AP753A - Novel taxoids, preparation thereof and pharmaceutical compositions containing same. - Google Patents
Novel taxoids, preparation thereof and pharmaceutical compositions containing same. Download PDFInfo
- Publication number
- AP753A AP753A APAP/P/1997/001093A AP9701093A AP753A AP 753 A AP753 A AP 753A AP 9701093 A AP9701093 A AP 9701093A AP 753 A AP753 A AP 753A
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- ARIPO
- Prior art keywords
- radical
- carbon atoms
- general formula
- radicals
- atoms
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- -1 cycloallcenyl Chemical group 0.000 claims abstract description 239
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 17
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 159
- 150000003254 radicals Chemical class 0.000 claims description 78
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 125000005843 halogen group Chemical group 0.000 claims description 26
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 25
- 229920006395 saturated elastomer Polymers 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 230000009471 action Effects 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 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 claims description 9
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 8
- 150000005840 aryl radicals Chemical class 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 230000032050 esterification Effects 0.000 claims description 7
- 238000005886 esterification reaction Methods 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 6
- 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 claims description 5
- 125000004442 acylamino group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl 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
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- KKFDJZZADQONDE-UHFFFAOYSA-N (hydridonitrato)hydroxidocarbon(.) Chemical compound O[C]=N KKFDJZZADQONDE-UHFFFAOYSA-N 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 claims description 4
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 4
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-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 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- IIVWHGMLFGNMOW-UHFFFAOYSA-N 2-methylpropane Chemical group C[C](C)C IIVWHGMLFGNMOW-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004104 aryloxy 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 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
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 claims description 3
- JAVBBFXUGDCHLZ-UHFFFAOYSA-N 1-$l^{1}-oxidanylpropane Chemical compound CCC[O] JAVBBFXUGDCHLZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005239 aroylamino group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- 238000009903 catalytic hydrogenation reaction Methods 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
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 150000004820 halides Chemical group 0.000 claims description 2
- 238000011065 in-situ storage Methods 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
- 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
- 150000001875 compounds Chemical class 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims 2
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical class [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 abstract 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 125000003302 alkenyloxy group Chemical group 0.000 abstract 1
- 150000001602 bicycloalkyls Chemical group 0.000 abstract 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- 239000000047 product Substances 0.000 description 106
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 49
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 230000002829 reductive effect Effects 0.000 description 38
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- 239000000203 mixture Substances 0.000 description 31
- 239000006260 foam Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 20
- 239000012300 argon atmosphere Substances 0.000 description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000004587 chromatography analysis Methods 0.000 description 18
- 239000012153 distilled water Substances 0.000 description 18
- 239000000126 substance Substances 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 230000008878 coupling Effects 0.000 description 17
- 238000010168 coupling process Methods 0.000 description 17
- 238000005859 coupling reaction Methods 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- 239000000377 silicon dioxide Substances 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000011521 glass Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 238000010828 elution Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229940057995 liquid paraffin Drugs 0.000 description 9
- 239000011780 sodium chloride 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
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 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
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 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 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 229920000742 Cotton Polymers 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 230000000670 limiting effect Effects 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
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910000040 hydrogen fluoride Inorganic materials 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
- POALUPLKPJWUJR-UHFFFAOYSA-N phenyl 1,3-oxazolidine-5-carboxylate Chemical compound O=C(Oc1ccccc1)C1CNCO1 POALUPLKPJWUJR-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- PLRPKVNZGONHKD-UHFFFAOYSA-N 1,3-oxazolidine-5-carboxylic acid Chemical compound OC(=O)C1CNCO1 PLRPKVNZGONHKD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- 208000001382 Experimental Melanoma Diseases 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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 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
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical class [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 238000007918 intramuscular administration Methods 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-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004807 localization Effects 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
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 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
- 239000003607 modifier Substances 0.000 description 1
- OVMSOCFBDVBLFW-IAGPSASASA-N molport-003-665-782 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(C21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-IAGPSASASA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002815 nickel Chemical class 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
- 150000002895 organic esters Chemical class 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
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 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
- 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
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux 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
- 210000003491 skin Anatomy 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
- 239000003826 tablet Substances 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
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 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
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 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
- 229960003087 tioguanine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000004654 triazenes Chemical class 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
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- 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)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Novel taxoidi of general formula (I), the preparation thereof, and pharmaceutical compositions containing same, are disclosed. In general formula (I), Z is a hydroge in .torn or a radical of general formula (II), wherein RI is an optionally substiaicd benzoyl radical or a thenoyl or furoyl radical, a radical Rj-O-CO-, where RI it an alfcyl, alStenyl, alkynyl, cycloalkyl, cycloallcenyl, bicycloalkyl, opdonally su'osrimed phenyl or heterocyclyl radical, Rs is an aromatic heterocyclic alley 1. altenyl, alkynyl. cycloalkyl, phenyl or naphtyl radical, f Is art optionally substicued alkoxy, tllxnyloxy or alkynyloxy radical or a cycloalkyloxy or cycloalkenyloxy radicil, and RS is an optional substirued alkoxy, alkenyloxy or ilkynyloxy radical or a cycloalkyloxy or cydcalkcnyloxy radical. The novel products of general formu (I), wherein Z is a radical of general formula (II), have remarkable antitumoral and antilukaemic properties.
Description
NEW TAXOIDS, THEIR PREPARATION AND PHARMACEUTICAL
COMPOSITIONS CONTAINING THEM
The present invention relates to new taxoids of general formula:
(I) in which:
Z represents a hydrogen atom or a radical of general formula:
R,NH 0
R, (II)
OH
AP/P/ 9 7 / 0 1 0 9 3 in which:
R-]_ 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 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 alkynyl radical containing 3 to 8 carbon atoms, a
AP . Ο Ο 7 5 3 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 more substituents chosen from halogen atoms and 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 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 atoms,
- a phenyl or a- or β-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,
AP/P/ 9 7 / 0 1 0 9 3
AP.00753
- or a saturated heterocyclic radical containing 4 to 5 carbon atoms, optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms,
R3 represents an unbranched or branched alkyl 5 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 /S-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, f
mercapto, formyl, acyl, acylamino, aroylamino, 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 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, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkoxycarbonyl radicals, on the understanding that, in the substituents of the phenyl, o'- or /S-naphthyl and aromatic heterocyclic radicals, the alkyl radicals and
AP/P/ 9 7 / 0 1 0 9 3
AP. Ο Ο 7 5 3 the alkyl portions of the other radicals contain 1 to 4 carbon atoms, and that the alkenyl and alkynyl radicals contain 2 to 3 carbon atoms, and that the aryl radicals are phenyl or a- or /S-naphthyl radicals,
R4 represents an alkoxy radical containing 1 to 6 carbon atoms in an unbranched or branched chain, an alkenyloxy radical containing 3 to 6 carbon atoms in an unbranched or branched chain, an alkynyloxy radical containing 3 to 6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy radical containing 3 to 6 carbon atoms or a cycloalkenyloxy radical containing 4 to 6 carbon atoms, these radicals being optionally substituted with one or more halogen atoms or with an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 1 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or 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 heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur or nitrogen atoms, 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,
Rs represents an alkoxy radical containing 1
AP/P/ 9 7 / 0 1 0 9 3
AP. ΰ ϋ 7 5 3
| to | 6 carbon atoms in | an unbranched | or | branched | chain, | |
| an | alkenyloxy radical | containing | 3 | to | 5 carbon | atoms , |
| an | alkynyloxy radical | containing | 3 | to | 5 carbon | atoms, a |
| cycloalkyloxy radical | containing | 3 | to | 6 carbon | atoms or |
a cycloalkenyloxy radical containing 3 to 5 carbon atoms, these radicals being optionally substituted with one or more halogen atoms or with an alkoxy radical containing 1 to 4 carbon atoms or an alkylthio radical containing 2 to 4 carbon atoms or with a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or 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 heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur or nitrogen atoms, 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.
Preferably, the aryl radicals which can be represented by R3 are phenyl or a- or /3-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,
AP/P/ 9 7 / 0 1 0 9 3
AP. ο ΰ 7 5 3 acylamino, arovlamino, alkoxycarbonylamino, amino, alkylamino, dialkyiamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyi 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 a- or /3-naphthyl radicals .
Preferably, the heterocyclic radicals vzhich can he represented by R3 are 5-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, dialkyiamino 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
AP/P/ 9 7 / 0 1 0 9 3
AP . Ο Ο 7 5 3 carbamoyl radicals, alkylcarbamoyl radicals in which che 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, the radicals R4 and R5, which may be identical or different, represent unbranched or branched alkoxy radicals containing 1 to 6 carbon atoms, optionally substituted with a methoxy, ethoxy, ethylthio, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-pyrrolidinocarbonyl or N-piperidinocarbonyl radical.
More especially, the present 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 R2 represents a benzoyl radical or a radical R2-O-CO- in which R2 represents a tert20 butyl radical and R3 represents an alkyl radical
AP/P/ 9 7 / 0 1 0 9 3
| containing | 1 | to | 6 | carbon | atoms, | an alkenyl radical |
| containing | 2 | to | S | carbon | atoms, | a cycloalkyl radical |
| containing | 3 | to | 5 | 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),
AP.00753 alkoxycarbonylamino (tert-butoxycarbonylamino) or trifluoromethyl radicals, or a 2 - or 3-furyl, 2- or 3-thienyl or 2-, 4- or 5-thiazolyl radical, and R4 and R_, which may be identical or different, each represent an unbranched or. branched alkoxy radical containing 1 to 6 carbon atoms.
Still more especially, the present 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 tertbutyl 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 R4 and R5, which may be identical or different, each represent a methoxy, ethoxy or propoxy 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 present invention, the new 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/ 9 7 / 0 1 0 9 3
AP . 0 0 7 5 3
HO.....
(Ill) in which R4 and Rg are defined as above acid of general formula:
by means of an
O-R?
(IV) 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 Rg and R7 together form a saturated 5- or 6-membered heterocycle, or by means of a derivative of this acid, to obtain an ester of general formula:
AP/P/ 97/01093 in which Rlz R3, R4, R5, Rg and R7 are defined as above, followed by replacement of the protective groups represented by R? and/or Rg and R7 by hydrogen atoms.
ο Ο 7 5 3
The esterification, by means of an acid of general formula (IV) may be performed in the presence of a condensing agent (carbodiimide, reactive 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 9 0 °C.
The esterification may also be carried out 10 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 9 0 °C.
The esterification may also be carried out 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.
Preferably, Rs represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or alternatively R5 and R? together form a saturated 5AP/P/ 9 7 / 0 1 0 9 3
AP .00753 or δ-membered heterocycle.
When Rs represents a hydrogen atom, R? preferably represents a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, β-trimethylsilylethoxymethyl, henzyloxycarhonyl or tetrahydropyranyl radical.
When Re and R7 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 Re and R7 by hydrogen- atoms may be performed, depending on their nature, in the following manner:
1) when Rg represents a hydrogen atom and R7 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) used 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, or by means of a source of fluoride ions such as a hydrofluorine acid/triethylamine complex, or by catalytic hydrogenation,
2) when Rg and R? together form a saturated 5- or 6AP/P/ 9 7 / 0 1 0 9 3
AP. Ο Ο 7 5 3 membered heterocycle, and more especially an oxazolidine ring of general formula:
RrN^O Rg R?
(VI) in which Ρχ is defined as above and Rg and Rg, which may 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 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 Rs 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 trichloromethyl and Rg represents a hydrogen atom, or alternatively Rg and Rg, together with the carbon atom to which they are linked, form a 4- to 7-membered ring, replacement of the protective group formed by Rg and R? by hydrogen atoms may be performed, depending on the meanings of Rx, Rg and Rg, in the following manner:
a) when Rx represents a tert-butoxycarbonyl.
radical and Rg and Rg, which may he identical or £ 6 0 t 0 / L 6 /d/dV
AP.00753 different, represent an alkyl radical or an aralkyl (benzyl) or aryl (phenyl) radical, or alternatively Rg represents a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and Rg represents a hydrogen atom, or alternatively Rg and Rg 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, yields the product of general formula:
(VII)
OCOC6H5 in which R3, R, and R5 are 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:
AP/P/ 9 7 / 0 1 0 9 3
R2-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
AP. Ο Ο 7 5 3 (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 5 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 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 dichloromethane or 1,2-dichloroethane, in the presence of an inorganic base such as sodium bicarbonate or an c
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 P.·^ represents an optionally substituted benzoyl radical, a thenoyl or furoyl radical or a radical R2O-CO- in which R2 is defined as above, Rs 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 R9 represents a hydrogen atom, replacement of the protective group
5 formed by R6 and R7 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,
AP/P/ 9 7 / 0 1 0 9 3
AP.00753 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 60°C, and preferably between 15 and
30°C.
According to the invention, the products of general formula (III), that is to say the products of general formula (I) in which Z represents a hydrogen atom and R4 and R5 are defined as above, may be obtained from 10-deacetylbaccatin III of formula:
AP/P/ 9 7 / 0 1 0 9 3
It can be especially advantageous to protect the hydroxyl functions at the positions 7 and 13 selectively, for example in the form of a silyl diether which may be obtained by the action of a silyl halide of general formula:
(R)3-Si-Hal (X) in which the symbols R, which may be identical or different, represent an alkyl radical containing 1 to 6 carbon atoms, optionally substituted with a phenyl radical, or a cycloalkyl radical containing 3 to 6
AP.00753 carbon atoms or a phenyl radical, on
10-deacetylbaccatin III, to obtain a product of general f o rmu1a :
(XI) in which R is defined as above, followed by the action of a product of general formula:
R'4-Xi (XU) in which R'4 represents a radical such that R'4-0 is identical to R4 defined as above and represents a reactive ester residue such as a sulphuric or sulphonic ester residue or a halogen atom,, to obtain a product of general formula:
(XIII)
AP/P/ 97/01 09 3 in which R and R4 are defined as above, the silyl protective groups of which are replaced by hydrogen atoms to obtain a product of general formula:
AP . 0 0 7 5 3
in which R4 is defined, as above, which is etherified selectively at position 7 by the action of a product of general formula:
R'5-x2 (xv) in which R'5 represents a radical such that R'5-0 is identical to R5 defined as above and X2 represents a halogen atom or a reactive ester residue such as a sulphuric or sulphonic ester residue, to give the product of general formula (III).
Generally, the action of a silyl derivative of general formula (X) on 10-deacetylbaccatin III is performed in pyridine or triethylamine, where appropriate in the presence of an organic solvent such as an aromatic hydrocarbon, for instance benzene, toluene or xylenes, at a temperature between 0°C and the refluxing temperature of the reaction mixture.
Generally, the action of a product of general formula (XII) on a product of general formula (XI) is performed, after metalation of the hydroxyl function at position 10 by means of an alkali metal hydride such as sodium hydride, an alkali metal amide such as lithium
AP/P/ 9 7 / 0 1 0 9 3
AP.00753 amide or an alkali metal alkylide such as butyllithium, working in an organic solvent such as dimethylformamide or tetrahydrofuran at a temperature of between 0 and
50°C.
Generally, the replacement of the silyl protective groups of the product of general formula (XIII) by hydrogen atoms is performed by means of an acid such as hydrofluoric acid or trifluoroacetic acid in the presence of a base such as triethylamine or pyridine optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, the base optionally being combined with an inert organic solvent such as a nitrile, for instance acetonitrile, or a halogenated aliphatic hydrocarbon such as dichloromethane at a temperature of between 0 and 80°C.
Generally, the action of a product of general formula (XV) on a product of general formula (XIV) is performed under the conditions described above for the action of a product of general formula (XII) on a product of general formula (XI) .
According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II), R4 is defined as above and R5 is defined as above may be obtained from a product of general formula:
AP/P/ 9 7 / 0 1 0 9 3
AP.00753
HO
ococ6h5 in which Rx, R3, Rg and R7 are defined as above, by silylation at position 7 by means of a product of general formula (X), to obtain a product of general formula:
AP/P/ 9 7 / 0 1 0 9 3 in which R, Rlz R3, Rg and R7 are defined as above, which is functionalized at position 10 by means of a product of general formula (XII) to give a product of general formula:
in which R, R3, R3, R4, Rg and R7 are defined as above,
AP.00753 the silyl protective group of which is replaced by a hydrogen atom to give a product of general formula:
which, by the action of a product of general formula (XV), yields the product of general formula (V), the protective groups of which are replaced by hydrogen atoms to give a product of general formula (I) in which Z represents a radical of general formula (II).
The reactions used for silylation, functionalization and replacement of the protective groups by hydrogen atoms are performed under conditions similar to those described above.
The products of general formula (XVI) may be obtained under the conditions described in European Patent EP 0,336,841 and international Applications PCT WO 92/09589 and WO 94/07878, or from the products
AP/P/ 9 7 / 0 1 0 9 3 of general formula:
OH
(XX)
AP.00753 in which and R3 are defined as above, according to known methods for protecting the hydroxyl function of the side chain without affecting the remainder of the molecule.
According to the invention, the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) may be obtained by the action of activated Raney nickel, in the presence of an aliphatic alcohol containing 1 to 3 carbon atoms or an ether such as tetrahydrofuran or dioxane, on a product of general formula:
AP/P/ 9 7 / 0 1 0 9 3 in which R4 is defined as above and R' and R, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 6 carbon
| 15 | atoms, | an alkenyl radical containing 2 | to | 6 | carbon |
| atoms, | an alkynyl radical containing 2 | to | 6 | carbon | |
| atoms, | a cycloalkyl radical containing | 3 | to | 6 carbon |
atoms or a cycloalkenyl radical containing 3 to 6 carbon atoms, optionally substituted, or alternatively
AP.00753
R' and R, together with the carbon atom to which they are linked, form a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 4 to 6 carbon atoms, and represents a hydrogen atom or a radical of general formula:
(XXII) in which Rlz R3, Rg and R? are defined as above, and, to obtain. a product of general formula:
(XXIII)
AP/P/ 9 7 / 0 1 0 9 3 followed, when Zx represents a radical of general formula (XXII), that is to say when the product of general formula (XXIII) is identical to the product of general formula (V), by replacement of the protective groups represented by Rg and/or Rg and R7 by hydrogen atoms under the conditions described above.
Generally, the action of activated Raney nickel in the presence of an aliphatic alcohol or an ether is performed at a temperature of between -10 and
60°C.
AP.00753
According to the invention, the product of general formula (XXI) in which and R4 are defined as above may be obtained by the action of a sulphoxide of general formula:
R> R’ R.._l X-R„ (XXIV) ^so in which R' and R are defined as above, on a product of general formula (XIX).
Generally, the reaction of the sulphoxide of general formula (XXIV), preferably dimethyl sulphoxide, with the product of general formula (XIX) is performed in the presence of a mixture of acetic acid and acetic anhydride or a derivative of acetic acid such as a haloacetic acid at a temperature of between 0° and 50°C, and preferably in the region of 25°C.
The products of general formula (I) obtained by carrying out the process according to the invention may be purified according to known methods such as crystallization or chromatography.
The new products of general formula (I) obtained by carrying out the processes according to the invention may be purified according to known methods 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.
AP/P/ 9 7 / 0 1 0 9 3
In vitro, measurement of the biological
AP. Ο Ο 7 5 3 brain by the method, of M.L. Shelanski et al. , Proc.
Natl. Acad. Sci. USA, 7 0 , 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 30 mg/kg administered intraperitoneally, as well as on other liquid or solid tumours. More especially, in vivo, on B16 melanoma, the product of general formula (I) for which Rx represents a tert-butoxycarbonyl radical, R3 represents a phenyl radical and R4 and Rs each represent a methoxy radical possesses a log cell kill of 2.9, whereas the product of general formula (I) for which Rx represents a tert-butoxycarbonyl radical, R3 represents a phenyl radical and R4 represents a methoxy radical and Rs represents a hydroxyl radical, described in
Tetrahedron Letters, 35, 5543 (1994), possesses a log cell kill of 0.7.
The new products have antitumour properties, and more especially activity against tumours which are
AP/P/ 97/01093
REPLACEMENT SHEET (RULE 26)
AP . ο Ο 7 5 3 resistant to Taxol® or to Taxotere5. 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 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 expresses mdr 1.
The examples which follow illustrate the present invention.
EXAMPLE 1
126 mg of dicyclohexylcarbodiimide and then 15 14 mg of 4 - (N, N'-dimethylamino)pyridine are added successively at a temperature in the region of 20 °C to a suspension containing 217.8 mg of 4a-acetoxy-2abenzoyloxy-5/3,2 0-epoxy-1/3,13 a-dihydroxy-7/3,10/3dimethoxy-9-oxo-ll-taxene, 200 mg of (2R,4S,5R)-3-tert2 0 butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3oxazolidine-5-carboxylic acid and 50 mg of powdered 4A molecular sieve in 2 cm3 of ethyl acetate. The suspension obtained is stirred at a temperature in the region of 20 °C under an argon atmosphere for 16 hours, and then concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40 °C. The residue obtained is purified by chromatography at
AP/P/ 9 7 / 0 1 0 9 3
REPLACEMENT SHEET (RULE 26)
AP . 0 0 7 5 3 atmospheric pressure on 50 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter (elution gradient: ethyl acetate/dichloromethane from 10:90 to 40:60 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 40°C for 2 hours. 271.8 mg of 4a-acetoxy2 a-benz oy1oxy- 5 β,2 0 -epoxy-1β-hydroxy-7 β,10 β-dime thoxy 9-οχθ-ll-taxen-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyΙΙΟ 2 -(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5carboxylate are thereby obtained in the form of a white solid, the characteristics of which are as follows:
1H NMR spectrum (400 MHz; CDC13 with a few drops of
CD3OD-d4; chemical shifts δ in ppm; coupling constants J 15 in Hz): 1.02 (s, 9H: C(CH3)3); 1.10 (s, 3H: CH3) ; 1.17 (s, 3H: CH3) ; 1.63 (s, 3H: CH3) ; from 1.65 to 1.85 and
2.60 (2 mts, IH each; CH2 at position 6); 1.78 (unres. comp., 3H: CH3) ; 2.02 and 2.15 (2 dd, J = 14 and 9, IH each: CH2 at position 14); 2.14 (s, 3H: CH3) ; 3.22 and
3.35 (2 s, 3H each: OCH3) ; 3.64 (d, J = 7, IH: H at position 3); 3.73 (mt, IH: H at position 7); 3.76 (s,
3H: ArOCH3) ; 4.0 6 and 4.16 ’(2 d, J = 8.5, IH each; CH2 at position 20); 4.53 (d, J = 5, IH: H at position 2'}; 4.67 (s, IH: H at position 10); 4.85 (broad d, J = 10,
IH: H at position 5); 5.36 (mt, IH: H at position 3'); 5.52 (d, J = 7, IH: H at position 2); 6.07 (mt, IH: H at position 13); 6.33 (unres. comp., IH: H at position,
5'); 6.88 (d, J = 8, 2H: aromatic H at the ortho
AP/P/ 9 7 / 0 1 0 9 3
AP. Ο Ο 7 5 3 at position 13); 5.33 (unres. comp., IH: H at position
5'); 6.88 (d, J = 8, 2H: aromatic H at the ortho position with respect to OCH3); from 7.25 to 7.40 (mt, 7H: aromatic H at position 3' and aromatic H at the meta position with’ respect to OCH3) ; 7.43 (t, J = 7.5,
2H: OCOCgK5 H at the meta position); 7.58 (t, J = 7.5,
IH; OCOCgH5 H at the para position); 7.96 (d, J = 7.5,
2H: OCOCgH5 Ξ at the ortho position) .
A solution of 446.3 mg of 4a-acetoxy-2a10 benzoyloxy-5/3, 20-epoxy-l/3-hydroxy-7jS, 10/3-dimethoxy-9oxo-11-taxen-13o:-yl (2R, 4S, 5R) -3 - tert-butoxycarbonyl-2 (4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5carboxylate in 11.6 cm3 of a 0. IN solution of hydrogen chloride in ethanol is kept stirring at a temperature in the.region of 0°C for 16 hours under an argon atmosphere. The reaction mixture is then diluted with 40 cm3 of dichloromethane and 5 cm3 of distilled water. After settling has taken place, the aqueous phase is separated and extracted with 5 cm3 of dichioromethane.
The organic phases are combined, dried over magnesium sulphate, filtered through sintered glass and then concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40°C.
424.2 mg of a pale yellow solid are obtained, which product is purified by preparative thin-layer chromatography (12 Merck preparative silica gel 60F254 plates, thickness 1 mm, application in solution in a methanol/dichloromethane (5:95 by volume) mixture,
AP/P/ 9 7 / 0 1 0 9 3
AP.00753 eluting with a methanol/dichloromethane (5:95 by volume) mixture]. After elution of the zone corresponding to the main product with a methanol/ dichloromethane (15:85 by volume) mixture, filtration through sintered glass and evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40°C, 126 mg of 4a-acetoxy-2a-benzoyloxy5/3,20- epoxy -1/5-hydroxy-7/3,10/3- dimethoxy - 9 - oxo-11 - taxen13o;-yl (2R,3S) -3-tert-butoxycarhonylamino-2-hydroxy-ΒΙΟ phenylpropionate are obtained in the form of an ivorycoloured foam, the characteristics of which are as follows :
- optical rotation [a] 20 = 32.9 (c = 0.5; methanol)
- 1H NMR spectrum (400 MHz; CDC13; chemical shifts δ in
| 15 | ppm; coupling constants | J in Hz): 1.23 (s, | 3H: | CH3) ; |
| 1.25 (s, 3H: CH3) ; 1.3 9 | (s, 9H: C(CH3)3); 1 | ..70 | (s, 1H: | |
| OH at position 1) ; 1.75 | (s, 3H: CH3); 1.82 | and | 2.72 | |
| (2 mts, 1H each: CH2 at | position 6); 1.91 | (s, | 3H: CH3) |
AP/P/ 9 7 / 0 1 0 9 3
2.31 (limiting AB, 2H: CH2 at position 14); 2,39 (s,
3H: COCH3); 3.33 and 3.48 (2 s, 3H each: OCH3); 3.48 (mt, 1H: OH at position 2'); 3.85 (d, J = 7, 1H: H 3); 3.88 (dd, J = 11 and 7, 1H: H 7); 4.20 and 4.33 (2 d, J = 8.5, 1H each: CH2 at position 20); 4.65 (mt, 1H: H at position 2'); 4.83 (s, 1H: H at position 10); 5.00 (broad d, J = 10, 1H: H at position 5); 5.30 (broad d,
J = 10, 1H: H at position 3'); 5.47 (d, J = 10, 1H: CONH); 5.66 (d, J = 7, 1H: H at position 2); 6.24 (broad t, J = 9, 1H: H at position 13); from 7.30 to
AP.00753
| 7.50 | (mt. | 5H: aromatic H | at position 3'); 7.52 | (t, J = |
| 7.5, | 2H: | OCOC-H- H at the 0 Z) | meta position); 7.63 | (t, J = |
| 7.5, | IH: | OCOC5H5 H at the | para position); 8.12 | (d, J = |
| 7.5, | 2H: | OCOCeK5 H at the | ortho position). | |
| 4a-Acetoxy-2a-benzoyloxy-5/3, 20-epoxy- | •1/3,13a- |
dihydroxy-7/3, 10/3-dimethoxy-9-oxo-11-taxene (or 7/3,10/3dimethoxy-10-deacetoxybaccatin III) may be prepared in the following manner:
mg of sodium hydride at a concentration of
50 % by weight in liquid paraffin are added portionwise to a solution, maintained under an argon atmosphere, at a temperature in the region of 0°C, of 500 mg of 4a-acetoxy-2a-benzoyloxy-5/5, 20-epoxy-l/S, Ί β, 13αtrihydroxy-10/3-methoxy-9-oxo-ll-taxene in 5 cm3 of iodomethane and 0.5 cm3 of dimethylformamide. After 45 minutes at a temperature in the region of 0°C, the reaction mixture is diluted with 50 cm3 of ethyl acetate and 8 cm3 of distilled water. After settling has taken place, the organic phase is separated and washed with twice 8 cm3 of distilled water and then 8 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered through sintered glass and concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40°C. 570 mg of a pale yellow solid are thereby obtained, which product is purified by chromatography at atmospheric pressure on 50 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in
AP/P/ 9 7 /.0 1 0 9 3
AP . ο Ο 7 5 3 diameter, eluting with a methanol/dichloromethane (2:98 by volume) mixture and collecting 10-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40 °C for 2 hours. 380 mg of
4a-acetoxy- 2a-benzoyl oxy- 5/3,2 0 - epoxy -1/3,13a- dihydroxy7/3,10/5-dimethoxy-9-oxo-11-taxene are thereby obtained in the form of a pale yellow solid, the characteristics of which are as follows:
- 1H. NMR spectrum (400 MHz; CDC13; with a few drops of
CD3OD-d4; chemical shifts δ in ppm; coupling constants J in Hz) : 1.03 (s, 3H: CH3) ; 1.11 (s, 3H: CH3); 1.65 (s,
3H: CH3) ; 1.72 and 2.67 (2 mts, 1H each: CH2 at position
6); 2.05 (s, 3H: CH3): 2.21 (limiting AB, J = 14 and 9,
2H: CH2 at position 14); 2.25 (s, 3H: COCH3); 3.26 and
3.40 (2 s, 3H each: OCH3) ; 3.85 (d, J = 7, 1H: H at position 3); 3.89 (dd, J = 11 and 6.5, 1H: H at position 7); 4.12 and 4.25 (2 d, J = 8.5, 1H each: CH2 at position 20); 4.78 (broad t, J = 9, 1H: H at position 13); 4.83 (s, 1H: H at position 10); 4.98 (broad d, J = 10, 1H: H at position 5); 5.53 (d, J = 7, 1H: H at position 2); 7.43 (t, J = 7.5, 2H: OCOC5H5 H at the meta position); 7.56 (t, J = 7.5, 1H: OCOCgH5 H at the para position); 8.05 (d, J = 7.5, 2H: OCOCgH5 H at the ortho position).
4a - Ac et oxy-2a-benzoyl oxy-5/3, 20-epoxy1/3,7/3,13a-trihydroxy-10/3-methoxy-9-oxo-11 - taxene (or
10/3-methoxy-10-deacetoxybaccatin III) may be prepared
AP/P/ 9 7 / 0 1 0 9 3
AP . 0 0 7 5 3 in the following manner:
cm3 of hydrogen fluoride/triethylamine complex (3HF.Et3N) are added slowly to a solution, maintained under an argon atmosphere, at a temperature in the region of 0°C, of 3.62 g of 4a-acetoxy-2abenzoyloxy-5/3,2 0-epoxy-l/3-hydroxy-10/3-methoxy-9-oxo7/3,13a-bis (triethylsilyoxy)-11-taxene in 30 cm3 of dichioromethane. After 48 hours at a temperature in the region of 20 °C, the reaction mixture is poured into a suspension of 100 cm3 of supersaturated aqueous sodium hydrogen carbonate solution maintained at a temperature in the region of 0°C. After settling has taken place, the aqueous phase is separated and re-extracted with three times 8 0 cm3 of dichioromethane and then twice
80 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered through magnesium sulphate and concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40°C. 3.45 g of a yellow foam are thereby obtained, which product is purified by chromatography at atmospheric pressure on 150 g of silica (0.063-0.2 mm) contained in a column 3.5 cm in diameter, eluting with a methanol/dichloromethane (5:95 by volume) mixture and collecting 35-cm3 fractions.
Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40°C for 2 hours. 1.97 g of 4a-acetoxy-2a-benzoyloxy-5/3,20-epoxy-l/S, 7/3,13aAP/P/ 9 7 / 0 1 0 9 3
AP . 0 G 7 5 3 trihydroxy-10/3-methoxy-9-oxo- 11 - taxene are thereby obtained in the form of a white solid, the characteristics of which are as follows:
- 1H NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 1.10 (s, 3H: CH3);
1.19 (s, 3H: CH3); 1.48 (d, J = 8.5, 1H: OH at position 13); 1.70 (s, 3H: CH3) ; 1.81 and 2.61 (2 aits, 1H each: CH2 at position 6); 2.09 (d, J = 5, 1H: OH at position
7); 2.11 (s, 3H: CH3) ; 2.30 (s, 3H: COCH3); 2.32 (d, J =
9, 2H: CH2 at position 14); 3.48 (s, 3H: OCH3); 3.97 (d,
J = 7, 1H: H at position 3); 4.18 and 4.33 (2d, J =
8.5, 1H each: CH2 at position 20); 4.31 (mt, 1H: H at position 7); 4.93 (mt, 1H: H at position 13); 4.99 (s, 1H: H at position 10) ; 5.01 (broad d, J = 10', 1H: H at
| 15 | position | 5) ; | 5.66 | (d, J = | 7, | 1H: | H at | position 2); 7.49 |
| (t, J = | 7.5, | 2Ξ: | OCOCeH5 H | at | the | meta | position); 7.63 | |
| (t, J = | 7.5, | 1H: | ococ5h5 H | at | the | para | position); 8.12 | |
| (d, J = | 7.5, | 2H: | ococ6h5 H | at | the | ortho position). |
4o;-Acetoxy-2ci-benzoyloxy-5^, 20-epoxy-l/3AP/P/ 9 7 / 0 1 0 9 3 hydroxy-10(S-methoxy-9-oxo-7/3,13a-bis (triethylsilyloxy) 11-taxene (or 10/3-methoxy-10-deacetoxy-7,13bis(triethylsilyl)baccatin III) may be prepared in the following manner:
375 mg of sodium hydride at a concentration of 50 % by weight in liquid paraffin are added .portionwise to a solution, maintained under an argon atmosphere, at a temperature in the region of 0°C, of g of 4a-acetoxy-2a:-benzoyloxy-5/3,20-epoxy-l/S, 10/3AP.00753 dihydroxy - 9 - oxo - 7/3,13a-bis(triethylsilyloxy) -11-taxene in 25 cm3 of iodomethane. The solution is kept stirring for 45 minutes at a temperature in the region of 0°C, and then for .5 hours 3 0 minutes at a temperature in the region of 20°C. The reaction mixture is cooled again to a temperature in the region of 0°C, and 125 mg of sodium hydride at a concentration of 50 % by weight in liquid paraffin are added portionwise. After 1 hour at 20°C and then 18 hours at 5°C, the reaction mixture is diluted by adding 5 0 cm3 of dichloromethane and poured into 50 cm3 of saturated aqueous ammonium chloride solution, and settling is allowed to take place. The aqueous phase is 'separated and extracted with twice
L
0 cm3 of dichloroemethane, and the organic phases are then combined, washed with 10 cm3 of distilled water, dried over magnesium sulphate, filtered through sintered glass and concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40°C. 5.15 g of a yellow foam are thereby obtained, which product is purified by chromatography at atmospheric pressure on 300 g of silica (0.063-0.2 mm) contained in a column 5 cm in diameter (elution gradient: ethyl acetate/dichloromethane from 0:100 to 10:90 by volume), collecting 30-cm3 fractions.
Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40°C for 2 hours. 3.62 g of 4o:-acetoxy-2<x-benzoyloxy- 5/5, 2 0 - epoxy-1/5-hydroxy -10/5AP/P/ 9 7 / 0 1 0 9 3
AP . θ θ 7 5 3 methoxy-9-oxo-7β,13a-bis(triethylsilyloxy)-11-taxene are thereby obtained in the form of a pale yellow foam, the characteristics of which are as follows:
- 1H NMR spectrum (600 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 0.58 and 0.69 (2 mts, 6H each: ethyl CH2); 0.97 and 1.04 (2 t, J = 7.5, 9H each: ethyl CH3); 1.15 (s, 3H: CH3) ; 1.18 (s, 3H: CH3) ; 1.58 (s, IH: OH at position 1); 1.68 (s, 3H: CH3) ; 1.89 and 2.48 (2 mts, IH each: CH2 at position 6); 2.04 (s,
3H: CH3); 2.15 and 2.23 (2 dd, J = 16 and 9, IH each:
CH2 at position 14); 2.29 (s, 3H: COCH3) ; 3.40 (s, 3H: OCH3) ; 3.83 (d, J = 7, IH: Η: H at position 13); 4.15 and 4.30 (2d, J = 8.5, 1Ξ each: CH2 at position 20); 4.43 (dd, J = 11 and 7, IH: H at position 7); 4.91 (s,
IH: H at position 10); 4.96 (broad d, J = 10, IH at position 5); 5.01 (broad t, J = 9, IH: H at position 13); 5.62 (d, J = 7, IH: Ξ at position 2); 7.46 (t, J =
AP/P/ 9 7 / 0 1 0 9 3
| 7.5, | 2H: | ococ6h5 | H | at | the | meta position); | 7.60 | (t, | J = |
| / 7.5, | IH: | OCOCeHs | H | at | the | para position); | 8.09 | (d, | J = |
| 20 7.5, | 2H: | OCOC6H5 | Ξ | at | the | ortho position) | • |
4a-Acetoxy-2a-henzoyloxy-5/3,20-epoxy-l/S, 10/3dihydroxy-9-oxo-7/S, 13a-bis (triethylsilyloxy) -11-taxene (or 10-deacetyl-7,13-bis(triethylsilyl)baccatin (III) may be prepared in the following manner:
. 10.8 cm3 of triethylsilyl chloride are added .to a solution, maintained under an argon atmosphere, at a temperature in the region of 20°C, of 14 g of 4a-acetoxy-2a-benzoyloxy-5/3, 20-epoxy-l/S, Ίβ, 10/3,13αAP . 0 0 7 5 3 tetrahydroxy-9-oxo-11-taxene (10-deacetylbaccatin (III) in 50 cm3 of anhydrous pyridine. After 17 hours at a temperature in the region of 20°C, the reaction mixture is brought to a temperature in the region of 115°C and
10.8 cm3 of triethylsilyl chloride are then added.
After 3 hours 15 minutes at a temperature in the region of 115°C, the reaction mixture is brought back to a temperature in the region of 20°C and diluted with 30 cm3 of ethyl acetate and 100 cm3 of distilled water.
After settling has taken place, the aqueous phase is separated and extracted with twice 50 cm3 of ethyl acetate. The organic phases are combined, washed with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered through sintered glass and then concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40°C. S3.1 g of a brown oil are thereby obtained, which product is purified by chromatography at atmospheric pressure on 800 g of silica (0.063-0.2 mm) contained in a column 7 cm in diameter (elution gradient: ethyl acetate/dichloromethane from 0:100 to 5:95 by volume), collecting 60-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40°C for 2 hours. 9.77 g of
4a-acetoxy-2a-benzoyloxy-5/3,20-epoxy-l/S, 10β-dihydroxy9-oxo-7β,13a-bis(triethylsilyloxy)-11-taxene are thereby obtained in the form of a cream-coloured foam,
AP/P/ 9 7 / 0 1 0 9 3
AP.00753 the characteristics of which are as follows:
- 1H NMR spectrum (400 MHz; CDC13; chemical shifts δ in. ppm; coupling constants J in Hz): 0.55 and 0.68 (2 mts,
6H each: ethyl CH2) ; 0.94 and 1.03 (2 t, J = 7.5, 9H each: ethyl CH3) ;. 1.08 (s, 3H: CH3) ; 1.17 (s, 3H: CH3) ; 1.58 (s, ΙΗ: 0Ξ at position 1); 1.73 (s, 3H: CH3) ; 1.91 and 2.57 (2 mts, 1H each: CH2 at position 2); 2.04 (s, 3H: CH3); 2.12 and 2.23 (2 dd, J = 16 and 9, 1H each:
CH2 at position 14); 2.30 (s, 3H: COCH3); 3.88 (d, J =
7, 1H: H at position 3); 4.16 and 4.32 (2 d, J = 8.5,
1H each: 0¾ at position 20); 4.27 (d, J = 1, 1H: OH at position 10); 4.40 (dd, J = 11 and 7, 1H: H at position 7); 4.95 (broad d, J = 10, 1H: H at position 5); 4.95 (mt, 1H: H at position 13); 5.16 (d, u = 1, 1H: H at position 10); 5.60 (d, J = 7, 1H: H at position 2);
| 7.46 | (t/ | J = 7.5, | 2H: | ococsh5 | H at | the | meta position); |
| 7.60 | (t, | J = 7.5, | 1Ξ: | ococ6h5 | H at | the para position); | |
| 8.09 | (d, | J = 7.5, | 2Ξ: | ococ6h5 | H at | the | ortho position). |
AP/P/ 9 7 / 0 1 0 9 3
AP . Ο Ο 7 5 3
EXAMPLE 2
340 mg of 4a-acetoxy-2a-benzoyloxy-5/3,20epoxy-l/3-hydroxy-7/S, 10/5-dimethoxy-9-oxo-11-taxen-13a-yl (2R, 4S, 5R) -3 - tert-butoxycarbonyl-2 - (4-methoxyphenyl) -45 phenyl-1,3-oxazolidine-5-carboxylate are dissolved in 8 cm3 of a 0.IN ethanolic solution of hydrochloric acid containing 1 % of water. The solution thereby obtained is stirred for 13 hours at a temperature in the region of 2 0°C and then for 80 hours at 4°C, and 2 0 cm3 of dichioromethane are added. The organic phase is separated after settling has taken place and washed successively with 3 times 5 cm3 of saturated aqueous sodium hydrogen carbonate solution, dried over , magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C.
300 mg of a white foam are obtained, which product is purified by chromatography on silica gel deposited on plates [(gel 1 mm thick, plates 20 x 20 cm, eluent: dichloromethane/methanol (95:5 by volume)] in 80-mg fractions (4 plates). After localization with UV rays of the zone corresponding to the adsorbed desired product, this zone is scraped off and the silica collected is washed on sintered glass with 10 times 5 cm3 of ethyl acetate. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. A white foam is obtained, which is repurified according to the same technique [(3 plates: 20 x 20 χ I mm; eluent: dichloromethane/ethyl acetate
AP/P/ 9 7 / 0 1 0 9 3
AP . 0 C 7 5 3 (90:10 by volume)] . 205 mg of 4ai-acetoxy-2o:-benzoyloxy5/3,20- epoxy-1 /3 - hydroxy- 70,100- dimethoxy- 9 - oxo -11 - taxen13a-yl (2R,3S)-3 -tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate are thereby obtained in the form of a white foam, the characteristics of which are as follows:
- optical rotation: [a]°o = “33 (c = °·5? methanol).
- XH NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 1.23 (s, 3H: -CH3) ;
1.25 (s, 3H: -CH3) ; 1.39 [s, 9H: -C(CH3)3]; 1.70 , (s,
1H: -OH at position 1); 1.75 (s, 3H: -CH3); 1.82 and 2.72 (2 mts, 1H each: -CH2 at position 6); 1.91 (s, 3H:
-CH3) ; 2.31 (limiting AB, 2H: -CH2 at position 14); 2.39 £
(s, 3H: -COCH3); 3.33 and 3.48 (2 s, 3H each: -OCH3)·;
3.48 (mt, 1H: OH at position 2'); 3.85 (d, J = 7, IE:
-H at position 3); 3.88 (dd, J = 11 and 7, 1H: -H at position 7); 4.20 and 4.33 (2d, J = 8.5, 1H each: -CH2 at position 20); 4.55 (mt, 1H: -H at position 2'); 4.83 (s, 1H: -H at position 10); 5.00 (broad d, J = 10, 1H:
-Ξ at position 5); 5.30 (broad d, J = 10, 1H: -H at position 3'); 5.47 (d, J = 10, 1H: -CONH-); 5.56 (d, J = 7, 1H: -Hat position 2); 6.24 (broad t, J = 9, 1H:
-Ξ at position 13); from 7.30 to 7.50 (mt, 5H: -C6H5 at position 3'); 7.52 [t, J = 7.5, 2H: -OCOCgH5 (-H at position 3 and H at position 5)]; 7.63 [t, J = 7.5, 1Ξ:
,-OCOCeHs (-H at position 4)]; 8.12 [d, J = 7.5, 2H:
-OCOCsH5 (-H at position 2 and H at position 6)] .
4a-Acetoxy-2o;-benzoyloxy-50, 2O-epoxy-10-hydroxy-70,100AP/P/ 9 7 / 0 1 0 9 3
AP . 0 0 7 5 3 dimethoxy-9-oxo-ll-taxen-13a-yl (2R,4S,5R)-3-tertbutoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3oxazolidine-5-carboxylate may be prepared in the following manner:
100 cm3 of an ethanolic suspension of activated nickel according to Raney (obtained from 30 cm3 of the approximately 50 % commercial aqueous suspension by successive washing, to a pH in the region of 7, with 15 times 100 cm3 of distilled water and with
5 times 100 cm3 of ethanol) are added at a temperature in the region of 20°C to a solution, maintained under an argon atmosphere and kept stirring, of 1 g of 4a-acetoxy-2a-benzoyloxy-5JS, 2 0-epoxy-1/3-hydroxy-7/3,10/3bis(methylthiomethoxy)-9-oxo-ll-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxypheny1)-4phenyl-1,3-oxazolidine-5-carboxylate in 100 cm3 of anhydrous ethanol. The reaction medium is kept stirring for 24 hours at a temperature in the region of 20°C and then filtered through sintered glass. The sintered glass is washed with 4 times 80 cm3 of ethanol, and the filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 710 mg of a yellow foam are obtained, which product is purified by chromatography on SO g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter [eluent: dichloromethane/ethyl acetate (90:10 by volume)], collecting 6-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to
AP/P/ 97/01093
AP . 0 0 7 5 3 dryness under reduced pressure (2.7 kPa) at 40 °C.
350 mg of 4a-acetoxy-2a-benzoyloxy-5jS, 20-epoxy-l/Shydroxy-7/3,10/3-dimethoxy-9 - oxo-11- taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-45 phenyl-1,3-oxazolidine-5-carboxylate are thereby obtained in the form of a white foam.
4a-Acetoxy-2a-benzoyloxy-5/3, 20 -epoxy- 1/3hydroxy-7/3,10/S-his (methylthiomethoxy) -9-oxo-ll-taxen13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2 -(4-methoxy10 phenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate may be prepared in the following manner:
2.3 cm3 of acetic acid and 7.55 cm3 of acetic anhydride are added at a temperature in the region of 20°C to a solution, maintained under an argon atmosphere and kept stirring, of 3.1 g of 4a-acetoxy2a-henzoyloxy-5/3, 20-epoxy-1/3-7/3,10/3-trihydroxy-9-oxoll - taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2 -(4me thoxypheny1)-4-phenyl-1,3 -oxaz ο1i dine- 5-c arboxy1ate dissolved in 102 cm3 of dimethyl sulphoxide. The reaction mixture is kept stirring for 7 days at a temperature in the region of 2 0°C, and then poured into a mixture of 500 cm3 of distilled water and 250 cm3 of dichloromethane. 30 cm3 of saturated aqueous potassium carbonate solution are then added with efficient stirring to a pH in the region of 7. After 10 minutes of stirring, the organic phase is separated after settling has taken place and the aqueous phase is re-extracted with twice 250 cm3 of dichloromethane. The
AP/P/ 9 7 / 0 1 0 9 3
AP . Ο Ο 7 5 3 organic phases are combined, washed with 250 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 5.2 g of a pale yellow oil are obtained, which product is purified by chromatography on 200 g of silica (0.063-0.4 mm) contained in a column 3 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. 1.25 g of 4a-acetoxy-2a:-benzoyloxy-5/5, 20-epoxy-l$-hydroxy-7/3,10βbis(methylthiomethoxy)-9-oxo-ll-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2 -(4-methoxyphenyl)-415 phenyl-1,3-oxazolidine-5-carboxylate are thereby obtained in the form of a white foam.
4o:-Acetoxy-2a'-benzoyloxy-5/3, 2 0-epoxyIjS, 7jS, 10£-trihydroxy-9-oxo-ll-taxen-13a-yl (2R,4S,5R) 3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,320 oxazolidine-5-carboxylate may be prepared in the following manner:
A solution of 5.1 g of 4o;-acetoxy-2abenzoyloxy-5/S, 20-epoxy-l(S-hydroxy-9-oxo-7jS, 10βbis(2,2,2-trichloroethoxy)carbonyloxy-ll-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4phenyl-1,3-oxazolidine-5-carboxylate in a mixture of
100 cm3 of methanol and 100 cm3 of acetic acid is heated, with stirring and under an argon atmosphere, to
AP/P/ 9 7 / 0 1 0 9 3
AP.00753 a temperature in the region of 60 °C, and 10 g of powdered zinc are then added. The reaction mixture is then stirred for 15 minutes at 60°C, thereafter cooled to a temperature in the region of 20°C and filtered 5 through sintered glass lined with Celite. The sintered glass is washed with twice 15 cm3 of methanol. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 50 cm3 of ethyl acetate and 25 cm3 of saturated aqueous sodium hydrogen carbonate solution are added to the residue. The organic phase is separated after settling has taken place and washed successively with 25 cm3 of saturated aqueous sodium hydrogen carbonate solution and with 25 cm3 of distilled water, then dried over magnesium sulphate, filtered through sintered glass and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 3.1 g of 4a-acetoxy-2orbenzoyloxy-5/5, 20-epoxy-l/S, 7 β , 10 β-trihydroxy-9-oxo-11taxen-13ct-yl (2R,4S, 5R) -3-tert-butoxycarbonyl-2- (420 methoxyphenyl) -4-phenyl-l,3-oxazolidine-5-carboxylate are thereby obtained in the form of a white foam.
4a-Acetoxy-2o:-benzoyloxy-5/3,20-epoxy-l/Shydroxy-9-oxo-7/S, 10/5-bis (2,2,2 - trichloroethoxy) carbonyloxy-11-taxen-13a-yl (2R,4S,5R))-3-tert-butoxy25 carbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine5-carboxylate may be prepared under the conditions described in Patent WO 94/07878.
AP/P/ 9 7 / 0 1 0 9 3
AP . 0 0 7 5 3
EXAMPLE 3 mg of dicyclohexylcarbodiimide and then
8.5 mg of 4-(N,N-dime thy lamino) pyridine are added successively at a temperature in the region of 2 0°C to a suspension containing 135 mg of 4o!-acetoxy-2abenzoyloxy-5/5,20-epoxy-10/5-ethoxy-1/5, 13 a-dihydroxy-7/3methoxy-9-oxo-11-taxene, 120 mg of (2R,4S,5R)-3-tertbutoxycarbonyl-2 - (4-methoxyphenyl) -4-phenyl-1,3oxazolidine-5-carboxylic acid and 50 mg of powdered 4A molecular sieve in 1 cm3 of anhydrous toluene. The suspension obtained is stirred at a temperature in the region of 20°C under an argon atmosphere for 1 hour, and then purified by direct application to a column for chromatography at atmospheric pressure on 30 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter (elution gradient: ethyl acetate/ dichioromethane from 2:98 to 10:90 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 for 2 hours. 320.6 mg of a white solid are thereby obtained, which product is purified by preparative thin-layer chromatography: 10 Merck preparative silica gel 60F254 plates, thickness 0.5 mm, application in solution in dichioromethane, eluting with a methanol/ dichioromethane (3:97 by volume) mixture. After elution of the zones corresponding to the main products with a methanol/dichloromethane (15:85 by volume) mixture,
AP/P/ 97/01 0 93
AP . Ο Ο 7 5 3 filtration through cotton wool and then evaporation of the solvents under reduced pressure (2.7 kPa) at a temperature in the region of 40°C, 47.7 mg of 4a-acetoxy-2a!-benzoyloxy-5/3,20-epoxy-10β-ethoxy-1β, 13α5 dihydroxy-7β-ιηβthoxy-9 -oxo-11 -taxene are obtained in the form of a cream-coloured solid and 37 mg of 4α-acetoxy-2α-benzoyloxy-5β/20-epoxy-10β-ethoxy-lβhydroxy-7β-methoxy-9-oxo-ll-taxen-13α-yl (2R,4S,5R)-3tert-butoxycarbonyl-2-(4-mefchoxyphenyl)-4-phenyl-1,3 10 oxazolidine-5-carboxylate are obtained in the form of a white foam, the characteristics of which are as follows :
- XH NMR spectrum (600 MHz; CDC13; at a temperature of
333°K; chemical shifts δ in ppm; coupling constants J »
in Hz): 1.09 (s, 9H: C(CH3)3; 1.19 (s, 3H: CH3); 1.21 (s, 3H: CH3); 1.27 (t, J = 7, 3H: ethyl CH3) ; 1.43 (s, IH: OH at position 1); 1.62 (s, 3H: CH3) ; 1.58 (s, 3H: CH3); 1.77 and 2.63 (2 mts, IH each: CH2 at position 6);
1.86 (s, 3Ξ: COCH3) ; 2.13 and 2.22 (2 dd, J = 16 and 9,
IH each: CH2 at position 14); 3.27 (s, 3H: OCH3); 3.45 and 3.68 (2 mts, 1Ξ each: ethyl CH2); 3.76 (d, J = 7,
IH: H3); 3.81 (s, 3Ξ: ArOCH3); 3.85 (dd, J = 11 and 7, IH: H at position 7); 4.13 and 4.23 (2 d, J = 8.5, IH each: CH2 at position 20); 4.58 (d, J = 4.5, IH: H at position 2'); 4.83 (s, IH: H at position 10); 4.90 (broad d, J = 10, IH: Ξ at position 5); 5.46 (d, J = 4.5, 1Ξ: H at position 3'); 5.50 (d, J = 7 Hz, IH: H2); 6.13 (broad t, J = 9 Hz, IH: H13); 6.38 (s, IH: H5');
AP/P/ 9 7 / 0 1 0 9 3
AP. Ο Ο 7 5 3
6.92 (d, J = 8.5, 2H: aromatic H at the ortho position with respect to OCH3) ; from 7.30 to 7.50 (mt, 9H: aromatic H at position 3' - aromatic H at the meta position with, respect to OCH3 and OCOC6H5 H at the meta position); 7.59 (t, J = 7.5, IH: OCOCgH5 Ξ at the para position); 8.03 (d, J = 7.5, 2H: OCOCSH5 Ξ at the ortho position).
A solution of 48 mg of 4of-acetoxy-2abenzoyloxy-5/S, 20-epoxy-l 0 β -ethoxy-1/3-hydroxy-7 β10 methoxy-9-oxo-11-taxen-13a-yl (2R,4S,5R)-3-tertbutoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3oxazolidine-5-carboxylate in 0.5 cm3 of ethyl acetate and 0.004 cm3 of concentrated 37 % hydrochloric acid is kept stirring at a temperature in the region of 20°C for 1.5 hours under an argon atmosphere. The reaction mixture is then purified by preparative thin-layer chromatography: application of the crude reaction mixture to 5 Merck preparative silica gel 60F254 plates, thickness 0.5 mm, eluting with a methanol/dichloromethane (4:96 by volume) mixture.
After elution of the zone corresponding to the main product with a methanol/dichloromethane (15:85 by volume) mixture, filtration through cotton wool and then evaporation of the solvents under reduced pressure (2.7 kPa) at a temperature in the region of 40°C,
28.5 mg of 4a-acetoxy-2a-benzoyloxy-5/S,20-epoxy-10/5ethoxy-l/5-hydroxy-7/3-methoxy-9-oxo-ll-taxen-13o:-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3AP/P/ 9 7 / 0 1 0 9 3
AP . Ο Ο 7 5 3 phenylpropionate are obtained in the form of an ivorycoloured foam, the characteristics of which are as follows :
- XH NMR spectrum (400 MHz; CDC13; chemical shifts δ in 5 ppm; coupling constants J in Hz) ; 1.22 (s, 3H; CH3) ;
1.25 (s, 3H: CH3); 1.32 (t, J = 7, 3H: ethyl CH3); 1.38 (s, 9H: C(CH3)3; 1.64 (s, IH: OH at position 1); 1.73 (s, 3H: CH3) ; 1.80 and 2.70 (2 mts, IH each: CH2 at position 6); 1.88 (s, 3H: CH3) ; 2.30 (mt, 2H: CH2 at position 14); 2.38 (s, 3H: COCH3) ; 3.31 (s, 3H: OCH3) ; 3.44 (unres. comp., IH: OH at position 2'); 3.50 and 3.70 (2 mts, IH each: ethyl OCH2) ; 3.84 (d, J = 7.5,
IH: H at position 3); 3.87 (dd, J = 11 and 6.5, IH: H at position 7); 4.18 and 4.32 (2 d, J = 8.5, IH each:
CH2 at position 20); 4.54 (mt, IH: H at position 21) ;
4.90 (s, IH: Ξ at position 10); 4.98 (broad d, J = 10,
IH: Ξ at position 5); 5.28 (broad d, J = 10, IH: H at position 3'); 5.42 (d, J = 10, IH: CONH); 5.64 (d, J =
7.5, 1Ξ: H at position 2); 6.22 (broad t, J = 9, IH: H at position 13); from 7.25 to 7.45 (mt, 5H: aromatic Ξ at position 3'); 7.50 (t, J = 7.5, 2Ξ: OCOC6H5 Ξ -at the meta position); 7.62 (t, J = 7.5, IH: OCOCgH5 Ξ at the para position); 8.12 (d, J = 7.5, 2H: OCOC6H5 Ξ at the ortho position).
4a-Acetoxy-2o'-benzoyloxy-5/8,20-epoxy-10/3e thoxy-1β,13 a -dihydroxy-7 β-me thoxy- 9 -oxo-11-1 axene (or
10/8-ethoxy-7/3-methoxy-10-deacetoxybaccatin III) may be prepared in the following manner:
AP/P/ 97 / 0 1 0 9 3
AP.00753 mg of sodium hydride at a concentration of 50 % by weight in liquid paraffin are added portionwise to a solution, maintained under an argon atmosphere, at a temperature in the region of 0°C, of 235 mg of 4a5 acetoxy-2a-benzoyloxy-5/5, 2 0 -epoxy- 1β, Ί β, 13 ο;- trihydroxy10/3-ethoxy-9-oxo-ll-taxene in 2.5 cm3 of iodomethane and 1 cm3 of dimethylformamide. After 3 0 minutes at a temperature in the region of 0°C, the reaction mixture is diluted with 40 cm3 of ethyl acetate, 6 cm3 of distilled water and 8 cm3 of saturated aqueous ammonium chloride solution. After settling has taken place, the organic phase is separated and washed with three times 8 cm3 of distilled water and then 8 cm3 of saturated aqueous NaCl solution, dried over magnesium sulphate, filtered through sintered glass and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 268 mg of a yellow solid are thereby obtained, which product is purified by chromatography at atmospheric pressure on 30 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter (elution gradient: ethyl acetate/ dichloromethane from 0:100 to 15:85 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 40°C for 2 hours. 380 mg of 4a-acetoxy-2a-benzoyloxy-5/8, 20-epoxy10 β-ethoxy-1β,13 a -dihydroxy-7 β- methoxy- 9 -oxo-11-taxene £6010//6 /d/dV
REPLACEMENT SHEET (RULE 26)
AP .00753 are thereby obtained in the form of a white powder, the characteristics of which are as follows:
- 1H NMR spectrum (3 0 0 MHz; CDClj with the addition of a few drops of CD3OD-d4; chemical shifts δ in ppm, coupling constants J in Hz): 0.99 (s, 3H: CH3); 1.09 (s,
3H: CH3) ; 1.22 (t, J = 7, 3H: ethyl CH3) ; 1.62 (s, 3H: CH3) ; 1.68 and 2.66 (2 mts, 1H each: CH26) ; 2.03 (s, 3Ξ: CH3) ; 2.13 and 2.22 (2 dd, J = 15 and 9, 1Ξ each: CH2 at
| position | 14),-2.23 (s, 3H: | COCHj) ; 3.23 | (s, | 3Ξ: | OCH3) ; | |
| 10 | from 3.40 | to 3.65 (mt, 2H: | ethyl CH2) ; | 3.84 | (d, | J = 7.5, |
| IK: H at | position 3); 3.88 | (dd, J = 10 | and | 6.5, | 1H: Ξ |
at position 7); 4.10 and 4.23 (2d, J = 8.5, 1H each:
CH2 20);,4.75 (broad t, J = 9, 1H: H at position 13); 4.90 (s, 1H: Ξ at position 10); 4.97 (broad d, J = 10,
1H: H at position 5); 5.51 (d, J = 7.5, 1H: Ξ at position 2); 7.42 (t, J - 7.5, 2H: OCOC6H5 H at the meta position); 7.53 (t, J = 7.5, 1H: OCOC6HS H at the para position); 8.03 (d, J = 7.5, 2H: OCOCSHS Ξ at the ortho position).
4a-Acetoxy-2a-benzoyloxy-5/S, 20-epoxy1/3, 7/3,13a-trihydroxy-10/S-ethoxy-9-oxo-ll-taxene (or 10/S-ethoxy-10-deacetoxybaccatin III) may be prepared in the following manner:
cm3 of hydrogen fluoride/triethylamine complex (3HF.Et3N) are added to a solution, maintained under an argon atmosphere, at a temperature in the
AP/P/ 9 7 / 0 1 0 9 3
REPLACEMENT SHEET (RULE 26)
AP. Ο Ο 7 5 3 region of 20°C, of 591 mg of 4a-acetoxy-2a-benzoyloxy5β, 20-epoxy-ljS,hydroxy-10/S-ethoxy-9-oxo-7/S, 13ahis(triethylsilyloxy)-11-taxene in 6 cm3 of dichioromethane. After 21 hours at a temperature in the region of 20°C, the.reaction mixture is diluted with 40 cm3 of dichioromethane and poured into a suspension of 40 cm3 of supersaturated aqueous sodium hydrogen carbonate solution maintained at a temperature in the region of 0°C. After dilution with 10 cm3 of distilled water and when settling has taken place, the aqueous phase is separated and re-extracted with twice 20 cm3 of diethyl ether. The organic phases are combined, washed with 2 0 cm3 of distilled water and 2 0 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered through magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C.
370 mg of a pale yellow foam are thereby obtained, which product is purified by chromatography at atmospheric pressure on 35 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol/dichloromethane (2:98 by volume) mixture and collecting 15-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C for 2 hours. 236.2 mg of 4a-acetoxy-2a-benzoyloxy-5)S, 20epoxy-ΐβ, Ίβ, 13α-trihydroxy-IOjS-ethoxy-9-oxo-11-taxene
AP/P/ 9 7 / 0 1 0 9 3
REPLACEMENT SHEET (RULE 26)
AP. 0 0 7 5 3 are thereby obtained in the form of a white solid, the characteristics of which are as follows:
- XH NMR spectrum (400 MHz; CDC13: chemical shifts δ in ppm, coupling constants J in Hz) : 1.08 (s, 3Ξ: CH3) ;
1.19 (s, 3H: CH3) 1.29 (t, J = 7.5, 3H: ethyl CH3) ;
1.38 (d, J = 9, IH: OH at position 7); 1.59 (s, IH: OH at position 1); 1.69 (s, 3H: CH3) ; 1.82 and 2.62 (2 mts, IH each: CH2 at position 6); 2.02 (d, J = 5, 1Ξ: OH at position 13); 2.08 (s, 3H: CH3) ; 2.30 (s, 3H: COCH3) ; 2.32 (d, J = 9, 2Ξ: CH2 at position 14); 3.56 and 3.67 (2 mts, IH each: ethyl OCH2) ;. 3.98 (d, J = 7, 1Ξ: H at position 3); 4.18 and 4.33 (2 d, J = 8.5 Hz, IH each: CH220); 4.30 (mt, IH: H7); 4.90 (mt, IH: H at position 13); 4.99 (dd, J = 10 and 1.5, IH: H at position 5); 5.05 (s, IH: H at position 10); 5.66 (d, J = 7, IE: Ξ
| at position 2); | 7.49 | (t, | J = | 7.5, | 2H: | OCOC6Hs | H | at | the |
| meta position); | 7.63 | (t, | J = | 7.5, | IH: | OCOC6Hs | Ξ | at | the |
| para position); | 8.12 | (d, | J = | 7.5, | 2H: | ococ6h5 | Ξ | at | the |
ortho position).
4a-Acetoxy-2a-benzoyloxy-5jS, 20-epoxy-ljShydroxy-10/S-ethoxy-9-oxo-7/3,13a-bis (triethylsilyloxy) 11-taxene (or lQ/S-ethoxy-10-deacetoxy-7,13 bis(triethylsilyl)baccatin III) may be prepared in the following manner:
mg of sodium hydride at a concentration of 50 % by weight of liquid paraffin are added portionwise to a solution, maintained under an argon atmosphere, at a temperature in the region of 20°C, of 1 g of 4aAP . ο ο 7 5 3 acetoxy-2a-benzoyloxy-5β, 2O-epoxy-10,10)3-dihydroxy-9σχο-7)3, 13a-bis (triethylsilyloxy)-11-taxene in 3 cm3 of iodoethane and 4 cm3 of dimethylformamide. The solution is kept stirring for 17 hours at a temperature in the region of 20°C, and 93 mg of sodium hydride at a concentration of 50 % by weight in liquid paraffin is then added portionwise. After 50 minutes at a temperature in the region of 2 0°C, the reaction mixture is diluted with 100 cm3 of ethyl acetate and 10 cm3 of saturated aqueous ammonium chloride solution. The organic phase is separated after settling has taken place and washed with six times 10 cm3 of distilled water and then 10 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered through sintered glass and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 1.2 g of a yellow foam are thereby obtained, which product is purified by chromatography at atmospheric pressure on 150 g of silica (0.053-0.2 mm) contained in a column 3.5 cm in diameter, eluting with an ethyl acetate/dichloromethane (2:98, then 5:95 by volume) mixture and collecting 15-cm3 fractions. Fractions containing only the desired products are pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40°C for 2 hours.
379.2 mg of 4o!-acetoxy-2a!-benzoyloxy-5jS, 20-epoxy1β, 10)3-dihydroxy-9-oxo-7b, 13a-bis (triethylsilyloxy) -11taxene are thereby obtained in the form of a pale
AP/P/ 9 7 / 0 1 0 9 3
AP.00753 yellow foam and 430 mg of 4a-acetoxy-2a-benzoyloxy5jS, 20-epoxy-l)S-hydroxy-10)S-ethoxy-9-oxo-7/S, 13q;bis(triethylsilyloxy)-11-taxene are thereby obtained in the form of a white foam, the characteristics of which are as follows:
- XH NMR spectrum (400 MHz; CDCl3; chemical shifts δ in ppm, coupling constants J in Hz): 0.57 and 0.70 (2 mts, 6H each; ethyl CH2) ; 0.97 and 1.03 (2 t, J = 7.5, 9H each: ethyl CH3) ; 1.13 {s, 3H: CH3) ; 1.20 (s, 3H: CH3) ; 1.29 (t, J = 7.5, 3H: CH3 of ethoxy at position 10); 1.58 (s, 1H: OH at position 1); 1.66 (s, 3H: CH3) ; 1.89 and 2.58 (2 mts, 1H each: CH2 at position 2); 2.03 (s, 3H: CH3) ; 2.13 and 2.23 (2 dd, J = 16 and 9, 1Ξ each:
CH2 at position 14); 2.30 (s, 3H: COCH3) ; 3.53 (mt, 2H: 0¾ of ethoxy at position 10); 3.84 (d, J = 7, 1H: H at position 3); 4.15 and 4.30 (2 d, J = 8.5, 1Ξ each: CH2 at position 20); 4.43 (dd, J = 11 and 6.5, 1Ξ: H at position 7); from 4.90 to 5.00 (mt, 2H: H at position 13 and H at position 5); 5.01 (s, 1Ξ: H at position 10); 5.61 (d, J = 7, 1H: H at position 2); 7.48 (t, J =
7.5, 2Ξ: OCOCsH5 H at the meta position); 7.61 (t, J =
7.5, 1H: OCOCgHj H at the para position); 8.10 (d, J =
7.5, 2H: OCOC6HS H at the ortho position).
EXAMPLE 4 mg of dicyclohexylcarhodiimide and then 7 mg of 4-(N,N-dimethylaminopyridine are added successively at a temperature in the region of 20°C to a suspension containing 115 mg of 4a-acetoxy-2aAP.00753 benzoyloxy-5/S, 20-epoxy-10/S- (1-propyl) oxy-l/S,13adihydroxy-7/S-methoxy-9-oxo-ll-taxene and 100 mg of (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4phenyl-1,3-oxazolidine-5-carboxylic acid in 1 cm3 of anhydrous toluene. The suspension obtained is stirred at a temperature in the region of 20°C under an argon atmosphere for 1 hour, and then purified by direct application to a column for chromatography at atmospheric pressure on 30 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter (elution gradient: ethyl acetate/dichloromethane from 2:98 to 10:90 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 for 2 hours. 276.2 mg of a white solid are thereby obtained, which product is purified by preparative thin-layer chromatography: 10 Merck preparative silica gel 60F254 plates, thickness 0.5 mm, application in solution in dichloromethane, eluting with a methanol/dichloromethane (3:97 by volume) mixture. After elution of the zones corresponding to the main products with a methanol/dichloromethane (15:85 by volume) mixture, filtration through cotton wool and then evaporation of the solvents under reduced pressure (2.7 kPa) at a temperature in the region of
40°C, 84.8 mg of 4a-acetoxy-2a-benzoyloxy-5/S, 20-epoxy10/3- (1-propyl) oxy-l/S-hydroxy-7/5-methoxy-9-oxo-11-taxen13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4AP/P/ 9 7 / 0 1 0 9 3
AP.00753 methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate are obtained in the form of a white foam, the characteristics of which are as follows:
- XH NMR spectrum (300 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 0.97 (t, J = 7, 3H: propyl CH3) ; 1.07 (s, 9H: C(CH3)3); 1.19 (s, 6H: CH3) ;
from 1.50 to 1.80 (mt, 3Ξ: OH at position 1 and central CH2 of propyl); 1.60 (s, 3H: CH3) ; 1.70 (s, 3H: CH3) ;
1.78 and 2.63 (2 mts, 1Ξ each: CH2 at position 6); 1.82 (unres. comp. 3Ξ: COCH3) ; 2.07 and 2.19 (2 dd, J = 16 and 9, 1H each: CH2 at position 14); 3.26 (s, 3H: OCH3) ; 3.30 and 3.58 (2 mts, 1H each: propyl OCH2) ; 3.73 (d, J = 7.5, 1H: H at position 3); 3.81 (s, 3H: ArOCH3) ; 3.81 (mt, 1H: H at position 7); 4.09 and 4.23 (2 d, J = 8.5,
1H each: CH2 at position 20) ; 4.57 (d, J = 4.5, 1H: H at position 2'); 4.79 (s, 1Ξ: Ξ at position 10); 4.90 (broad d, J = 10, 1H: H at position 5); 5.40 (unres. comp. 1H: H at position 3'}; 5.58 (d, J = 7.5, 1Ξ: Ξ at position 2); 6.13 (broad t, J = 9, ΙΗ: Ξ at position
13); 6.40 (spread unres. comp. 1H: H at position 5');
6.92 (d, J = 8.5, 2Ξ: aromatic H at the ortho position with respect to OCH3) ; from 7.30 to 7.60 (mt, 9H: aromatic H at position 3' - aromatic H at the meta position with respect to OCH3 and OCOCeH5 meta H) ; 7.63 (t, J = 7.5, 1H: OCOCSHS H at the para position); 8.03 (d, J = 7.5, 2H: OCOC6H5 H at the ortho position).
4a-Acetoxy-2a-benzoyloxy-5/S, 20-epoxy-10/3- (1propy1)oxy-1β-hydroxy-7 β-methoxy-9-oxo-11-1axen-13 a-y1
AP/P/ 9 7 / 0 1 0 9 3
AP.00753 (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate may be prepared in the following manner:
A solution of 84 mg of 4ai-acetoxy-2Q;5 benzoyl oxy-5/3, 20-epoxy-10/3- (1-propyl) oxy-1/3-hydroxy-7/5methoxy-9-oxo-ll-taxen-13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2- (4-methoxyphenyl)-4-phenyl-l,3-oxazolidine5-carboxylate in 0.84 cm3 of ethyl acetate and 0.0071 cm3 of concentrated 37 % hydrochloric acid is kept stirring at a temperature in the region of 20°C for 1 hour under an argon atmosphere. The reaction mixture is then purified by preparative thin-layer chromatography: application of the crude reaction mixture to 6 Merck preparative silica gel 60F2S4 plates, thickness 0.5 mm, eluting with a methanol/acetonitrile/ dichloromethane (3:7:90 by volume) mixture. After elution of the zone corresponding to the main product with a methanol/dichloromethane (15:85 by volume) mixture, filtration through cotton wool and then evaporation of the solvents under reduced pressure (2.7 kPa) at a temperature in the region of 40°C, 27 mg of 4af-acetoxy-2of-benzoyloxy-5/S, 2 0-epoxy-10/3- (1propy1)oxy-1β-hydroxy-7 β-methoxy-9-oxo-11-1axen-13 a-y1 (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl25 propionate are obtained in the form of a white foam, the characteristics of which are as follows:
- 3H NMR spectrum (400 MHz; CDC13; chemical shifts δ in ppm; coupling constants J in Hz): 0.99 (t, J = 7, 3H:
AP/P/ 97/01093
AP.00753 propyl CH3) ; 1.22 (s, 3H: CH3) ; 1.25 (s, 3H: CH3) ; 1.38 (s, 9H: C(CH3)3; 1.64 (s, 1H: OH at position 1); 1.69 (mt, 2H: central CH2 of propyl); 1.73 (s, 3H: CH3) ; 1.80 and 2.70 (2 mts, 1H each: CH2 at position 6); 1.88 (s,
3H: CH3) ; 2.30 (mt, 2H: CH2 at position 14); 2.38 (s,
3H: COCH3) ; 3.31 (s, 3H: OCH3) ; 3.36 and 3.64 (2 mts, 1H each: propyl OCH2) ; 3.44 (unres. comp. 1H: OH at position 2'); 3.84 (d, J = 7.5, Hz, 1H: H at position 3); 3.87 (dd, J = 11 and 6.5, 1H: H at position 7);
4.18 and 4.30 (2d, J = 8.5, 1H each: CH2 at position
20); 4.64 (mt, 1H: H at position 2'); 4.89 (s, 1H: H at position 10); 4.98 (broad d, J = 10, 1H: H at position 5); 5.28 (broad d, J = 10, 1H: H at position 3Z); 5.42 (d, J = 10, 1H: CONH); 5.64 (d, J = 7.5, 1H: H at 15 position 2); 6.22 (broad t, J = 9, 1H: H at position
13); from 7.25 to 7.45 (mt, 5H: aromatic H at position 3'); 7.50 (t, J = 7.5, 2H: OCOC6HS H at the meta position); 7.61 (t, J = 7.5, 1H: OCOCSHS H at the para position); 8.12 (d, J = 7.5, 2H: OCOCSH5 H at the ortho position).
£ 6 0 I 0 7 Z 6 /d/dV
4a-Acetoxy-2a-benzoyloxy-50, 2O-epoxy-lO0- (1propyl)oxy-10,13a-dihydroxy-70-methoxy-9-oxo-11-taxene (or 100- (1-propyl)oxy-70-methoxy-lO-deacetoxybaccatin III) may be prepared in the following manner:
30 mg of sodium hydride at a concentration of % by weight in liquid paraffin are added portionwise to a solution, maintained under an argon atmosphere, at a temperature in the region of 0°C, of 165 mg of
AP . 0 0 7 5 3
4a-acetoxy-2a-benzoyloxy-5/S, 20-epoxy-1/3,7/3, 13atrihydroxy-10jS- (1-propyl) oxy-9-oxo-ll-taxene in 1.7 cm3 of iodomethane and 1 cm3 of dimethylformamide. After 3 0 minutes at a temperature in the region of 0°C, the reaction mixture is' diluted with 40 cm3 of ethyl acetate, 5 cm3 of distilled, water and 7 cm3 of saturated aqueous ammonium chloride solution. After settling has taken place, the organic phase is separated and washed with three times 7 cm3 of distilled water and then 7 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered through sintered glass and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 224 mg of the yellow solid are thereby obtained, which product is purified by chromatography at atmospheric pressure on 20 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter (elution gradient: ethyl acetate/dichloromethane from 0:100 to 15:85 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 40°C for 2 hours. 117.5 mg of 4a-acetoxy2a-benzoyloxy-5/S, 20-epoxy- 10/8- (1-propyl) oxy-1/3,13adihydroxy-7/3-methoxy-9-oxo-11-taxene are thereby obtained in the form of a white foam, the characteristics of which are as follows:
- XH NMR spectrum (300 MHz; CDC13; chemical shifts δ in ppm, coupling constants J in Hz): 0.98 (t, J = 7, 3H:
AP/P/ 9 7 / 0 1 0 9 3
AP . 0 0 7 5 3 propyl CH3) ; 1.05 (s, 3H: CH3) ; 1.19 (s, 3H: CH3) ; from 1.60 to 1.80 (mt, 2H: central CH2 of propyl); from 1.65 to 1.85 and 2.66 (2 mts, 1H each: CH2 at position 6); 1.72 (s, 3H: CH3) ; 2.10 (s, 3H: CH3) ; from 2.05 to 2.35 (mt, 2H: CE2 at position 14); 2.28 (s, 3H: COCH3) ; 3.32 (s, 3H: OCH3) ; 3.45 and 3.65 (2 mts, 1H each: propyl
OCH2) ; 3.92 (d, J = 7.5, 1H: H3); 3.93 (dd, J = 11 and 6, 1H: H at position 7); 4.16 and 4.32 (2d, J = 8.5,
1H each: CH2 at position 20); 4.90 (mt, 1Ξ: H at position 13); 4.94 (s, 1Ξ: H at position 10); 5.03 (broad d, J = 10, 1H: H at position 5); 5.50 (d, J = 7.5, 1H: H at position 2); 7.48 (t, J = 7.5, 2Ξ: OCOC6H5 H at the meta position); 7.62 (t, J = 7.5, IE: OCOCeHs H at the para position); 8.11 (d, J = 7.5, 2H: OCOCSHS Ξ at the ortho position).
4a-Acetoxy-2a-benzoyloxy- 5/5,20-epoxy1/3,7/5,13o:-trihydroxy-10/3- (l-propyl) oxy-9-oxo-11-taxene (or 10/5-(l-propyl) oxy-10-deacetoxybaccatin III) may be prepared in the following manner:
0 8.75 cm3 of hydrogen fluoride/triethylamine complex (3EF.Et3N) are added to a solution, maintained under an argon atmosphere, at a temperature in the region of 20°C, of 585 mg of 4a-acetoxy-2a-benzoyloxy5/5,20-epoxy-l/3-hydroxy-10/3- (l-propyl) oxy-9-oxo-7/3,13a25 bis(triethylsilyloxy)-11-taxene in 6 cm3 of dichloromethane. After 24 hours at a temperature in the region of 2 0°C, the reaction mixture is diluted with 30 cm3 of dichloromethane and poured into a suspension
AP/P/ 9 7/01093
AP . ο Ο 7 5 3 of 3 0 cm3 of supersaturated aqueous sodium hydrogen, carbonate solution maintained at a temperature in the region of 0°C. After dilution with 10 cm3 of distilled water and when settling has taken place, the aqueous phase is separated and re-extracted with twice 20 cm3 of diethyl ether. The organic phases are combined, washed with 2 0 cm3 of distilled water and 2 0 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered through magnesium sulphate and concentrated, to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C.
500 mg of a pale yellow foam are thereby obtained, which product is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.2 mm) , contained in a column 2.5 cm in diameter, eluting with a methanol/dichloromethane (2:98 by volume) mixture and collecting 15-cm3 fractions. Fractions containing only the desired product are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C for 2 hours. 373.8 mg of 4a-acetoxy-2a-benzoyloxy-5/S,20epoxy-l/S,7/S, 13a-trihydroxy-10/3- (1-propyl) oxy-9-oxo-lltaxene are thereby obtained in the form of a white solid, the characteristics of which are as follows:
- XH NMR spectrum (300 MHz; CDC13; chemical shifts δ in ppm, coupling constants J in Hz): 0.95 (t, J = 7, 3Ξ: propyl CH3) ; 1.06 (s, 3Ξ: CH3) ; 1.22 (s, 3H: CH3) ; 1.45 (d, J = 7.5, IH: OH at position 7); from 1.60 to 1.80 (mt, 2Ξ: central 0¾ of propyl); 1.67 (s, 3H: CH3) ; 1.83
AP/P/ 9 7 / 0 1 0 9 3
AP . Ο 0 7 5 3 and 2.62 (2 mts, IH each: CH2 at position 6); 2.05 (s, 3H: CH3); 2.05 (mt, IH: OH at position 13); 2.27 (limiting AB, 2H: CH2 at position 4); 2.28 (s, 3H:
COCH3) ; 3.40 and 3.57 (2 mts, IH each: propyl OCH2) ;
3.97. (d, J = 7.5, IH: H at position 3); 4.15 and 4.30 (2d, J = 8.5, IH each: CH2 at position 20); 4.28 (mt, IH: H at position 7); 4.90 (mt, IH: H at position 13); 4.98 (broad d, J = 10, IH: Ξ at position 5); 5.03 (s,
IH: H at position 10); 5.65 (d, J = 7.5, IH: Hat position 2); 7.50 (t, J = 7.5, 2H: OCOC6H5 Ξ at the meta position); 7.60 (t, J = 7.5,.1H: OCOC6H5 H at the para position); 8.00 (d, J = 7.5, 2H: OCOCSH5 H at the ortho position).
4a-Acetoxy-2o!-benzoyloxy-5/3,2 0 - epoxy-1/315 hydroxy-10/S- (1-propyl) oxy-9-oxo-7β, 13a-bis (triethylsilyloxy)-11-taxene (or 10/3-(l-propyl)oxy-10-deacetoxy7,13-bis(triethylsilyl)baccatin III) may be prepared in the following manner:
mg of sodium hydride at a concentration of
50 % by weight in liquid paraffin are added portionwise to a solution, maintained under an argon atmosphere, at a temperature in the region of 20°C, of 1 g of
4od-acetoxy-2of-benzoyloxy-5/3, 2 0-epoxy-10,10/3-dihydroxy 9-oxo-7/3,13a-bis (triethylsilyloxy)-11-taxene in 3 cm3 of
5 iodoethane and 4 cm3 of dimethylformami de . The solution is kept stirring for 19 hours at a temperature in the region of 20°C, and 93 mg of sodium hydride at a concentration of 50 % hy weight in liquid paraffin are
AP/P/ 9 7 / 0 1 0 9 3
AP . 0 G 7 5 3 then added portionwise. After 3 hours at a temperature in the region of 20°C, the reaction mixture is diluted with 100 cm3 of ethyl acetate and 10 cm3 of saturated aqueous ammonium chloride solution. The organic phase is separated after settling has taken place and washed with six times 10 cm3 of distilled water and then 10 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered through sintered glass and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 1.32 g of a pale yellow foam are thereby obtained, which product is purified by chromatography at atmospheric pressure on 150 g of silica (0.063-0.2 mm) contained in a column 3.5 cm in diameter, eluting with an ethyl acetate/dichloromethane (2:98, then 5:95 by volume) mixture and collecting 15-cm3 fractions. Fractions containing only the desired products are pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40°C for 2 hours.
376.3 mg of 4a-acetoxy-2a-benzoyloxy-5/S, 20 - epoxy1/S, 10β-dihydroxy-9-oxo-7β, 13a-bis (triethylsilyloxy) -11taxene are thereby obtained in the form of a pale yellow foam and 395.3 mg of 4a-acetoxy-2a-benzoyloxy5/5, 20-epoxy-l/5-hydroxy-10/5- (1-propyl) oxy-9-oxo-7/5,13a25 bis(triethylsilyloxy)-11-taxene are thereby obtained in the form of a pale yellow foam, the characteristics of which are as follows:
- XH NMR spectrum (400 MHz; CDC13; chemical shifts δ in
AP/P/ 9 7 / 0 1 0 9 3
AP . 0 0 7 5 3 ppm; coupling constants J in Hz): 0.57 and 0.70 (2 mts, 6H each: ethyl CH2) ; 0.94 and 1.03 (2 t, J = 7.5, 9H each: ethyl CH3) ; 0.94 (t, J = 7.5, 3H: propyl CH3) ;
1.14 (s, 3H: CH3) ; 1.21 (s, 3H: CH3) ; 1.67 (s, 3H: CH3) ;
1.69 (mt, 2H: central CH2 of propyl); 1.88 and 2.48 (2 mts, 1H each: CH2 at position 6); 2.03 (s, 3H: CH3) ;
2.13 and 2.23 (2 dd, J = 16 and 9, 1H each: CH2 at position 14); 2.30 (s, 3Ξ: COCH3) ; 3.40 (mt, 2H: propyl OCHj) ; 3.84 (d, J = 7.5, 1H: H at position 3); 4.16 and
4.30 (2d, J = 8.5, 1Ξ each: CH2 at position 20); 4.44 (dd, J = 11 and 6.5, 1Ξ: H at position 7); 4.96 (broad d, J = 10 Hz, 1Ξ: H5); 4.97 (s, 1H: H 10); 4.99 (broad t, J = 9Hz, 1Ξ: Ξ at position 13); 5.62 (d, J = 7.5,
1H: H at position 2); 7.48 (t, J = 7.5, 2H: OCOC<;HS H at the meta position); 7.60 (t, J = 7.5, 1H: OCOCSHS H at the para position); 8.10 (d, J = 7.5, 2H: OCOC6H5 H at the ortho position).
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 nonmalignamt cells of various tissues and/or organs, comprising, without implied limitation, muscle, bone or connective tissue, the skin, brain, lungs, sex organs,
AP/P/ 9 7 / 0 1 0 9 3
AP .0 0 7 5 3 the lymphatic or renal systems, mammary or blood cells, liver, the digestive system, pancreas and thyroid or adrenal glands. These pathological conditions can also 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, qr 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 adm-ini at-rat-ϊ nn ,
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 a sufficient amount suitable for use in human or veterinary therapy. The
K>
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El a
<£ compositions may be prepared according to the customary
AP . Ο Ο 7 5 3 methods, using one or more pharmaceutically acceptable adjuvants, vehicles or excipients. Suitable vehicles 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 agents, colourings, preservatives or stabilizers. However, the compositions can also take the form of tablets, pills, powders or granules which can be administered orally.
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 organic 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
AP/P/ 9 7 / 0 1 0 9 3
AP.00753 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 used.
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 (a, 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
AP/P/ 9 7 / 0 1 0 9 3
AP. ο Ο 7 5 3 instance methotrexate, pyrimidine analogues such as fluorouracil and cytarabine, purine analogues such as mercaptopurine and thioguanine, natural products, for instance vinca alkaloids such as vinblastine, vincristine and vindesine, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as Lasparaginase, 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 such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, oestrogens such as diethylstilboestrol and ethynyloestradiol, 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
APIPI 9 7 / 0 1 0 9 3
AP . 0 0 7 5 3 disorders due to abnormal cell proliferation. The products according to the invention may be arf-m-i rn Χρτ-ρΗ 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 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.
ΑΡ/Γ/ 9 7 / 0 1 0 9 3
AP . 0 0 7 5 3
The example which follows illustrates a composition according to the invention.
EXAMPLE mg of the product obtained in Example 1 5 are dissolved in 1 cm3 of Emulphor EL 62 0 and 1 cm3 of ethanol, and the solution is then diluted by adding 18 cm3 of physiological saline.
The composition is administered by perfusion over 1 hour by introduction in physiological solution.
Claims (2)
- (I) in which:Z represents a hydrogen atom or a radical of 5 general formula:RXNH 0R.(Π)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 alkyl10 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 R2-O-CO- in which R2 represents:- an alkyl radical containing 1 to 8 carbon atoms, an15 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 orAP/P/ 9 7 / 0 1 0 9 300753 a bicycloalkyl 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 45 carbon atoms, 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 phenylalkyl10 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 cwith one or more atoms or radicals chosen from halogen15 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 atoms,20 - a phenyl or a- or β-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 heterocyclic25 radical preferably chosen from furyl and thienyl radicals,- or a saturated heterocyclic radical containing 4 to 6 carbon atoms, optionally substituted with one or moreAP/P/ 9 7 / 0 1 0 9 3AP. Ο Ο 7 5 3 alkyl radicals containing 1 to 4 carbon atoms,R3 represents an unbranched or branched alkyl radical containing 1 to 8 carbon atoms, an unbranched or branched alkenyl radical containing 2 to 8 carbon5 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 and10 alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl,15 dialkylcarbamoyl, cyano, nitro and trifiuoromethyl radicals, or a 5-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 identical20 or different substituents chosen from halogen atoms and alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkoxycarbonyl radicals, on the understanding that,25 in the substituents of the phenyl, a- or jS-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 radicalsAP/P/ 9 7 / 0 1 0 9 3AP.00753 contain 2 to 8 carbon atoms, and that the aryl radicals are phenyl or a- or β-naphthyl radicals,R4 represents an alkoxy radical containing 1 to 6 carbon atoms in an unbranched or branched chain,5 an alkenyloxy radical containing 3 to 6 carbon atoms in an unbranched or branched chain, an alkynyloxy radical containing 3 to 6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy radical containing 3 to 6 carbon atoms or a cycloalkenyloxy radical containing10 4 to 6 carbon atoms, these radicals being optionally substituted with one or more halogen atoms or with an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 1 to 4 carbon atoms or a £carboxyl radical, an alkyloxycarbonyl radical in which15 the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or 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 saturated20 5- or 6-membered heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur or nitrogen atoms, optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the25 alkyl portion contains 1 to 4 carbon atoms,R5 represents an alkoxy radical containing 1 to 6 carbon atoms in an unbranched or branched chain (optionally substituted with an alkoxy radicalAP/P/ 9 7 / 0 1 0 9 3AP.09753
73 containing 1 to 4 carbon atoms) containing 3 to 6 carbon atoms, containing 3 to 6 carbon atoms, containing 3 to 6 carbon atoms 5 radical containing'3 to 6 carbon atoms, these radicals being optionally substituted with one or more halogen atoms or with an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 2 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl10 radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or Ν,Ν-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms15 a saturated 5- or 6-membered heterocyclic radical optionally containing a second hetero atom chosen from oxygen, sulphur or nitrogen atoms, optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl20 radical in which the alkyl portion contains 1 to 4 carbon atoms .AP/P/ 97/010932. 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 benzoyl25 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 cycloalkyl radicalAP. Ο Ο 7 5 3 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 and alkyl, alkoxy, dialkylamino, acylamino,5 alkoxycarbonylamino or trifluoromethyl radical, or a 2or 3-furyl, 2- or 3-thienyl or 2-, 4- or 5-thiazolyl radical, and R4 and Rs, which may be identical or different, each represent an unbranched or branched alkyloxy radical containing 1 to 6 carbon atoms.10 3. 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 tert-butyl radical and R3 represents an isobutyl,15 isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, and R4 and R5, which may be identical or different, each represent a methoxy, ethoxy or propoxy radical.20 4. Process for preparing the taxoids according to one of claims 1, 2 and 3 for which Z represents a radical of general formula (II), characterized in that a product of general formula:AP/P/ 97/01093AP. Ο Ο 7 5 3 (ΠΙ) in which R4 and Rs are defined as in one of claims 1, 2 and 3, is esterified by means of an acid of general formula:(IV) in which R-j. and R3 are defined as above, and either Rg 5 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or Rg and R? together form a saturated 5- or 6-membered heterocycle, or by means of a derivative of this, acid, to obtain an ester of general formula:AP/P/ 9 7 /- 0 1 0 9 3 in which R1# R3, R4, R5, Rg and R7 are defined as above, the protective groups of which, represented by R7 and/or Rg and R7, are replaced by hydrogen atoms.AP . 0 0 7 5 35. 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 agent5 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 form10 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 performed15 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, working in an organic solvent at a temperature of between 0 and 80°C.20 8. Process according to claim 4, characterized in that the protective groups R? and/or Rs and R7 are replaced by hydrogen atoms, working, depending on their nature, in the following manner:1) when Rg represents a hydrogen atom and R7 represents25 a group protecting the hydroxyl function, the 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 fromART/ 9 7 / 0 1 0 9 3AP. 0 0 7 5 3 alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature of-between -10 and 60°C, or by means of a source of fluoride ions such as a hydrofluoric acid/triethylamine complex, or by catalytic hydrogenation, - 2) when R6 and R7 together form a saturated 5- or 6membered heterocycle of general formula:in which RT is defined as above and R8 and Rg, which may 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 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 Rs 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 trichloromethyl and Rg represents a hydrogen atom, or alternatively R8 and Rg, together with the carbon atomΑΡ/Γ; 9 7 / 0 1 0 9 3AP.00753 to which they are linked, form a 4- to 7-membered ring, the protective group formed by Rg and R7 is replaced by hydrogen atoms, working, depending on the meanings of Rlz Rs and Rg, in the following manner:5 a) when R-j_ represents a tert-butoxycarbonyl radical and Rg and Rg, which may be identical or different, represent an alkyl radical or an aralkyl or aryl radical, or alternatively R8 represents a trihalomethyl radical or a phenyl radical substituted10 with a trihalomethyl radical and Rg represents a hydrogen atom, or alternatively R8 and Rg together form 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 such as an alcohol,15 to obtain the product of general formula:AP/P/ 9 7 / 0 1 0 9 3 in which R3, R4 and R5 are 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 of20 general formula:R2-O-CO-X (VIII) in which R2 is defined as above and X represents aAP. Ο Ο 7 5 J 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),b) when Rj, represents an optionally substituted benzoyl 5 radical, a thenoyl or furoyl radical or a radical R20C0- in which R2 is defined as above, Rg 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 atoms10 and Rg represents a hydrogen atom, the protective group formed by Rs and R7 is replaced by hydrogen atoms is performed in the presence of an inorganic or organic acid used alone or mixed in a stoichiometric or lcatalytic amount, working in an organic solvent chosen15 from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature of between -10 and 60°C, and preferably between 15 and 3 0°C.9. Process for preparing a new taxoid20 according to one of claims 1, 2 and 3 for which Z represents a hydrogen atom and R4 and Rs are defined as in one of claims 1, 2 and 3, characterized in that 10-deacetylbaccatin III of formula:ΑΡ/Γ7 9 7 / 0 1 0 9 3AP . 0 0 7 5 3 (IX) is treated with a silyl halide of general formula:(R) ,-Si-Hal (X) in which the symbols R, which may be identical or different, represent an alkyl radical containing 1 to 6 carbon atoms, optionally substituted with a phenyl radical, a cycloalkyl radical containing 3 to 6 carbon atoms or a phenyl radical, to obtain a product of general formula:(XI)ΑΡ/Γ,' 9 7 / 0 1 0 9 310 in which R is defined as above, which is treated with a product of general formula:R'4-Xi (xii) in which R'4 represents a radical such that R'4-0 is identical to R4 defined as in one of claims 1, 2 and 315 and represents a halogen atom or a reactive ester residue, to obtain a product of general formula:AP.00753 (XIII) in which. R and R4 are defined as above, the silyl protective groups of which are replaced by hydrogen atoms to obtain a product of general formula:(XIV) in which R4 is defined as above, which is etherified 5 selectively at position 7 by the action of a product of general formula:R'5-X2 (XV) in which R's represents a radical such that R'5-0 is identical to R5 defined as in one of claims 1, 2 and 310 and X2 represents a reactive ester residue or a halogen atom, to give the product of general formula (I) in which Z represents a hydrogen atom.10. Process for preparing a product according to one of claims 1, 2 and 3 for which Z15 represents a radical of general formula (II) and R4 and R5 are defined as in one of claims 1, 2 and 3,AP/P/ 9 7 / 0 1 0 9 3AP . 0 ο 7 5 3 characterized in that a product of general formula:in which Rlf R3, Re and R7 are defined as in one of claims 1, 2, 3 and 4, is treated by means of a product of general formula:(R)3Si-Hal (X) in which the symbols R, which may be identical or different, represent an alkyl radical containing 1 to 6 fcarbon atoms, optionally substituted with a phenyl radical, or a cycloalkyl radical containing 3 to 6 carbon atoms or a phenyl radical, to obtain a product of general formula:(XVII)97/01093 r;<in which R, Rlz R3, Rg and R7 are defined as above, which is functionalized at position 10 by means of a product of general formula:R'4-Χχ (XII) in which R'4 represents a radical such that R'4-0 isAP.00753 identical to R4 defined as in one o and Χχ represents a halogen atom or residue, to give a product of genei· claims 1, 2 and 3 reactive esterL formula·:(XVIII) in which R, R1# R3, R4, Re and R7 aa the silyi protective group of whicl· give a product of hydrogen atom toO-R- defined as above, is replaced by a aneral formula:(XIX) ococ6h5 £6 0 I 0 / L 6 Zd/dV which, by the action of a product (XV), yields the product of genera protective groups of which are rep atoms to give a product of general Z represents a radical of general11. Process for prepari according to one of claims 1, 2 an that activated Raney nickel, in th aliphatic alcohol containing 1 to . ether, is reacted with a product o :; general formula formula (V), the•.;ced by hydrogen formula (I) in which armula (II).o a product3, characterized in presence of an carbon atoms or an general formula:AP.00753 (XXI) in which R4 is defined as in one of claims 1, 2 and 3 and R' and R, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical5 containing 2 to 6 carbon atoms, an alkynyl radical containing 3 to 6 carbon atoms, a cycloalkyl radical containing 2 to 6 carbon atoms or a cycloalkenyl radical containing 3 to 6 carbon atoms, optionally substituted, or alternatively R' and R”, together with10 the carbon atom to which they are linked, form a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 4 to 6 carbon atoms, and Z1 represents a hydrogen atom or a radical of general formula:R, *N (XXII)97/01093CLO-R?in which Rx and R3 are defined as in one of claims 1 to &r> 007533 and Rg and R7 are defined as in claim 4, to obtain a product of general formula:(XXIII) followed, when Z2 represents a radical of general formula (XXII), by replacement of the protective groups5 represented by R6 and/or Rg and R- by hydrogen atoms under the conditions of claim 8.12. Preparation process according to claim 11, characterized in that it is carried out at a temperature of between -10 and 60°C.10 13. 4Qr-Acetoxy-2Qr-benzoyloxy-5j3,20-epoxy-ljShydroxy-7/5, 10/3-dimethoxy-9-oxo-ll-taxen-13a-yl (2R,3S) 3 -tert-butoxycarbonylamino-2-hydroxy-3 phenylpropionate.14. 4a-Acetoxy-2a-benzoyloxy-l/S-hydroxy15 5/3, 20-epoxy-7^-methoxy-10/3-ethoxy-9-oxo-11-taxen-13o;-yl (2R,3S)-3 -tert-butoxycarbonylamino-2-hydroxy-3 phenylpropionate.15. 4o;-Acetoxy-2o'-benzoyloxy-l/S-hydroxy5/3, 2 0-epoxy-7/5-methoxy-10/S- (1-propyl) oxy-9-oxo-ll20 taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2hydroxy-3-phenylpropionate.16. Pharmaceutical composition,AP/P/ 9 7 / 0 1 0 9 3AP . 0 0 7 5 3 characterized in that it contains at least one product according to one of claims 1, 2 and 3 for which Z represents a radical of general formula (II), in combination with one or more pharmaceutically acceptable diluents or adjuvants and optionally one or more compatible and pharmacologically active compounds.17. Pharmaceutical composition, characterized in that it contains at least the product according to claim 13 in combination with one or more pharmaceutically acceptable diluents or adjuvants and optionally one or more compatible and pharmacologically active compounds.18. Pharmaceutical composition, characterized in that it contains at least the product according to claim 14 in combination with one or more0.pharmaceutically acceptable diluents or adjuvants and optionally one or more compatible and pharmacologically active compounds.19. Pharmaceutical composition, characterized in that it contains at least the product according to claim 15 in combination with one or more pharmaceutically acceptable diluents or adjuvants and optionally one or more compatible and pharmacologically active compounds.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9503545A FR2732340B1 (en) | 1995-03-27 | 1995-03-27 | NOVEL TAXOIDS, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR9515381A FR2742754B1 (en) | 1995-12-22 | 1995-12-22 | PROCESS FOR THE PREPARATION OF TAXOIDS |
| PCT/FR1996/000440 WO1996030355A1 (en) | 1995-03-27 | 1996-03-25 | Novel taxoids, preparation thereof and pharmaceutical compositions containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9701093A0 AP9701093A0 (en) | 1997-10-31 |
| AP753A true AP753A (en) | 1999-07-21 |
Family
ID=26231838
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1997/001090A AP785A (en) | 1995-03-27 | 1996-03-25 | Novel taxoids, preparation thereof and pharmaceutical compositions containing same. |
| APAP/P/1997/001093A AP753A (en) | 1995-03-27 | 1996-03-25 | Novel taxoids, preparation thereof and pharmaceutical compositions containing same. |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1997/001090A AP785A (en) | 1995-03-27 | 1996-03-25 | Novel taxoids, preparation thereof and pharmaceutical compositions containing same. |
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| US (3) | US5889043A (en) |
| EP (2) | EP0817779B1 (en) |
| JP (2) | JP2941951B2 (en) |
| KR (2) | KR100297196B1 (en) |
| CN (2) | CN1152870C (en) |
| AP (2) | AP785A (en) |
| AR (1) | AR001440A1 (en) |
| AT (2) | ATE188471T1 (en) |
| AU (2) | AU703278B2 (en) |
| BG (2) | BG63121B1 (en) |
| BR (2) | BR9607930A (en) |
| CA (2) | CA2214321C (en) |
| CO (1) | CO4700576A1 (en) |
| CZ (2) | CZ287326B6 (en) |
| DE (2) | DE69604653T2 (en) |
| DK (2) | DK0817780T3 (en) |
| DZ (1) | DZ2009A1 (en) |
| EA (2) | EA000709B1 (en) |
| EE (2) | EE03609B1 (en) |
| ES (2) | ES2140075T3 (en) |
| GE (2) | GEP20002188B (en) |
| GR (2) | GR3031526T3 (en) |
| HU (2) | HU223732B1 (en) |
| IL (1) | IL117636A (en) |
| IS (2) | IS2058B (en) |
| MA (1) | MA23823A1 (en) |
| MY (1) | MY121225A (en) |
| NO (2) | NO316607B1 (en) |
| NZ (2) | NZ304901A (en) |
| OA (2) | OA10514A (en) |
| PE (1) | PE51097A1 (en) |
| PL (2) | PL188284B1 (en) |
| PT (1) | PT817779E (en) |
| RO (2) | RO115877B1 (en) |
| SK (2) | SK281928B6 (en) |
| TN (1) | TNSN96043A1 (en) |
| TR (2) | TR199701040T1 (en) |
| TW (1) | TW394765B (en) |
| UY (2) | UY24192A1 (en) |
| WO (2) | WO1996030356A1 (en) |
| ZA (1) | ZA962399B (en) |
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