (99:1 by volume)], collecting 50-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 2.7 g of
2a-benzoyloxy-4a, lO0-diacetoxy-10,13a-dihydroxy-5/3,20epoxy-7jS, 80-methylene-9-oxo-19-nor-ll-taxene are thereby obtained in the form of a white foam.
AP/P/ 9 7 / 0 1 0 9 4
2a-Benzoyloxy-4a,10β-diacetoxy-1β,13aAP. Ο Ο 7 8 4 dihydroxy-50,20-epoxy- 9 -oxo-7 0-1ri fluoronethylsulphonyloxy-ll-taxene may be prepared in the following manner:
0.32 cm3 of anhydrous pyridine are added at a 5 temperature in the region of 20°C to a solution, maintained under an argon atmosphere and kept stirring, of 0.59 g of 2a-benzoyloxy-4a,lO0-diacetoxy-50,20epoxy-9-oxo-10,70,13a-trihydroxy-11-taxene (baccatin III) in 50 cm3 of diehloromethane, and 0.25 cm3 of trifluoromethanesulphonic anhydride are then added dropwise at a temperature in the region of 20°C. The .reaction medium is then heated to reflux (40°C) for 3 hours, a further 0.08 cm3 of trif luoromethanesulphonic anhydride is add- thereafter and heating to reflux is continued for 1 hour. After cooling to a temperature in the region of 20°C, the reaction medium is poured into a mixture of 50 cm3 of diehloromethane and 20 cm3 of distilled water. The organic phase is separated after settling has taken place, washed successively with
10 cm3 of IN aqueous hydrochloric acid solution and with twice 10 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 0.75 g of a white foam is obtained, which product is purified by chromatography on 60 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter [eluent: dichloromethane/methanol (98.5:1.5 by volume)], collecting 20-cm3 fractions. Fractions containing only y 6 0 1 υ / Z 6 /d/dV
AP.00784 the desired product are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C.
0.675 g of 2a-benzoyloxy-4a, 10/S-diacetoxy-l/S, 13adihydr oxy- 5/6,20- epoxy- 9 - oxo - 7 β - trifiuoromethyl 5 sulphonyloxy-11-taxene is thereby obtained in the form of a white foam.
2a-Benzoyloxy-4a, 10/5-diacetoxy-5/S,20-epoxy-9oxo-l/S, 7/3,13a-trihydroxy-ll-taxene (baccatin III) may be prepared in the following manner;
V 10 182 g of triethylsilyl chloride are added over 1 hour 20 minutes to a solution of 293.9 g of .10-deacetylbaccatin III in 2.7 litres of pyridine. The solution obtained is stirred for.40 hours at 5°C. 360 g of acetic anhydride are then added while the temperature is maintained at 5 °C. The suspension obtained is stirred for 48 hours at 20°C and then poured into 40 litres of ice-cold water. The precipitate obtained is separated by filtration, then / washed with 8 times 2 litres of water and lastly dissolved in 3 litres of ethyl acetate. The organic phase is dried over magnesium sulphate. After filtration and concentration under reduced pressure, the product obtained is crystallized in isopropyl ether. 7-(Triethylsilyl)baccatin III is thereby obtained in a 77 % yield, the characteristics of which product are as follows:
- melting point: 254°C
- proton nuclear magnetic resonance spectrum (400 MHz;
AP/P/ 97 / 0 1 0 9 4
AP. Ο Ο 7 β $
CDC13; δ in ppm): 0.58 (mt, 6H: ethyl CH?) ; 0.92 (t, J =
7.5 Hz, 9H: ethyl CH3) ; 1.02 (s, 3Ξ: CH3) ; 1.18 (s, 3H: CH3) ; 1.68 (s, 3H: CH3) ; 1.75 (broad s, IH: OH at position 1); 1.87 and 2.53 (2 mt, IH each: CH, at position 6); 2.18 (s, 6H: CH3 and COCH3) ; 2.27 (mt, 2Ξ: CH? at position 14); 2.28 (s, 3Ξ: COCH3) ; 2.47 (broad s, IH: OH at position 13); 3.88 (d, J = 7 Hz, IH: H 3); 4.13 and 4.30 (2d, J = 8.5 Hz, 1Ξ each: CH? at position 20); 4.50 (dd, J = 11 and 7 Hz, 1Ξ: Ξ at position 7);
4.81 (mt, 1Ξ: Ξ at position 13); 4.95 (broad d, J = 10
Hz, 1Ξ: Ξ at position 5); 5.63 (d, J = 7 Hz, 1Ξ: Ξ 2) ;
' 6.46 (a·., 1Ξ: Ξ at position 10); 7.46 (t, J = 8.5 Hz,
2H: -OCOCSH5 H at the nata position); 7.60 (t, J = 8.5 Hz, IH: -OCOCSH5 ’ - the para position); 8.10 (d, J =
8.5 Hz, 2H: -OCOCSHS H at the ortho position).
2.3 g of trifluoroacetic acid are added to a solution of 350 mg of 7-(triethylsilyl)baccatin III in 3 cm3 of acetonitrile and 2.4 cm3 of pyridine. The reaction mixture is stirred for 48 hours at 50°C. After cooling, it is taken up with 50 cm3 of methylene chloride, washed with twice 5 cm3 of distilled water, cm3 of N hydrochloric acid and twice 5 cm3 of distilled water and dried over magnesium sulphate.
After filtration and concentration to dryness under reduced pressure, 330 mg of a product are obtained, which product is purified by chromatography on 30 g of silica contained in a column 2 cm in diameter, eluting with a methylene chloride/methanol (99:1 by volume)
AP/P/ 97/1094
AP.00784 mixture. The first 300 cm3 eluted are discarded. The next 275 cm3 yield, after concentration to dryness,
235 mg of baccatin III in the form of a white foam. The yield is 83 %.
EXAMPLE 2
Working as in Example 1, but starting from 270 mg of 4a-acetoxy-2a-benzoyloxy-10,100-dihydroxy50, 2O-epoxy-70,80-methylene-9-oxo-19-nor-11-taxen-13ayl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(410 methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate and 46 mg of 2-thiophenecarboxylic acid, 230 mg of 4a-acetoxy-2a-benzoyloxy-50,2O-epoxy-10-hydroxy-70, 80methylene-9-oxo-100-(2-thienylcarbonyl)oxy-19-nor-11taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(415 methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from 225 mg of 4a-acetoxy-2a-benzoyloxy-50,2O-epoxy-10hydroxy-70,80-methylene-9-oxo-100-(2-thienylcarbonyl)20 oxy-19-nor-11-taxen-13a-yl (2R,4S,5R)-3-tertbutoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3oxazolidine-5-carboxylate, 151 mg of 4a-acetoxy-2abenzoyloxy-50,20-epoxy-10-hydroxy-70,80-methylene-9oxo-100-(2-thienylcarbonyl)oxy-19-nor-ll-taxen-13a-yl (2R,3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]°20 =-23 (c = 0.5; methanol)
AP/P/ 97 /0 1 09 4
(.
AP. Ο Ο 7 8 4
- ΧΗ NMR spectrum (300 MHz; CDC13; chemical shifts 5 in ppm; coupling constants J in Hz): 1.27 (s, 9H:
-C(CH3)3); 1.32 (s, 3H: -(¾ at position 16 or at position 17); 1.39 (s, 3H: -(¾ at position 16 or at position 17); 1.43 (mt,lH: -H at position 7); 1.70 and
2.27 (respectively dd and mt, J = 6.5 and 5, 1Ξ each: -CB^- at position 19); 1.89 (s, 1Ξ: -OH at position 1); 1.91 (s, 3H: CH3) ; 2.13 and 2.48 (respectively broad d and dt, J = 16 and J = 16 and 4.5, IH each: -(¾ at position 6); 2.25 and 2.39 (respectively dd and mt, J =
15.5 and 9, IH each: -(¾ at position 14); 2.39 (s, 3Ξ: .-00(¾) ;. 3.28 (mt, 1Ξ: -OH at position 2') ; 4.05 and
4.33 (2 d, J = 9, IH each: -(¾ at position 20); 4.14 (d, J = 7.5, IH: -H at position 3); 4.62 (mt, 1Ξ: -H at position 2'); 4.75 (d, J = 4.5, IH: -H at position 5);
5.28 (broad d, J = 10, IE: -H at position 3'); 5.37 (d, J = 10, IH: -C0NH-); 5.72 (d, J = 7.5, IH: -H at position 2); 6.30 (broad t, J - 9, IH: -H at position 13); 6.52 (s, IH: -H at position 10); 7.15 [(dd, J = 5 and 3.5, IH: -C4H3S (-H at position 4); from 7.25 to
7.45 (mt, 5H: -0¾ at position 3'); 7.51 [(t, J = 7.5, 2H: 0000¾ (-H at position 3 and H at position 5)];
7.61 [(t, J = 7.5, 1Ξ: 0000¾ (-H at position 4)]; 7.62 [ (dd, J = 5 and 1.5, IH: -C4H3S (-H at position 5)];
7.88 [(dd, J = 3.5 and 1.5, IH: -C4H3S (-H at position
3)]; 8.15 (d, J = 7.5, 2Ξ: 0000¾ (-H at position 2 and H at position 6).
EXAMPLE 3
AP/P’ 9 7/. C 9 4
AP. ο ο 7 8 4
Working as in Example 1, but starting from 270 mg of 4a-acetoxy-2ce-benzoyloxy-l/S, 10/5-dihydroxy5)3, 20epoxy-7/3,8/3-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R) -3-tert-butoxycarbonyl-2- {4-methoxyphenyl) -45 phenyl-1,3-oxazolidine-5-carboxylate and 0.038 cm3 of cyclopentanecarboxylic acid, 187 mg of 4a-acetoxy-2abenzoyloxy- 10/3-cyclopentylcarbonyloxy- 5/3,2 0 -epoxy- 1βhydroxy-7/3,8/5-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4i . ’ phenyl-1,3-oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from 182 mg of 4a-acetoxy-2a-benzoyloxy-10/5-cyclopentylcarbonyloxy-5/3,20-epoxy-1/3-hydroxy-7/3, 8/S-methylene-915 oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R)-3-tertbutoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-l, 3oxazolidine-5-carboxylate, 100 mg of 4a-acetoxy-2ab enz oyloxy-10 /5 - cy c 1 op en ty 1 carbony1oxy-5 β,20-epoxy-1β( hydroxy-7/S,8/S-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R,3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]D20 = -40 (c = 0.5; methanol)
- ’Ή NMR spectrum (300 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 1.26 (s, 3H: -CH3 at position 16 or at position 17); 1.29 (s, 3H: -CH3 at position 16 or at position 17); 1.29 (s, 9H: -C(CH3)3); 1.40 (mt, 1Ξ: -H at position 7); from 1.50 to 1.80
AP/P/ 97/01094
AP.00784 [(mt, 4H: -C5H3 (-(¾ at position 3 and -CH2 at position
4) and IH -CH2 at position 19)]; 1.86 (s, 4Ξ: -CH3 and -OH at position 1); from 1.85 to 2.05 [(mt, 4H: -CSHS (-CH, at position 2 and -CHj at position 5)]; 2.11 and
2.47 (respectively broad d and dt, J = 16 and J = 16 and 4.5, IH each: -CHj- at position 6); 2.22 and 2.38 (respectively dd and mt, J = 15.5 and 9, 1Ξ each: -(¾ at position 14); 2.25 (mt, 1Ξ: -(¾ at position 19);
2.39 (s, 3H: -00(¾) ; 2.90 (mt, IH: -C5H, (-CH< at position 1)]; 3.26 (mt, IH: -OH at position 2'); 4.03 and 4.31 (2 d, J = 9,1H each: -(¾ at position 20); 4.11
-(d, J * 7.5, IH: -H at position 3); 4.62 (mt, 1Ξ: H at position 2'); 4.74 (d, J = 4.5, 1Ξ: -H at position 5),
5.28 (broad d, J = 10, IH: -H at position □ '); 5.35 (d,
J = 10, 1Ξ: -CONH-); 5.68 (d, J = 7.5, IH: -H at position 2); 6.27 (broad t, J = 9, 1Ξ: -H at position 13); 6.32 (s, IH: -H at position 10); from 7.25 to 7.45 (mt, 5H: -CSHS at position 3'); 7.51 [(t, J = 7,5, 2H: -OCOCSHS (-H at position 3 and H at position 5)]; 7.60 [(t, J = 7.5, 1Ξ: -OCOCSH5 (-H at position 4)]; 8.15 (d,
J = 7.5, 2H: -OCOCgHj (-H at position 2 and H at position 6)].
EXAMPLE 4
Working as in Example 1, but starting from
270 mg of 4a!-acetoxy-2a-benzoyloxy-10,10/3-dihydroxy5/3,20-epoxy-7/3, 8/3-methylene-9-oxo-19-nor-ll- taxen-13ayl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl) -4-phenyl-l, 3-oxazolidine-5-carboxylate and
AP/P/ 9 7/010 9 4 (2
Γ
Vj.
ΑΡ. Ο V Ί8 4
0.028 cm3 of cyclopropanecarboxylic acid, 110 mg of 4a-acetoxy-2a-benzoyloxy-10/S-cyclopropylcarbonyloxy5β,20-epoxy-1β-hydroxy-7β, 8β-methy1ene-9-oxo-19-nor-11taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(45 methoxyphenyl)-4-phenyl-1, 3-oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from 110 mg of 4a-acetoxy-2a-benzoyloxy-10/8cyclopropylcarbonyloxy-5/S, 20-epoxy-l/8-hydroxy-7/3, 8/310 methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R/-3tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-'oxazolidine-5-carboxylate, 62 mg of 4a-acetoxy-2abenzoyloxy-10/8-cyclopropylcarbonyloxy-5/S, 2 0-epoxy-1/3hydroxy-7/3, 8/S-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R,3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]D30 = -35 (c = 0.5; methanol)
- 3H NMR spectrum (400 MHz; CDC13; chemical shifts δ in 20 ppm; coupling constants J in Hz) : 0.98 and 1.13 (2 mt,
2H each: -C3H5 (-CHj- at position 2 and -CH2- at position
3); 1.27 (s, 3H: -CH3 at position 16 or at position 17);
1.30 (s, 12H: -CH3 at position 16 or at position 17 and -C(CH3)3); 1.38 (mt, 1Ξ: -H at position 7); 1.67 and
2.26 (respectively dd and mt, J = 6.5 and 5, IH each:
-CH2- at position 19); 1.74 (mt, IH: -C3H5 (-CH< at position 1); 1.86 (s, 4H: -OH at position 1 and -CH3) ; 2.12 and 2.44 (respectively broad d and dt, J a 16 and
AP/P/ 9 7 / 0 1 0 9 4
AP. ο Ο 7 8 4
J a 16 and 4.5, 1Ξ each.: -CH,- at position 6); 2.25 and 2.38 (respectively dd and mt, J = 16 and 9, IH each: -CH,- at position 14); 2.38 (s, 3Ξ: -COCH3) ; 3.27 (mt,
IH: -OH at position 27); 4.03 and 4.32 (2d, J = 9, IH each: -CH,- at position 20); 4.10 (d, J = 7.5, IH: -H at position 3); 4.62 (mt, IH: -H at position 2'); 4.72 (d, J = 4.5, 1Ξ: -H at position 5); 5.29 (broad d, J = 10, 1Ξ: -H at position 3'); 5.36 (d, J = 10, 1Ξ: -CONH-); 5.67 (d, J = 7.5,1Ξ: -H at position 2); 6.28 (broad t,
J = 9., IH: -H at position 13); 6.34 (s, IH: -H at position 10); from 7.25 to 7.45 (mt, 5H: -CSHS at .position 3'); 7.51 [(t, J = 7.5, 2Ξ: -OCOCSHS (-H at position 3 and H at position 5)3; 7.61 [{t, J = 7.5,
IH: -OCOCSHS (-H at position 4)3; 8.15 [(d, J = 7.5, 2Ξ:
-OCOCSHS (-H at position 2 and Ξ at position 6)3 *
EXAMPLE 5
Working as in Example 1, but starting from 280 mg of 4a-acetoxy-2a-benzoyloxy-l/S, 10/5-dihydroxy5/3, 20-epoxy-7/5, 8/3-methylene-9-oxo-19-nor-11-tax en-13 a20 yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl) -4-phenyl-l,3-oxazolidine-5-carboxylate and
41.5 mg of 2-furancarboxylic acid, 201 mg of 4a-acetoxy-2a-benzoyloxy-5/S, 20-epoxy-10/3(2 - furyl c arbony 1) oxy-1 β - hydroxy - 7 β, 8 β - me thy 1 ene -9-oxo25 19-nor-ll-taxen-13a-yl (2R,4S,5R)-3-tertbutoxycarbonyl-2 - (4-methoxyphenyl)-4-phenyl-1,3oxazolidine-5-carhoxylate are obtained in the form of a *6010/16 /d/dV white foam.
,Λ
ΑΡ.Ο Ο 7 8 4
Working as in Example 1, but starting from 197 mg of 4a-acetoxy-2a-benzoyloxy-50,20-epoxy-10/3(2 - furyl carbonyl) oxy -10 - hydroxy - 7 0, 8 0 - me thyl ene - 9 - oxo 19-nor-ll-taxen-13a-yl (2R,4S,5R)-3-tert5 butoxycarbonyl-2 - (4-methoxyphenyl) -4-phenyl-l,3oxazolidine-5-carhoxylate, 137 mg of 4a-acetoxy-2abenzoyloxy-50,20-epoxy-100- (2-furylcarbonyl) oxy-10hy dr oxy-70, 80-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R, 3S) -3 - tert-butoxycarbonylamino-2-hydroxy-3-phenyl10 propionate are obtained in the form of a white foam, the characteristics of which are as follows:
- - optical rotation: [a]D,0 = -19 (c = 0.5? methanol)
- 3H NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz) : 1.28 (s, 9Ξ:
-C(CH3)3); 1.32 (s, 3H: -CH3 at position 16 or at position 17) ; 1.38 (s, 3H: -CH3 at position 16 or at position 17); 1.43 (mt, IH: -H at position 7); 1.70 and
2.28 (respectively dd and mt, J = 7 and 5, IH each:
-CH,- at position 19); 1.89 (s, IH: -OH at position 1):
1.91 (s, 3H: -CH3); 2.12 and 2.49 (respectively broad d and d, J = 16 and J = 16 and 4.5, IH each: -CH,- at position 6); 2.27 and 2.40 (respectively dd and mt, J = 16 and 9, IH each: -CH,- at position 14); 2.40 (s, 3H: -COCH3) ; 3.26 (mt, IH: -OH at position 2'); 4.05 and
4.33) (2 d, J = 9, IH each: -CH,- at position 20); 4.10 (d, J = 7.5, IH: -H 3) ; 4.63 (mt, IH: H at position 2'); 4.72 (d, J = 4.5, IH: -H at position 5); 5.29 (broad d, J = 10, 1Ξ: -H at position 3'); 5.36 (d, J =
AP/P/ 9 7/010 9 4
AP. Ο Ο 7 8 4 (,· </··'
10, IH: -CONH-); 5.71 (d, J = 7.5, IH: -H at position 2); 6.29 (broad t, J = 9 IH: -H at position 13); 6.53 (s, IH: -H at position 10); 6.56 [ (dd, J = 5 and 1.5,
IH: -C4H3O (-H at position 4)]; 7.26 [ (d, J = 4, IH:
-C4H3O (-H at position 3)]; from 7.25 to 7.45 (mt, 5H: -CSHS at position 3'); 7.51 (t, J = 7.5, 2Ξ: -OCOCSHS (-H at position 3 and H at position 5)]; 7.61 (t, J = 7.5, IH: -OCOCSHS (-H at position 4)]; 7.64 (broad s, IH: -C4H3O (-H at position 5)]; 8.15 (d, J = 7.5, 2H:
-OCOCeHs (-H at position 2 and H at position 6)] .
EXAMPLE 6
Working as in Example 1, but starting from 280 mg of 4a-acetoxy-2a-benzoyloxy-l£, 100-dihydroxy5/3,2O-epoxy-70, 8/3-methylene-9-oxo-19-nor-ll-taxen-13e. 15 yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl) -4-phenyl-l,3-oxazolidine-5-carboxylate and 45 mg of benzoic acid, 190 mg of 4a-acetoxy-2a, 10/3dibenzoyloxy- 5β, 2 0 - epoxy- 1β-hydroxy- 7β, 8/3-methylene - 9 oxo-19-nor-11-taxen-13a-yl (2R,4S,5R)-3-tert20 butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-l,3oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from 190 mg of 4a-acetoxy-2a, 10/3-dibenzoyloxy-5/3, 20-epoxy25 1β-hydroxy-7β,8/3-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4phenyl-1,3-oxazolidine-5-carboxylate, 120 mg of 4a-acetoxy-2a, lO0-dibenzoyloxy-50, 20 -epoxy-1/3-hydroxyAP/P/ 9 7 / ζ 10 9 4
AP . Ο Ο 7 8 4
Ίβ, 8/J-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R, 3S) -3tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]D20 = -28 (c = 0.5; methanol)
- 1H NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 1.29 (s, 9H:
-C(CH3)3); 1.34 {s, 3H: -(¾ at position 16 or at position 17) ; 1.42 (s, 3H: -(¾ at position 16 or at position 17); 1.42 (mt, 1H: -H at position 7); 1.69 and 2.27 (respectively dd and mt, J = 7 and 5, 1H each: -GH2 •at position 19); 1.91 (s, 1H: -OH at position 1); 1.92 (s, 3H: -CH3) ; 2.13 and 2.50 (respectively broad d and dt, J = 15 and J = 16 and 4.5, IH each: -CH2- at position 6); 2.26 and 2.41 (respectively dd and mt, J = 16 and 9, IH each: -CHj- at position 14); 2.41 (s, 3H: -COCH3) ; 3.26 (mt,lH: -OH at position 2'); 4.07 and 4.34 (2d, J = 9, IH each: -(¾ - at position 20) ; 4.18 (d, J = 7.5, 1Ξ: -H at position 3); 4.63 (mt, IH: -H at position 2'); 4.75 (d, J = 4.5, IH: -H at position 5);
5.29 (broad d, J = 10, 1Ξ: -H at position 3'); 5.37 (d, J = 10, IH: -CONH-); 5.73 (d, J = 7.5, IH: -H at position 2); 6.29 (broad t, J = 9, IH: -H at position 13); 6.60 (s, IH: -H at position 10); from 7.25 to 7.45 (mt, 5H: -CSHS at position 3'); 7.49 and 7.51 [(2 t, J =
7.5, 2H each: -OCOCSH5 (-H at position 3 and H at position 5)]; from 7.55 to 7.65 [{mt, 2H: -OCOCSH5 (-H at position 4)]; 8.09 and 8.17 [(2d, J = 7.5, 2H each:
fc 6 0 I 0 / L 6 /d/dV
AP. Ο Ο 7 8 4
-OCOCSH5 (-Η at position 2 and H at position 6)] .
EXAMPLE 7
Working as in Example 1, but starting from 300 mg of 4a-acetoxy-2a-benzoyloxy-10,100-dihydroxy5 50,2O-epoxy-70,80-methylene-9-oxo-19-nor-ll-taxen-13ayl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate and 0.686 cm3 of 3-methyl-2-propenoic anhydride, 237 mg of 4a-acetoxy-2oi-benzoyloxy-50,20-epoxy-10-hydroxy-lO0- (310 methyl-2-propenoyl)oxy-70,80-methylene-9-oxo-19-nor-lltaxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4.me thoxypheny1)-4-phenyl-1,3 -oxazolidine-5-carboxylate are obtained in the form of a white foam.
Wcr.--.ng as in Example 1, but starting z.rc j
270 mg of 4a-acetoxy-2a-benzoyloxy-50,2O-epoxy-10hydroxy-100-(3-methyl-2-propenoyl)oxy-70,80-methylene9-oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R)-3-tertbutoxycarhonyl-2-(4-methoxyphenyl)-4-phenyl-l,3 oxazolidine-5-carboxylate, 192 mg of 4a-acetoxy-2di20 benzoyloxy-50,2O-epoxy-10-hydroxy-lO0-(3-methyl-2propenoyl)oxy-70,80-methylene-9-oxo-19-nor-11-taxen13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]D20 = -34 (c = 0.5; methanol)
- 3H NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 1.27 (s, 12Ξ: -C(CH3)3 and -CH3 at position 16 or at position 17); 1.30 (s, 3H:
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4
-CH3 at position 16 or at position 17); 1.39 (mt, 1H: -H at position 7); 1.67 and 2.26 (respectively dd and mt,
J = 6.5 and 5.5, 1H each.: -CH, at position 19); 1.86 (s, 4H: -OH at position 1 and -CH3) ; 1.93 (dd, J = 7.5 and
1.5, 3H: -CH3) ; 2.11 and 2.47 (respectively broad d and dt, J = 16 and J = 16 and 4.5, 1H each: -CH2- at position 6); 2.23 and 2.39 (respectively dd and mt, J = and 9, 1H each: -CH2- at position 14); 2.38 (s, 3H: -COCH3) ; 3.25 (mt, 1H: -OH at position 2'); 4.04 and
4.30 (2 d, J = 9, 1H each: -CH,- at position 20); 4.12 (d, J = 7.5,1H: -H at position 3); 4.62 (mt, 1H: -H at position 2'); 4.73 (d, J = 4.5, 1H: -H at position 5);
5.29 (broad d, J = 10, 1Ξ: -Ξ at position 3') 5.36 (d,
J = 10, 1H: -C0NH-); 5.68 (d, J = 7.5, 1H: -H at position 2); 5.98 [(dd, J = 16 and 1.5, 1Ξ:
-OCOCH=CH-CH3) ] ; 6.27 (broad t, J = 9, 1Ξ: -H at position 13); 6.40 (s, 1Ξ: -H at position 10); 7.07 [(dt, J » 16 and 7.5, 1H: -OCOCH=CH-CH3) ] ; from 7.25 to 7.50 (mt, 5H: -CgHj at position 3'); 7.51 E(t, J = 7.5,
2H: OCOCSHS (-H at position 3 and H at position 5)];
7.61 [(t, J = 7.5, 1H: -OCOCgHg (-H at position 4)];
8.15 [(d, J = 7.5, 2Ξ: OCOCeHs (-H at position 2 and H at position 6)].
EXAMPLE 8
Working as in Example 1, but starting from
220 mg of 4a-acetoxy-2a-benzoyloxy-l/S,10/5-dihydroxy50,20-epoxy-7/3, 80-methylene-9-oxo-19-nor-ll-taxen-13ayl (2R,4S,5R) -3 - tert-butoxycarbonyl-2 - (4-methoxy* 6 0 I 0 / L 6 Zd/dV f
AP. Ο Ο 7 8 4 phenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate and 28 mg of chloroacetic acid, 100 mg of 4a-acetoxy-2abenzoyloxy-10 β-chloroace toxy- 5(3, 2 0 - epoxy- 1/3-hydroxy 7/3, 8/S-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1,3-oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from
155 mg of 4a-acetoxy-2a-benzoyloxy-10/S-chloroacetoxy10 5/3, 2 0-epoxy-l/3-hydroxy-7/S, 8/5-methylene-9-oxo-19-nor-11taxen-13a-yl (2R, 4S, 5R) -3-tert-butoxycarbonyl-2-(4' methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate, 64 mg of 4a-acetoxy-2a-benzoyloxy-10/S-chloroacetoxy5β, 20-epoxy-1,5-hydroxy-7/3, 8£-methylene-9-oxo-19-nor-1115 taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2hydroxy-3-phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]D20 = -39 (c = 0.5; methanol)
- NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz) : 1.27 (s, 3Ξ: -CH3 at position 16 or at position 17); 1.29 (s, 12H: -CH3 at position 16 or at position 17 and -C(CH3)3); 1.39 (mt, 1H: -H at position 7); 1.71 and 2.26 (respectively dd and mt, J = 7 and 5.5, 1H each: -CH3- at position 19);
1.87 (s, 4H: -OH at position 1 and -CH3); 2.12 and 2.47 (respectively broad d and dt, J = 16 and J = 16 and
4.5, 1Ξ each: -CHj- at position 6); 2.27 and 2.38
AP/P/ 97 / 'MM
AP. Ο Ο 7 8 4 (respectively dd and mt, J = 16 and 9, 1H each: -CH?- at position 14); 2.40 (s, 3H: -COCHJ; 3.27 (mt, 1H: -OH at position 2'); 4.03 and 4.32 (2 d, J = 9, 1H each: -CH?at position 20); 4.07 (d, J = 7.5, 1H: -H at position
3); 4.26 (limiting AB, J = 16, 2H: -OCOCH2C1) ; 4.62 (mt,
1Ξ: -H at position 2'); 4.74 (d, J = 4.5, 1H: -H at position 5); 5.28 (broad d, J = 10 Hz, 1H: -Hat position 3'); 5.35 (d, J = 10, 1Ξ: -CONH-); 5.68 (d, J = 7.5, 1H: -H2); 6.28 (broad t, J = 9 Hz, 1H: -H at position 13); 6.38 (s,lH: -Ξ at position 10); from 7.25 to 7.45 (mt, 5Hs -CgHs at position 3'); 7.51 [(t, J = . 7.5, 2H.: -OCOCSHS (-H at position 3 and H at position
5)]; 7.61 ((t, J = 7.5, 1H: -OCOCeH5 (-H at position
4)]; 8.16 (d, J = 7.5, 2H: -OCOCSHS (-H at position 2 15 and H at position 6) ] .
EXAMPLE 9
Working as in Example 7, but starting from
00 mg of 4a-acetoxy-2a-benzoyloxy-l/8,100-dihydroxy5/3, 20-epoxy-7/S, 8/3-methylene-9-oxo-19-nor-11-taxen-13a20 yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate and
52.4 mg of ethoxycarbonylacetic acid, 180 mg of
4a-acetoxy-2a-benzoy1oxy-5β,20-epoxy-10βe thoxycarbony1ac e toxy-1β- hydroxy-7β,8 β-methylene-9-oxo25 19-nor-11-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2- (4-methoxyphenyl)-4-phenyl-l,3-oxazolidine5-carboxylate are obtained in the form of a white foam.
Working as in Example 7, but starting from
AP/P/ 97 / 0 1 0 9 4
AP. Ο Ο 7 8 4
190 mg of 4a-acetoxy-2a-benzoyloxy-50,2O-epoxy-lO£ethoxycarbonylac etoxy- 1β - hydroxy - Ίβ,Ββ -methyl ene - 9 - oxo 19-nor-ll-taxen-13a-yl (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-l,3-oxazolidine5 5-carboxylate, 73 mg of 4a-acetoxy-2a-benzoyloxy-5jS,20epoxy-10/5-ethoxycarbonylacetoxy-l/S-hydroxy-7/5, 8βmethylene-9-oxo-19-nor-11-taxen-13a-yl (2R,3S)-3-tertbutoxycarbonylami.no-2 -hydroxy- 3 -phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]D20 = -28 (c = 0.5; methanol) .- 1H NMR spectrum (300 ΜΞζ; CDCl3; chemical shifts δ in ppm; coupling constants J in Hz) : 1.24 (s, 3H: -(¾ at position 16 or at -/i} 1.28 (s, 12Ξ: --(/.^3)3 and -(¾ at position 16 or at position 17); 1.32 (t, J =
7.5, 3H: -OCOCH2COOCH2OT3) ; 1.41 (mt, 1Ξ: -H at position 7); 1.72 and 2.22 (respectively dd and mt, J = 6.5 and 5, 1H each: -CHj- at position 19); 1.89 (s, 4H: -OH at position 1 and -¾); 2.15 and 2.50 (respectively broad d and dt, J = 16 and J = 16 and 4.5, 1H each: -CH2- at position 6); 2.28 and 2.40 (respectively dd and mt, J = 16 and 9, 1H each: -CH2- at position 14); 2.42 (s, 3H: -COCH3) ; 3.32 (mt, 1Ξ: -OH at position 2'); 3.58 (limiting AB, 2H: -OCOCHjCOOCHjCH3) ; 4.08 and 4.35 (2 d,
J = 9 Hz, 1H each: -CHj- at position 20); 4.10 (d, J =
7.5, 1Ξ: -H at position 3); 4.28 (q, J = 7.5, 2H: -OCOCHjCOOCHjCHj) ; 4.53 (mt, 1H: -H at position 2')l
4.75 (d, J = 4.5, 1H: -H at position 5); 5.29 broad d,
AP/P/97/0 :09 4
ΑΡ.00784
J « 10, IH: -H at position 3'); 5.39 (d, J = 10, IH: -CONH-); 5.69 (d, J = 7.5, 1Ξ: H at position 2); 6.30 (broad t, J = 9, 1Ξ: -H at position 13); 6.38 (s, 1Ξ:
-H at position 10); from 7.25 to 7.50 (mt, 5H: -CgHj at position 3'); 7.53 [(t, J = 7.5, 2Ξ: -OCOCSHS (-H at position 3 and H at position 5)]; 7.62 [(t, J = 7.5,
1Ξ: -OCOCSHS (-H at position 4)]; 8.18 [(d, J = 7.5, 2H: -OCOCSHS (-H at position 2 and H- at position 6)].
EXAMPLE 10
Working as in Example 1, but starting from
4a-acetoxy-2a-benzoyloxy-10/ 10/5-dihydroxy-5/3,20-epoxy7/3, 8/3-methylene-9-oxo-19-nor-ll-taxen-13o!-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4phenyl-1,3-oxazolidine-5-carboxylate and 584 mg of acrylic anhydride, 160 mg of 4a-acetoxy-10/5acryloyloxy-2a-benzoyloxy-5/3, 20-epoxy-l/8-hydroxy-7/S, 8/3methylene-9-oxo- 19-nor-ll-taxen-13a-yl (2R, 4S, 5R) -3tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1, 3oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from 196 mg of 4a-acetoxy-10/S-acryloyloxy-2a-benzoyloxy5/3, 20-epoxy-l/S-hydroxy-7/5, 8/3-methylene-9-oxo-19-nor-lltaxen-13a-yl (2R,4S,5R) -3-tert-butoxycarbonyl-2-(425 methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate, 113 mg of 4a-acetoxy-10/?-acryloyloxy-2a-benzoyloxy5/3,20-epoxy-1/3-hydroxy-7/3, 8/S-methylene-9-oxo-19-nor-lltaxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4 hydroxy-3 -phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
, - optical rotation: [a] °20 » -39 (c = 0.5; methanol)
- NMR spectrum (400 MHz; CDC13; obem-ϊ oal shifts δ in ppm; coupling constants J in Hz): 1.27 [s, 12Ξ: -C(CH3)3 and CH3 at position 16 or at position 17]; 1.30 (s, 3Ξ: -CH3 at position 16 or at position 17); 1.39 (mt, IH: -H at position 7); 1.68 and 2.26 (respectively dd and mt,
Χ.?.'
J = 6.5 and 5, IH each: -CHj- at position 19); 1.86 (s, IH: -OH 1); 1.88 (s, 3Ξ: -CH3) ; 2.13 and 2.49 (respectively broad d and dt, J a 15 and J a 15 and 4,
IH each: -CHj- at position 6); 2.25 and 2.39 (2 mts, IH each: -C32- at position 14); 2.38 (s, 3H: -COCH3) ; 3.27 (mt, IH: -OH at position 2'); 4.06 and 4.34 (2 d, J =
9, IH each) : -CHj- at position 20); 4.13 (d, J a 7, IH: -H at position 3); 4.63 (mt, 1Ξ: -H at position 2');
4.75 (d, J a 4, 1Ξ: -H at position 5); 5.29 (broad d, J
Q. = 10, IH: -H at position 3'); 5.35 (d, J a 10, IH:
-CONH-); 5.69 (d, J = 7, 1Ξ: -H at position 2); 5.95 and 6.53 (2 dd, respectively J = 10 and 1.5 and J = 16 and 1.5, IH each: -OCOCHaCHJ ; 6.27 (dd, J = 16 and 10, IH: -OCOCHaCH,) ; 6.29 (mt, IH: -H at position 13); 6.42 (s, IH: -H at position 10); from 7.25 to 7.45 (mt, 5H:
-CSHS at position 3'); 7.53 [(t, J = 7.5, 2H: -OCOCSHS (-H at position 3 and H at position 5)]; 7.63 [(t, J =
7.5, 1Ξ: -OCOCSHS (-Ξ at position 4)]; 8.17 (d, J = 7.5, 2H: -OCOCSHS (-H at position 2 and H- at position 6)].
AP/P/ 97 / 0 1 09 4
AP.00784
EXAMPLE 11
Working as in Example 1, but starting from 250 mg of 4a-acetoxy-2a-benzoyloxy-10,100-dihydoxy50,20-epoxy-70,80-methylene-9-oxo-19-nor-11-taxen-13a5 yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxypheny 1) -4-phenyl-l,3-oxazolidine-5-carboxylate and 41 mg of 3-pyridinecarboxylic acid, 269 mg of 4a-acetoxy-2a-benzoyloxy-50, 20-epoxy-10-hydroxy-70,80methylene- 9-oxo-100-(3-pyridylcarbonyl)oxy-19-nor-1110 taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4methoxyphenyl) -4-phenyl-l, 3-oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from 264 mg of 4a-acetoxy-2a-benzoyloxy-50,20-epoxy-1015 hydroxy-70, 80-methylene-9-0X0-100- (3-pyridylcarbonyl)oxy-19-nor-ll-taxen-13a-yl (2R,4S,5R)-3-tertbu t oxy c arbony 1 - 2 - (4 - me thoxypheny1 )-4- phenyl -1,3 oxazolidine-5-carboxylate, 169 mg of 4a-acetoxy-2abenzoyloxy-50,2O-epoxy-10-hydroxy-70, 80-methylene-920 oxo-100- (3-pyridylcarbonyl) oxy-19-nor-11-taxen-13a-yl (2R,3S)-3 - tert-butoxycarbonylamino - 2 - hydroxy- 3 -phenyl propionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a] “20 = -25 (c = 0.5; methanol)
- XH NMR spectrum (400 MHz; CDCl3; chemical shifts δ in ppm? coupling constants J in Hz): 1.29 [s, 9H: -C(CH3)3]; 1.34 (s, 3H: -CH3 at position 16 or at position 17); 1.41 (s, 3H: -CH3 at position 16 or at
AP/P/ 97 / 0 1 0 9 4
t.·
AP. Ο Ο 7 8 4 position 17) ; 1.45 (mt, IH: -H at position 7) ; 1.74 and
2.29 (respectively dd and mt, J = 6.5 and 5.5, IH each: -CH,- at position 19); 1.94 (s, 3H: -CH,) ; 2.14 and 2.52 (respectively broad d and dt, J = 16 and J = 16 and 4,
IH each: -CH,- at position 6); 2.29 and 2.43 (2 mts, 1Ξ each: -CH,- at position 14); 2.43 (s, 3H: -COCH,); 3.31 (mt, IH: -OH at position 2'); 4.07 and 4.35 (2d, J =
9, IH each: -CH,- at position 20); 4.17 (d, J = 7.5, IH: -H at position 3); 4.64 (mt, 1Ξ: -H at position 2');
4.77 (d, J = 4, 1Ξ: -H at position 5); 5.30 (broad d, J = 10, 1Ξ: -H at position 3'); 5.37 (d, J = 10, IH:
. -CONH-); 5.74 (d, J = 7.5, IH: -H at position 2); 6.32 (broad t, J = 8.5, IH: -H at position 13); 6.63 (s, IH: -H at position 10); from 7.25 t. .45 (mt. /1: -CSHS at position 3'); 7.45 [ (dd, J = 8 and 5.5, 1Ξ: -OCOC5H4N (-H at position 5)]; 7.53 [(t, J = 7.5, 2Ξ: -OCOCSHS (-H at position 3 and H at position 5)]; 7.63 C(t, J = 7.5, IH: -OCOCSHS (-H at position 4)3; 8.18 [ (d, J = 7.5, 2H: -OCOCsH5 (-H at position 2 and -H at position 6)3; 8.36 [(dt, J = 8 and 1.5, IH: -OCOC,H4N (-H at position 4)3;
8.84 (dd, J = 5.5 and 1.5, IH: -OCOCsHtN (-H at position
6)3? 9.29 (d, J = 1.5, IH: -OCOC5H4N (-H at position 2)] .
EXAMPLE 12
Working as in Example 1, but starting from
250 mg of 4a-acetoxy-2a-benzoyioxy-1^, 10/S-dihydroxy5/3, 20-epoxy-7/5, 8/S-methylene-9-oxo-19-nor-ll-taxen-13ayl (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4-methoxyAP/P/ 9 7/110 9 4 k;.
AP. Ο Ο 7 8 4 phenyl) -4-phenyl-l, 3-oxazolidine-5-carboxylate and 42 mg of 3-thiophenecarboxylic acid, 180 mg of 4a-acetoxy-2a-benzoyloxy-5)S, 20 -epoxy-1/3-hydroxy-7)3, 8)5methylene-9-oxo-10)3- (3-thenoyl) oxy-19-nor-11-taxen-13a5 yl (2R,4S,5R)-3-tert-butoxycarbonyl-2 - (4-met hoxyphenyl) -4-phenyl-l, 3-oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from 175 mg of 4a-acetoxy-2a-benzoyloxy-5/S,20-epoxy-l/310 hydroxy-7)S, 8)S-methylene-9-oxo-10)S- (3-thenoyl) oxy-19nor-11-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2(4-methoxyphenyl) -4-phenyl-l, 3-oxazolidine-5carboxylate, 102 mg of 4a-acetoxy-2a-benzoyloxy-5)S,20epoxy-10-hydroxy-7 )5, 8/3-methylene-9-oxo-10)3- (315 thenoyl)oxy-19-nor-ll-taxen-13a-yl (2R,3S)-3-tertbutoxycarbonylamino-2 -hydroxy-3 -phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a] °20 = -16 (c = 0.5; methanol)
- τΗ NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz) : 1.30 [s, 9H:
AP/P/ 9 7 / 0 1 0 9 4
| -C(CH3)3] | ; 1.33 (s, | 3H: | -ch3 | at position 16 or at |
| position | 17); 1.40 | (s, | 3H: | -CH3 at position 16 or at |
| position | 17); 1.44 | (mt, | 1H: | -H at position 7); 1.72 and |
2.29 (2 dd, respectively J = 6.5 and 5.5 and J = 10 and
6.5, 1H each: -CHj- 19); 1.92 (s, 4H: -CH3 and -OH at position 1); 2.14 and 2.51 (respectively broad d and dt, J = 16 and J = 16 and 4, 1H each: -CH2- at position
AP. Ο Ο 7 8 4
6) ; 2.26 and 2.42 (2 mts, 1Ξ each.: -CH,- at position 14); 2.42 (s, 3H: -COCH3) ; 3.27 (mt, 1H: -OH at position 2'); 4.06 and 4.32 (2d, J = 9, 1H each: -CH,- at position 20); 4.17 (d, J = 7.5, 1H: -H at position 3);
4.63 (mt, 1H: -H at position 2'); 4.76 (d, J = 4, 1H:
-H at position 5); 5.29 (broad d, J = 10, 1H: -H at position 3'); 5.35 (d, J = 10, 1Ξ: -CONH-); 5.72 (d, J = 7.5, 1H: -Ξ at position 2); 6.30 (broad t, J = 8.5,
1Ξ: -H at position 13); 6.53 (s, 1Ξ: -H at position
10); from 7.25 to 7.45 [mt, 6Ξ: -CSHS at position 3' and
-OCOC4H3S (-H at position 5)3; 7.53 [(t, J = 7.5, 2H:
'-OCOCsHj (-H at position 3 and H at position 5)]; 7.57
| [broad d, | J | = 5.5, | 1H: | -OCOC,H3S (-H at position 4)3; | ||
| 7.62 [(t, | J | = 7.5, | 1Ξ: | -OCOCSHS (-H at position | 4)3; | |
| 15 | 8.17 [ (d, | J | = 7.5, | 2Ξ: | -OCOCSHS (-H at position | 2 and Ξ- |
| at position | 6)3; 8 | .19 | [mt, 1H: -OCOC4H3S (-H at | position |
2)] .
EXAMPLE 13
Working as in Example 1, but starting from
300 mg of 4a-acetoxy-2a-benzoyloxy-10,100-dihydroxy50,2O-epoxy-70,80-methylene-9-oxo-19-nor-11-taxen-13ayl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate and 713 mg of vinylacetic anhydride, 114 mg of 4a-acetoxy25 lO0-allylcarbonyloxy-2a-benzoyloxy-50,2O-epoxy-10hydroxy-70,80-methylene-9-oxo-19-nor-11-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4phenyl-1,3-oxazolidine-5-carboxylate are obtained in fr 6 0 I 0 / L 6 /d/dV
AP. Ο Ο 7 8 4 the form of a white foam.
Vinylacetic anhydride may be prepared in the following manner:
2.8 cm3 of vinylacetic acid are added dropwise %
and at a temperature in the region of 20°C to a solution, maintained under an argon atmosphere and kept stirring, of 3.42 g of N,N'-dicyclohexyl- carbodiimide in 20 cm3 of dichioromethane. The reaction medium is kept stirring at a temperature in the region of 20°C
U· io for 3’ days, and then filtered through sintered glass lined with Celite. The sintered glass is washed with ' twice 1Ό cm3 of dichioromethane, and the filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 2.96 g of vinylacetic anhydride are thereby obtained in the form of a yellow oil.
Working as in Example 1, hut starting from 140 mg of 4a-acetoxy-10/S-allylcarbonyloxy-2a(; benzoyl oxy-5/3,20-epoxy-l/S-hydroxy-7/8, 8/8-methyl ene-920 oxo-19-nor-ll-taxen-13a-yl (2R,4S,5R)-3-tertbutoxycarbonyl - 2 - (4-methoxyphenyl)-4-phenyl-1,3oxazolidine-5-carboxylate, 80 mg of 4ci-acetoxy-10jSallylcarbonyloxy- 2a-benzoyloxy- 5/3,2 0 - epoxy- 1/3-hydroxy7/8, 8/8-methylene-9-oxo-19-nor-ll-taxen-13a-yl (2R, 3S) -325 tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]D20 = -34 (c = 0.5; methanol)
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4
- ΧΗ NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 1.26 (a, 3H: -CH3 at position 16 or at position 17); 1.29 [s, 12H; -C(CH3)3 and -CH3 at position 16 or at position 17] ; 1.38 (mt,
IH: -H at position 7); 1.69 and 2.26 (2 dd, respectively J = 6.5 and 5.5 and J = 10 and 6.5, IH each: -CH2- at position 19) ; 1.84 (s, 1Ξ: -OH at position 1); 1.85 (s, 3Ξ: -CH3) ; 2.12 and 2.46 (respectively broad d and dt, J = 16 and J = 16 and 4,
IH each: -CH2- at position 6); 2.24 and 2.40 (2 mts, IH each: -CH,- at position 14); 2.40 (s, 3H: -COCH3) ; 3.27
-(mt, 3H: -OH at position 2' and OCOCH2-CH=CH2) ; 4.05 and 4.32 (2 d, J = 9, IH each: -CH,- at position 20); 4.11 (d, J = 7.5, IH: -H at position 3); 4.63 (mt, 1Ξ: -H at position 2'); 4.73 (d,J = 4, IH; -Ξ at position 5);
5.24 and 5.26 (2dd respectively J = 8 and 2 and J = 18 and 2, 1Ξ each: OCOCH,-CH=CH,) ; 5.29 (broad d, J = 10, IH: -H at position 3'); 5.34 (d, J = 10, IH: -CONH-);
5.69 (d, J = 7.5, IH: -H at position 2); 6.00 (mt, IH:
OCOCH,-CH=CH,) ; 6.28 (broad t, J = 8.5, 1Ξ: -H at position 13); 6.34 (s, 1Ξ: -Ξ at position 10); from
7.25 to 7.45 (mt, 5H: -CSHS at position 3'); 7.53 [(t, J = 7.5, 2H: -OCOCSHS (-H at position 3 and Ξ at position
5)]; 7.62 [(t, J = 7.5, IH: -OCOCSHS (-H at position
4) 3 ; 8.15 (d, J = 7.5, 2Ξ: -OCOCSHS (-H at position 2 and H- at position 5)].
EXAMPLE 14
AP/P/ 97 / 0 1 0 9 4
Working as in Example 1, but starting from
l·
AP. Ο Ο 7 8 4 55
300 mg of 4a-acetoxy-2a-benzoyloxy-l/3,10£-dihydroxy5/3,2 0-epoxy-7/3, 8/5-methylene-9-oxo-19-nor-ll-taxen-13ayl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate and
45 mg of 3-furancarboxylic acid, 282 mg of 4a-acetoxy2a-benzoyloxy-50,2O-epoxy-lO/5- (3-furoyl) oxy-1/3-hydroxy7/3, 8/3-me thyl ene-9-oxo-19-nor-11 - taxen-13a-yl (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1,3-oxazolidine-5-carboxylate are obtained in the form of a white foam.
Working as in Example 1, but starting from ”282 mg of 4a-acetoxy-2a-benzoyloxy-5/S,20-epoxy-10/S-(3furoyl) oxy-1/3-hydroxy-7/3, 8/S-methylene-9-oxo-19-nor-lltaxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(415 methoxyphenyl) -4-phenyl-l,3-oxazolidine-5-carboxylate, 143 mg of 4a-acetoxy-2a!-benzoyloxy-5/3,20-epoxy-10/3-(3furoyl) oxy-l/S-hydroxy-7β, 8/S-methylene-9-oxo-19-nor-lltaxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2hydroxy-3-phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]°20 = -26 (c = 0.5; methanol)
- XH NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 1.29 [mt, 12H:
-C(CH3)3 and -CH3 at position 16 or at position 17];
1.35 (s, 3H: -CH3 at position 16 or at position 17);
1.43 (mt, IH: -H at position 7); 1.70 and 2.27 (2 dd, respectively J = 6.5 and 5.5 and J = 10 and 5.5, IH
AP/P/ 97 / 0 1 0 9 4 ,,Λ
ΑΡ.00784 each: -CH,- 19)? 1.87 (s, IH: -OH at position 1); 1.92 (s, 3H: -CH3) ; 2.13 and 2.50 (respectively broad d and dt, J = 16 and J = 16 and 4, 1Ξ each: -CH,- at position
6); 2.27 and 2.40 (2 mts, 1Ξ each: -CH,- at position
14); 2.40 (s, 3H: -COCH3) ; 3.27 (mt, IH: -OH at position
2'); 4.05 and 4.33 (2 d, J = 9, IH each: -CH,- at position 20); 4.15 (d, J = 7.5, IH: -H at position 3); 4.63 (mt, IH: -H at position 2'); 4.76 (d, J = 4, IH:
-H at position 5); 5.29 (broad d, J = 10, 1Ξ: -H at position 3'); 5.36 (d, J = 10, IH: -CONH-); 5.72 (d, J = 7,5, IH: -H at position 2); 6.30 (broad t, J = 8.5,
1Ξ: -H at position 13); 6.52 (s, 1Ξ: -Ξ at position 10); 6.79 (d,J = 1.5, IH: -OCOC4H3O (-H at position 4)]; from 7.25 to 7.45 (mt, 5H: -CSHS at position 3'); 7.48 (broad t, J = 1.5, IH: -OCOC4H3O (-Ξ at position 5)];
7.53 [(t, J = 7.5, 2Ξ: -OCOCSHS (-H at position 3 and Ξ at position 5)]; 7.63 [(t, J = 7.5, IH: -OCOCSHS (-H at position 4)]; 8.09 [broad s, 1Ξ: -OCOC4H3O (-H at position 2)]; 8.17 [(d, J = 7.5,2H: -OCOCSHS (-H at position 2 and Ξ- at position 6)].
EXAMPLE 15
Working as in Example 1, but starting from 300 mg of 4a-acetoxy-2a-benzoyloxy-10,100-dibydroxy50,2O-epoxy-70,80-methylene-9-oxo-19-nor-11-taxen-13a25 yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl) -4-phenyl-l,3-oxazolidine-5-carboxylate and 50 mg of 4-pyridinecarboxylic acid, 296 mg of 4a-acetoxy-2a-benzoyloxy-50,2O-epoxy-10-hydroxy-70,80AP/P/ 97 / 0 1 09 4
AP . θ Ο 7 8 4 cr
(.
methylene-9-oxo-10/3- (4-pyridylcarbonyl) oxy-19-nor-11taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4methoxyphenyl) -4-phenyl-l, 3-oxazolidine-5-carboxylate are obtained in tbe form of a white foam.
Working as in Example 1, but starting from
296 mg of 4a-acetoxy-2a-benzoyloxy-5/S, 20-epoxy-l/8hydroxy-7/S, 8/8-methylene-9-oxo-lO|S- (4-pyridylcarbonyl) oxy-19-nor-11-taxen-13a-yl (2R,4S,5R)-3-tertbutoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-l,310 oxazolidine-5-carboxylate, 159 mg of 4a-acetoxy-2abenzoyloxy-5/8,20-epoxy-1/3-hydroxy-7/5, 8/8-methylene-9-oxo-10/8- (3 -pyridylcarbonyl) oxy-19-nor-11-taxen-13a-yl (2R,3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a] °20 = -23 (c = 0.5; methanol)
- XH NMR spectrum (300 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 1.27 [(s, 9H:
-C(CH3)3]; 1.32 (s, 3H: -CH3 at position 16 or at position 17); 1.39 (s, 3H; -CH3 at position 16 or at position 17); 1.42 (mt, 1Ξ: -H at position 7); 1.70 and 2.27 (respectively dd and mt, J = 6 and 5.5, IH each: -CHj- at position 19); 1.90 (s, 3Ξ: -CH3); 1.91 (s, IH: -OH at position 1); 2.13 and 2.50 (respectively broad d and dt, J = 16 and J = 16 and 4, IH each: -CHj- at position 6); 2.27 and 2.40 (2 mts, 1Ξ each: -CH2- at position 14); 2.40 (s, 3H: -COCH3) ; 3.27 (mt, IH: -OH at position 2'); 4.04 and 4.32 (2 d, J = 9, IH each: -CH,AP/P/ 9 7 / 0 1 0 9 4
Cf
ΑΡ. ο υ 7 8 4 at position 20); 4.13 (d, J = 7.5, IH: -H at position 3); 4.63 (mt, IH: -H at position 2'); 4.76 (d, J = 4, IH; -H at position 5); 5.27 (broad d, J = ΙΟζ, 1Ξ; -H at position 3'); 5.33 (d, J = 10, 1Ξ; -C0NH-); 5.72 (d,
J = 7.5, IH: -H at position 2); 6.29 (broad t, J = 8.5, IH: -H at position 13); 6.58 (s, IH; -H at position 10); 7.25 to 7.45 (mt, 5Ξ; -CSHS at position 3'); 7.53
I [(t, J = 7.5, 2H: -OCOCSH5 (-H at position 3 and H at position 5)]; 7.63 [(t, J = 7.5, 1Ξ; -OCOCSHS (-H at position 4)];7.88 [(dd, J = 6 and 1.5, 2Ξ; -OCOCSH4N (-H at position 3 and -Ξ at position 5)]; 8.17 [ (d, J '7.5, 2Ξ; -OCOCSHS (-H at position 2 and -H at position 6)]; 8.82 [(dd, J = 6 and 1.5, 2Ξ: -OCOC5H4N (-H at position 2 and -Ξ at position 6)3.
The new products of general formula (I) in which Z represents a radical of general formula (II) manifest significant inhibitory activity with respect to abnormal cell proliferation, and possess therapeutic properties permitting the treatment of patients having pathological conditions associated with abnormal cell proliferation. The pathological conditions include the abnormal cell proliferation of malignant or nonmalignant cells of various tissues and/or organs, comprising, without implied limitation, muscle, bone or connective tissue, the skin, brain, lungs, sex organs, the lymphatic or renal systems, mammary or blood cells, liver, the digestive system, pancreas and thyroid or adrenal glands. These pathological conditions can also
AP/P/ 97 / 0 1 0 9 4 include psoriasis, solid tumours, cancers of the ovary, breast, brain, prostate, colon, stomach, kidney or testicles, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour,
Hodgkin's disease, melanoma, multiple myeloma, chronic lymphocytic leukaemia and acute or chronic granulocytic lymphoma. The new products according to the invention are especially useful for the treatment of cancer of the ovary. The products according to the invention may be used to prevent or delay the appearance or reappearance of the pathological conditions, or to .treat these pathological conditions.
The products according to the invention may be administered to a patient according to different dosage forms suited to the chosen administration route, which is preferably the parenteral route. Parenteral administration comprises intravenous, intraperitoneal, intramuscular or subcutaneous administration.
Intraperitoneal or intravenous administration is more especially preferred.
The present invention also comprises pharmaceutical compositions containing at least one product of general formula (I) in which Z represents a radical of general formula (II), in a sufficient amount suitable for use in human or veterinary therapy. The compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants, vehicles or excipients. Suitable vehicles
AP/P/ 97/01094
AP. Ο Ο 7 8 4 include diluents, sterile aqueous media and various non-toxic solvents. Preferably, the compositions take the form of aqueous solutions or suspensions, injectable solutions which can contain emulsifying 5 agents, colourings, preservatives or stabilizers.
The choice of adjuvants or excipients may be determined by the solubility and the chemical properties of the product, the particular mode of administration and good pharmaceutical practice.
For parenteral administration, sterile, aqueous or non-aqueous solutions or suspensions are .used. For the preparation of non-aqueous solutions or suspensions, natural vegetable oils such as olive oil, sesame oil or liquid petroleum, or injectable Lc esters such as ethyl oleate, may be used. The sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water.
The aqueous solutions are suitable for intravenous • administration provided the pH is appropriately adjusted and the solution is made isotonic, for example with a sufficient amount of sodium chloride or glucose. The sterilization may be carried out by heating or by any other means which does not adversely affect the composition.
It is clearly understood that all the products participating in the compositions according to the invention must be pure and non-toxic in the amounts
AP/P/ 9 7 / 0 1 0 3 4 used.
AP. Ο Ο 7 8 4
The compositions can contain at least 0.01% of therapeutically active product. The amount of active product in a composition is such that a suitable dosage can be prescribed. Preferably, the compositions are prepared in such a way that a single dose contains from 0.01 to 1000 mg approximately of active product for parenteral administration.
The therapeutic treatment may be performed concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunotherapy or radiotherapy or biological response · * modifiers. The response modifiers include, without implied limitation, lymphokines and cytokines such as interleukins, interferons (α, β or δ) and TNF. Other chemotherapeutic agents which are useful in the treatment of disorders due to abnormal cell proliferation include, without implied limitation, alkylating agents, for instance nitrogen mustards such as mechlorethamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulphonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustine and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogues, for instance methotrexate, pyrimidine analogues such as fluorouracil and cytarabine, purine analogues such as mereaptopurine and thioguanine, natural products, for instance vinca alkaloids such as vinblastine, vincristine and vindesine, epipodophyllotoxins such as t 6 010/46 /d/dV
AP . Ο Ο 7 8 4 etoposide and teniposide, antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as , L-asparaginase, various agents such as coordination complexes of platinum, for instance cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocortical suppressants such as mitotane and aminoglutethimide, hormones and antagonists such as adrenocorticosteroids
Ck y 10 such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, oestrogens such as diethylstilboestrol and ethynyloestradic?.,. antioestrogens such as tamoxifen, and androgens such as testosterone propionate and fluoxymesterone.
The doses used for carrying out the methods according to the invention are those which permit a prophylactic treatment or a maximum therapeutic response. The doses vary according to the administration form, the particular product selected and features distinctive to the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation. The products according to the invention may be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond rapidly to relatively high or low doses, and then require low or zero
AP. Ο Ο 7 8 4
:ϊ maintenance doses. Generally, low doses will be used at the beginning of the treatment and, if necessary, increasingly stronger doses will be administered until an optimum effect is obtained. For other patients, it may be necessary to administer maintenance doses 1 to 8 times a day, and preferably 1 to 4 times, according to the physiological requirements of the patient in question. It is also possible that some patients may require the use of only one to two daily administrations.
In man, the doses are generally between 0.01 “ and 200’ mg/kg. For intraperitoneal administration, the doses will generally be between 0.1 and 100 mg/kg, preferably between 0.5 and 50 mg/kg and still more specifically between 1 and 10 mg/kg. For intravenous administration, the doses are generally between 0.1 and 50 mg/kg, preferably between 0.1 and 5 mg/kg and still more specifically between 1 and 2 mg/kg. It is understood that, in order to choose the most suitable dosage, account should be taken of the administration route, the patient's weight, general state of health and age and all factors which may influence the efficacy of the treatment.
The example which follows illustrates a composition according to the invention.
EXAMPLE mg of the product obtained in Example 1 are dissolved in 1 cm3 of Emulphor EL 620 and 1 cm3 of
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4 ethanol, and the solution is then diluted by adding cm3 of physiological saline.
The composition is administered by perfusion over 1 hour by introduction in physiological solution.
Claims (2)
1. New taxoids of general formula:
Z-0 ·
R-<
OCOC6H5 (I) ‘3 in which.:
R represents an unbranched or branched alkyl radical containing 1 to 81 carbon atoms, substituted with a halogen atom chosen from fluorine, chlorine, bromine and iodine atoms or with an amino radical, an alkylamino radical in which the alkyl portion contains 1 to 4 carbon atoms, a dialkylamino radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur and nitrogen atoms (and optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical, an N-alkylcarbamoyl radical in which the alkyl portion contains 1 to 4 carbon atoms or an
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4
Ν,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical optionally
5 containing a second hetero atom chosen from oxygen, sulphur and nitrogen atoms (and optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms),
10 - . an alkenyl radical containing 2 to 8 carbon atoms in an unbranched or branched chain, an alkynyl radical
- containing 2 to 8 carbon atoms in an unbranched or branched chain, a cycloalkyl radical containing 3 to 5 carbon atoms or a cycloalkenyl radical containing 3 to
15 6 carbon atoms, these radicals being optionally substituted with a halogen atom chosen from fluorine, chlorine, bromine and iodine atoms or with an amino radical, an alkylamino radical in which the alkyl portion contains 1 to 4 carbon atoms, a dialkylamino
20 radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or δ-membered heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur and nitrogen atoms (and
25 optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains
AP/P/ 3 7/3 i
1 to 4 carbon atoms), a carboxyl radical, an
AP . Ο Ο 7 8 4
Ci alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical, an N’-alkylcarbamoyl radical in which the alkyl portion contains 1 to 4 carbon atoms or an N,N-dialkyl5 carbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur and nitrogen
10 atoms (and optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a
- phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), or a phenyl radical or a 5- or 6-membered aromatic 15 heterocyclic radical containing an oxygen, sulphur or nitrogen atom as hetero atom, and
Z represents a hydrogen atom or a radical of general formula:
AP/P/ 9 7 / 0 1 0 9 4
(.
in which:
20 represents a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms or
AP . Ο Ο Ί 8 4 trifluoromethyl radicals, a thenoyl or furoyl radical or a radical R2-O-CO- in which R2 represents:
- an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an %
5 alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 10 carbon atoms, these radicals being optionally substituted with one or ,r10 more substituents chosen from halogen atoms and
W hydroxyl radicals, alkoxy radicals containing 1 to 4 ' carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals (optionally
15 substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 ( carbon atoms, cycloalkenyl radicals containing 4 to 6
20 carbon atoms, phenyl radicals (optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms), cyano or carboxyl radicals or alkoxycarbonyl radicals
25 in which the alkyl portion contains 1 to 4 carbon atoms,
- a phenyl or a- or 0-naphthyl radical optionally substituted with one or more atoms or radicals chosen
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4 from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms,
- or a 5-membered aromatic heterocyclic radical
5 preferably chosen from furyl and thienyl radicals,
- or a saturated heterocyclic radical containing 4 to 6 carbon atoms, optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms,
R3 represents an unbranched or branched alkyl
10 radical containing 1 to 8 carbon atoms, an unbranched or branched alkenyl radical containing 2 to 8 carbon
- atoms, an unbranched or branched alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl or a- or
15 0-naphthyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,
20 alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, or a 5-membered aromatic heterocycle containing one or more identical or different hetero
25 atoms chosen from nitrogen, oxygen and sulphur atoms and optionally substituted with one or more identical or different substituents chosen from halogen atoms and alkyl, alkoxy, aryl, aryloxy, amino, alkylamino,
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4 dialkylamino, acylamino, alkoxycarbonylamino, acyl, ax-ylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkoxycarbonyl radicals, on the understanding that, in the
5 substituents of the phenyl, a- or 0-naphthyl and aromatic heterocyclic radicals, the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, and that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and that the aryl radicals , 10 are phenyl or ct- or 0-naphthyl radicals.
2. New taxoids according to claim 1 for
- which Z represents a hydrogen atom or a radical of general formula (II) in which represents a benzoyl radical or a radical R2-O-CO- in which R2 represents a
15 tert-butyl radical and R3 represents an alkyl radical containing 1 to 5 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl radical , optionally substituted with one or more identical or
20 different atoms or radicals chosen from halogen atoms (fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy) , dialkylamino (dime thyl amino) , acylamino (acetylamino), alkoxycarbonylamino (tertbutoxycarbonylamino) or trifluoromethyl radicals, or a
25 2- or 3-furyl, 2- or 3-thienyl or 2-, 4- or 5-thiazolyl radical, and R represents a cycloalkyl radical containing 3 to 6 carbon atoms or a phenyl, 2-, 3- or
4-pyridyl, 2- or 3-furyl and 2- or 3-thienyl radical.
AP/P/ 9 7 / 2 1 4 9 4
AP .0 0 7 8 4 * ·.<
3. New taxoids according to claim 1 for which Z represents a hydrogen atom or a radical of general formula (II) in which Rx represents a benzoyl radical or a radical R2-O-CO- in which R2 represents a
5 tert-butyl radical and R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, and R represents a cyclopropyl, cyclopentyl, phenyl, 2-pyridyl, 2-thienyl or 2-furyl
10 radical.
4. Process for preparing a product
- according to one of claims 1, 2 and 3, characterized in that a product of general formula:
(ΙΠ)
AP/P/ 97 / 0 1 0 9 4 in which Rx and R3 are defined in one of claims 1, 2 and
15 3, and either Rs represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or Rs and R7 together form a saturated 5- or 6-membered heterocycle, is esterified by means of an acid of general formula:
2 0 R-CO-OH (IV) in which R is defined as above, or by means of a derivative of this acid, such as a halide, the •ν
AP.00784 symmetrical anhydride or a mixed anhydride, to obtain a product of general formula:
in which R1# R3, Rg and Rj are defined as above, and the protective groups R? or Rg and R7 are then replaced by
5 hydrogen atoms.
5. Process according to claim 4, characterized in that the esterification is performed by means of an acid of general formula (IV) in the presence of a condensing agent and an activating agent
10 in an organic solvent at a temperature of between -10 and 90°C.
6. Process according to claim 4, characterized in that the esterification is performed by means of an acid of general formula (IV) in the form
15 of the symmetrical anhydride, working in the presence of an activating agent in an organic solvent at a temperature of between 0 and 90°C.
7. Process according to claim 4, characterized in that the esterification is performed
20 by means of an acid of general formula (IV) in halide form or in the form of a mixed anhydride with an aliphatic or aromatic acid, optionally prepared in ϊ 6 0 4 C I L 6 /d/dV
AP. 0 0 7 8 4 situ, in the presence of a base, working in an organic solvent at a temperature of between 0 and 80°C.
8. Process according to claim 4, characterized in that replacement of the protective
5 groups R7 and/or Rs and by hydrogen atoms is performed, working, depending on their nature, in the following manner:
1) when Rs represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, the
10 protective groups are replaced by hydrogen atoms by means of an inorganic or organic acid used alone or . mixed,, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic
15 hydrocarbons or nitriles at a temperature of between -10 and 60°C,
2) when Rs and R7 form an oxazolidine ring of general formula:
Rg R9
AP/P/ 9 7 / 0 1 0 9 4 in which Rx is defined as above and Rg and Rg, which may 20 be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical in which the alkyl portion contains 1 to 4 carbon atoms and the aryl portion represents a phenyl radical optionally substituted with one or more
AP.00784 alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical representing a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R8 represents an
5 alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and Rg represents a hydrogen atom, or alternatively R8 and Rg, together with the carbon atom to which they are linked, form a 4- to
10 7-membered ring, the protective group formed by Rs. and R7 is replaced by hydrogen atoms, working, depending on * the meanings of Rx, R8 and Rg, in the following manner:
a) when Rx represents a tert-butoxycarbonyl radical and R8 and R9, which may be identical or 15 different, represent an alkyl radical or an aralkyl or aryl radical, or alternatively R8 represents a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and Rg represents a hydrogen atom, or alternatively Ra and Rg together form
20 a 4- to 7-membered ring, the ester of general formula (V) is treated with an inorganic or organic acid, where appropriate in an organic solvent, to obtain a product of general formula:
(VII)
AP.00784 in which R3 is defined as above, which is acylated by means of benzoyl chloride in which the phenyl ring is optionally substituted or by means of thenoyl chloride, of furoyl chloride or of a product of general formula:
5 Rj-O-CO-X (VIII).
* in which R2 is defined as above and X represents a halogen atom or a residue -O-R2 or -O-CO-O-R2, to obtain a product of general formula (I) in which Z represents a radical of general formula (II),
10 b) when Rx represents an optionally substituted benzoyl radical, a thenoyl or furoyl radical or a radical R2O-CO- in which R2 is defined as above, Ra represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl
15 radical substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms and R9 represents a hydrogen atom, replacement of the protective group formed by Rs and by hydrogen atoms is performed in the presence of an inorganic or organic acid used alone
20 or mixed in a stoichiometric or catalytic amount, working in an organic solvent at a temperature of between -10 and 60°C.
AP/P/ 9 7 / 0 1 0 9 4
AP. Ο Ο 7 8 4
9. Process for preparing a product of general formula (I) in which. Z represents a radical of general formula (II), characterized in that a baccatin
III derivative of formula;
(XI)
5 is esterified by means of an acid of general formula;
MSP in which Rx and R3 are defined as in one of claims 1, ' and 3, and Rs and R7 are defined as in claim 4, or by means of a derivative of this acid such as a halide, the symmetrical anhydride or a mixed anhydride,
10 followed by replacement of the protective groups, and the protective groups R7 or Rs and are then replaced by hydrogen atoms.
10. Process according to claim 9, characterized in that the esterification is performed
15 according to the process of one of claims 5, 6 and 7.
11. Process according to claim 9, characterized in that the protective groups R7 or Rs and R7 are replaced by hydrogen atoms according to the fi.
<
AP. Ο Ο 7 8 4 conditions of claim. 8.
12. Process for preparing a product according to claim 1 for which Z represents a hydrogen atom, characterized in that a product of formula:
5 in which Zx represents a group protecting the hydroxyl - function, is esterified by means of an acid of general formula (IV) or of a derivative of this acid such as a halide or the symmetrical anhydride or a mixed anhydride, and the protective group Ζχ is then replaced
10 by a hydrogen atom under conditions which do not affect the remainder of the molecule.
13. Pharmaceutical composition, characterized in that it contains at least one product according to one of claims 1 to 3 for which Z
15 represents a radical of general formula (II), in combination with one or more pharmaceutically acceptable products, which may be inert or pharmacologically active.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9503868A FR2732342B1 (en) | 1995-04-03 | 1995-04-03 | NOVEL TAXOIDS, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| PCT/FR1996/000487 WO1996031493A1 (en) | 1995-04-03 | 1996-04-01 | Novel taxoids, preparation thereof, and pharmaceutical compositions containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9701094A0 AP9701094A0 (en) | 1997-10-31 |
| AP784A true AP784A (en) | 1999-11-22 |
Family
ID=9477663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1997/001094A AP784A (en) | 1995-04-03 | 1996-04-01 | Novel taxoids, preparation thereof and pharmaceutiacl compositions containing same. |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US5959125A (en) |
| EP (1) | EP0821680B1 (en) |
| JP (1) | JPH11504004A (en) |
| KR (1) | KR19980703520A (en) |
| CN (1) | CN1073106C (en) |
| AP (1) | AP784A (en) |
| AR (1) | AR002730A1 (en) |
| AT (1) | ATE195940T1 (en) |
| AU (1) | AU703918B2 (en) |
| BG (1) | BG62964B1 (en) |
| BR (1) | BR9604799A (en) |
| CA (1) | CA2214322C (en) |
| CZ (1) | CZ287430B6 (en) |
| DE (1) | DE69610085T2 (en) |
| DK (1) | DK0821680T3 (en) |
| EA (1) | EA000726B1 (en) |
| ES (1) | ES2151155T3 (en) |
| FR (1) | FR2732342B1 (en) |
| GE (1) | GEP19991872B (en) |
| GR (1) | GR3034203T3 (en) |
| HU (1) | HUP9802042A3 (en) |
| IL (1) | IL117760A (en) |
| MX (1) | MX9707427A (en) |
| NO (1) | NO974563L (en) |
| NZ (1) | NZ305898A (en) |
| PL (1) | PL322581A1 (en) |
| PT (1) | PT821680E (en) |
| RO (1) | RO115879B1 (en) |
| SK (1) | SK282047B6 (en) |
| TW (1) | TW347389B (en) |
| WO (1) | WO1996031493A1 (en) |
| ZA (1) | ZA962633B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6495579B1 (en) | 1996-12-02 | 2002-12-17 | Angiotech Pharmaceuticals, Inc. | Method for treating multiple sclerosis |
| FR2764118B1 (en) * | 1997-05-30 | 2000-08-04 | Thomson Csf | STABILIZED BIPOLAR TRANSISTOR WITH ELECTRICAL INSULATING ELEMENTS |
| US6156789A (en) * | 1998-03-17 | 2000-12-05 | Rhone-Poulenc Rorer S.A. | Method for treating abnormal cell proliferation in the brain |
| CA2365776A1 (en) * | 1999-05-03 | 2000-11-09 | Alain Renard | Method for treating abnormal cell proliferation in the brain |
| KR20020000159A (en) * | 2000-02-02 | 2002-01-04 | 플로리다 스테이트 유니버시티 리서치 파운데이션, 인크 | C10 Carbamoyloxy Substituted Taxanes as Antitumor Agents |
| US6649632B2 (en) * | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
| MXPA01009902A (en) * | 2000-02-02 | 2003-07-28 | Univ Florida State Res Found | C10 carbonate substituted taxanes as antitumor agents. |
| JP2004339475A (en) * | 2003-02-03 | 2004-12-02 | Merck Patent Gmbh | Pearlescent pigment based on fluoride, oxyfluoride, fluorosulfide and/or oxyfluorosulfide |
| EP1663153A4 (en) * | 2003-05-20 | 2011-01-05 | Aronex Pharmaceuticals Inc | Combination chemotherapy comprising a liposomal platinum complex |
| HN2005000054A (en) | 2004-02-13 | 2009-02-18 | Florida State University Foundation Inc | REPLACED TAXANS WITH CYCLOPENTILO ESTERS IN C10 |
| US20060189679A1 (en) * | 2005-02-14 | 2006-08-24 | Florida State University Research Foundation, Inc. | C10 cyclopropyl ester substituted taxane compositions |
| JP2011517455A (en) * | 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) ethyl ester and C (10) cyclopropyl ester substituted taxanes |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5254580A (en) * | 1993-01-19 | 1993-10-19 | Bristol-Myers Squibb Company | 7,8-cyclopropataxanes |
| FR2698871A1 (en) * | 1992-12-09 | 1994-06-10 | Rhone Poulenc Rorer Sa | New taxoids, their preparation and pharmaceutical compositions containing them. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL174374B1 (en) * | 1992-07-01 | 1998-07-31 | Bristol Myers Squibb Co | Fluorotaxoles |
| IL107950A (en) * | 1992-12-15 | 2001-04-30 | Upjohn Co | 7β, 8β - METHANO-TAXOLS, THEIR PREPARATION AND ANTINEOPLASTIC PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1995
- 1995-04-03 FR FR9503868A patent/FR2732342B1/en not_active Expired - Fee Related
-
1996
- 1996-04-01 MX MX9707427A patent/MX9707427A/en not_active IP Right Cessation
- 1996-04-01 AU AU54028/96A patent/AU703918B2/en not_active Ceased
- 1996-04-01 US US08/930,561 patent/US5959125A/en not_active Expired - Fee Related
- 1996-04-01 CN CN96192946A patent/CN1073106C/en not_active Expired - Fee Related
- 1996-04-01 KR KR1019970706924A patent/KR19980703520A/en not_active Ceased
- 1996-04-01 RO RO97-01817A patent/RO115879B1/en unknown
- 1996-04-01 EA EA199700288A patent/EA000726B1/en not_active IP Right Cessation
- 1996-04-01 CZ CZ19973109A patent/CZ287430B6/en not_active IP Right Cessation
- 1996-04-01 NZ NZ305898A patent/NZ305898A/en unknown
- 1996-04-01 AP APAP/P/1997/001094A patent/AP784A/en active
- 1996-04-01 AT AT96911009T patent/ATE195940T1/en not_active IP Right Cessation
- 1996-04-01 SK SK1333-97A patent/SK282047B6/en unknown
- 1996-04-01 BR BR9604799A patent/BR9604799A/en not_active Application Discontinuation
- 1996-04-01 TW TW085103805A patent/TW347389B/en active
- 1996-04-01 EP EP96911009A patent/EP0821680B1/en not_active Expired - Lifetime
- 1996-04-01 DE DE69610085T patent/DE69610085T2/en not_active Expired - Fee Related
- 1996-04-01 WO PCT/FR1996/000487 patent/WO1996031493A1/en not_active Application Discontinuation
- 1996-04-01 GE GEAP19963965A patent/GEP19991872B/en unknown
- 1996-04-01 CA CA002214322A patent/CA2214322C/en not_active Expired - Fee Related
- 1996-04-01 PL PL96322581A patent/PL322581A1/en unknown
- 1996-04-01 DK DK96911009T patent/DK0821680T3/en active
- 1996-04-01 JP JP8530026A patent/JPH11504004A/en not_active Ceased
- 1996-04-01 IL IL11776096A patent/IL117760A/en not_active IP Right Cessation
- 1996-04-01 ES ES96911009T patent/ES2151155T3/en not_active Expired - Lifetime
- 1996-04-01 PT PT96911009T patent/PT821680E/en unknown
- 1996-04-01 HU HU9802042A patent/HUP9802042A3/en unknown
- 1996-04-02 ZA ZA962633A patent/ZA962633B/en unknown
- 1996-04-03 AR ARP960102049A patent/AR002730A1/en not_active Application Discontinuation
-
1997
- 1997-10-02 NO NO974563A patent/NO974563L/en not_active Application Discontinuation
- 1997-10-03 BG BG101940A patent/BG62964B1/en unknown
-
2000
- 2000-08-31 GR GR20000400100T patent/GR3034203T3/en not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2698871A1 (en) * | 1992-12-09 | 1994-06-10 | Rhone Poulenc Rorer Sa | New taxoids, their preparation and pharmaceutical compositions containing them. |
| US5254580A (en) * | 1993-01-19 | 1993-10-19 | Bristol-Myers Squibb Company | 7,8-cyclopropataxanes |
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