RU2343155C2 - Способ получения производных эпотилона - Google Patents
Способ получения производных эпотилона Download PDFInfo
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- RU2343155C2 RU2343155C2 RU2005110925/04A RU2005110925A RU2343155C2 RU 2343155 C2 RU2343155 C2 RU 2343155C2 RU 2005110925/04 A RU2005110925/04 A RU 2005110925/04A RU 2005110925 A RU2005110925 A RU 2005110925A RU 2343155 C2 RU2343155 C2 RU 2343155C2
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- 238000000034 method Methods 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- -1 epoxide mesilate Chemical class 0.000 claims abstract description 57
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 25
- 150000003883 epothilone derivatives Chemical class 0.000 claims abstract description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 69
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 55
- 239000000203 mixture Substances 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 239000012442 inert solvent Substances 0.000 claims description 23
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 229930013356 epothilone Natural products 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 238000003776 cleavage reaction Methods 0.000 claims description 8
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 8
- 230000007017 scission Effects 0.000 claims description 8
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 7
- 238000005882 aldol condensation reaction Methods 0.000 claims description 7
- 230000003993 interaction Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 7
- 238000006841 macrolactonization reaction Methods 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 5
- 238000010561 standard procedure Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- OZGSEIVTQLXWRO-UHFFFAOYSA-N 2,4,6-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=C(Cl)C=C1Cl OZGSEIVTQLXWRO-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 150000001261 hydroxy acids Chemical class 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims 3
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 229950002475 mesilate Drugs 0.000 abstract 1
- 229950004288 tosilate Drugs 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 71
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- 239000003480 eluent Substances 0.000 description 41
- 229910004298 SiO 2 Inorganic materials 0.000 description 39
- 239000010410 layer Substances 0.000 description 35
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 239000000460 chlorine Substances 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 239000012267 brine Substances 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- NCGARFWFKHNMJK-UHFFFAOYSA-N oxiran-2-ylmethyl methanesulfonate Chemical compound CS(=O)(=O)OCC1CO1 NCGARFWFKHNMJK-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- NFQNAHAVODPNID-YJGFFAQZSA-N (2e,5s,6e)-5-[tert-butyl(dimethyl)silyl]oxy-2-[(4s)-5-[tert-butyl(dimethyl)silyl]oxy-4-methylpentyl]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)hepta-2,6-dien-1-ol Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H](C)CCC\C(CO)=C/C[C@H](O[Si](C)(C)C(C)(C)C)C(\C)=C\C1=CSC(C)=N1 NFQNAHAVODPNID-YJGFFAQZSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Chemical class 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- ZEFWSPAKYKXYSH-JMHIDFSWSA-N [(2s,3s)-3-[(e,2s)-2-[tert-butyl(dimethyl)silyl]oxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)but-3-enyl]-2-[(4s)-5-[tert-butyl(dimethyl)silyl]oxy-4-methylpentyl]oxiran-2-yl]methanol Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H](C)CCC[C@@]1(CO)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C(\C)=C\C1=CSC(C)=N1 ZEFWSPAKYKXYSH-JMHIDFSWSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000012047 saturated solution Substances 0.000 description 8
- 239000012300 argon atmosphere Substances 0.000 description 7
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- UYKNJJNTDPBCHE-MHZLTWQESA-N methyl (6s)-7-[tert-butyl(dimethyl)silyl]oxy-6-methyl-2-(triphenyl-$l^{5}-phosphanylidene)heptanoate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=C(CCC[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)OC)C1=CC=CC=C1 UYKNJJNTDPBCHE-MHZLTWQESA-N 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 150000002009 diols Chemical class 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 5
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- DDCPKNYKNWXULB-RXMQYKEDSA-N (2r)-2-azaniumyl-3-[(2-methylpropan-2-yl)oxy]propanoate Chemical compound CC(C)(C)OC[C@@H]([NH3+])C([O-])=O DDCPKNYKNWXULB-RXMQYKEDSA-N 0.000 description 4
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000005103 alkyl silyl group Chemical group 0.000 description 4
- 239000011575 calcium Chemical class 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 4
- QQVKNEQDEIZBLC-AATRIKPKSA-N (2e)-hepta-2,6-dienoic acid Chemical compound OC(=O)\C=C\CCC=C QQVKNEQDEIZBLC-AATRIKPKSA-N 0.000 description 3
- BQSGURVIULEWSB-ZDUSSCGKSA-N (2s)-2-methyl-6-phenylmethoxyhexan-1-ol Chemical compound OC[C@@H](C)CCCCOCC1=CC=CC=C1 BQSGURVIULEWSB-ZDUSSCGKSA-N 0.000 description 3
- LKMLQQQDCBKJJO-UGKGYDQZSA-N (4s)-4-benzyl-3-[(2s)-2-methyl-6-phenylmethoxyhexanoyl]-1,3-oxazolidin-2-one Chemical compound C([C@H](C)C(=O)N1C(OC[C@@H]1CC=1C=CC=CC=1)=O)CCCOCC1=CC=CC=C1 LKMLQQQDCBKJJO-UGKGYDQZSA-N 0.000 description 3
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 3
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 3
- IILIIPOEUNIPFG-UHFFFAOYSA-N 6-phenylmethoxyhexanoic acid Chemical compound OC(=O)CCCCCOCC1=CC=CC=C1 IILIIPOEUNIPFG-UHFFFAOYSA-N 0.000 description 3
- MZERPDPKLCBRRI-UHFFFAOYSA-N 6-phenylmethoxyhexanoyl chloride Chemical compound ClC(=O)CCCCCOCC1=CC=CC=C1 MZERPDPKLCBRRI-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- YSAVZVORKRDODB-PHDIDXHHSA-N diethyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC YSAVZVORKRDODB-PHDIDXHHSA-N 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- PBYKOZZKRNXAPT-LBPRGKRZSA-N (5s)-6-[tert-butyl(dimethyl)silyl]oxy-5-methylhexan-1-ol Chemical compound OCCCC[C@H](C)CO[Si](C)(C)C(C)(C)C PBYKOZZKRNXAPT-LBPRGKRZSA-N 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical class [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DHUJMERMFNKERL-LBPRGKRZSA-N tert-butyl-[(2s)-6-iodo-2-methylhexoxy]-dimethylsilane Chemical compound ICCCC[C@H](C)CO[Si](C)(C)C(C)(C)C DHUJMERMFNKERL-LBPRGKRZSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 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
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 229910052725 zinc Chemical class 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- 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
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Communicable Diseases (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0221312.2A GB0221312D0 (en) | 2002-09-13 | 2002-09-13 | Organic compounds |
| GB0221312.2 | 2002-09-13 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2008129613/04A Division RU2404985C2 (ru) | 2002-09-13 | 2003-09-12 | Способ получения производных эпотилона, новые производные эпотилона, а также новые промежуточные соединения для реализации способа и способы их получения |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2005110925A RU2005110925A (ru) | 2006-01-20 |
| RU2343155C2 true RU2343155C2 (ru) | 2009-01-10 |
Family
ID=9944042
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2005110925/04A RU2343155C2 (ru) | 2002-09-13 | 2003-09-12 | Способ получения производных эпотилона |
| RU2008129613/04A RU2404985C2 (ru) | 2002-09-13 | 2003-09-12 | Способ получения производных эпотилона, новые производные эпотилона, а также новые промежуточные соединения для реализации способа и способы их получения |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2008129613/04A RU2404985C2 (ru) | 2002-09-13 | 2003-09-12 | Способ получения производных эпотилона, новые производные эпотилона, а также новые промежуточные соединения для реализации способа и способы их получения |
Country Status (29)
| Country | Link |
|---|---|
| US (1) | US7470792B2 (enExample) |
| EP (1) | EP1539768B1 (enExample) |
| JP (1) | JP4628102B2 (enExample) |
| KR (1) | KR20050042500A (enExample) |
| CN (1) | CN100522968C (enExample) |
| AR (1) | AR041231A1 (enExample) |
| AT (1) | ATE373663T1 (enExample) |
| AU (2) | AU2003267349B2 (enExample) |
| BR (1) | BR0314263A (enExample) |
| CA (1) | CA2497119C (enExample) |
| CY (1) | CY1107794T1 (enExample) |
| DE (1) | DE60316456T2 (enExample) |
| DK (1) | DK1539768T3 (enExample) |
| EC (1) | ECSP055652A (enExample) |
| ES (1) | ES2290489T3 (enExample) |
| GB (1) | GB0221312D0 (enExample) |
| IL (1) | IL166829A (enExample) |
| MX (1) | MXPA05002785A (enExample) |
| MY (1) | MY140442A (enExample) |
| NO (1) | NO20051794L (enExample) |
| NZ (1) | NZ538612A (enExample) |
| PE (1) | PE20050052A1 (enExample) |
| PL (1) | PL375039A1 (enExample) |
| PT (1) | PT1539768E (enExample) |
| RU (2) | RU2343155C2 (enExample) |
| SG (1) | SG155770A1 (enExample) |
| TW (1) | TWI289563B (enExample) |
| WO (1) | WO2004024735A2 (enExample) |
| ZA (1) | ZA200501008B (enExample) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4579351B2 (ja) | 1996-12-03 | 2010-11-10 | スローン−ケッタリング インスティトュート フォア キャンサー リサーチ | エポチロンの合成とその中間体及びその類似物並びにその使用 |
| US7649006B2 (en) | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US6921769B2 (en) | 2002-08-23 | 2005-07-26 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| CA2496477C (en) | 2002-08-23 | 2012-10-16 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| US20110300150A1 (en) | 2010-05-18 | 2011-12-08 | Scott Eliasof | Compositions and methods for treatment of autoimmune and other disease |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998008849A1 (de) * | 1996-08-30 | 1998-03-05 | Novartis Aktiengesellschaft | Verfahren zur herstellung von epothilonen und zwischenprodukte innerhalb des verfahrens |
| WO1998025929A1 (en) * | 1996-12-13 | 1998-06-18 | Novartis Ag | Epothilone analogs |
| WO2002030356A2 (en) * | 2000-10-13 | 2002-04-18 | The University Of Mississipi | Synthesis of epothilones and relates analogs |
| US6387927B1 (en) * | 1998-12-22 | 2002-05-14 | Novatis Ag | Epothilone derivatives and their use as antitumor agents |
| RU2201932C2 (ru) * | 1997-02-25 | 2003-04-10 | Гезелльшафт Фюр Биотехнологише Форшунг Мбх (Гбф) | Модифицированные в боковой цепи эпотилоны |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6380394B1 (en) * | 1996-12-13 | 2002-04-30 | The Scripps Research Institute | Epothilone analogs |
| US6498257B1 (en) * | 1998-04-21 | 2002-12-24 | Bristol-Myers Squibb Company | 2,3-olefinic epothilone derivatives |
| GB9810659D0 (en) * | 1998-05-18 | 1998-07-15 | Ciba Geigy Ag | Organic compounds |
| AU6233600A (en) * | 1999-07-22 | 2001-02-13 | Schering Aktiengesellschaft | Process for the production of epothiolone b and derivatives as well as intermediate products for this process |
| US6593115B2 (en) * | 2000-03-24 | 2003-07-15 | Bristol-Myers Squibb Co. | Preparation of epothilone intermediates |
| IL166039A0 (en) * | 2002-07-31 | 2006-01-15 | Schering Ag | New effector conjugates process for their production and their pharmaceutical use |
-
2002
- 2002-09-13 GB GBGB0221312.2A patent/GB0221312D0/en not_active Ceased
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2003
- 2003-09-11 AR ARP030103290A patent/AR041231A1/es active IP Right Grant
- 2003-09-11 PE PE2003000922A patent/PE20050052A1/es not_active Application Discontinuation
- 2003-09-12 AT AT03748015T patent/ATE373663T1/de active
- 2003-09-12 SG SG200701814-6A patent/SG155770A1/en unknown
- 2003-09-12 DK DK03748015T patent/DK1539768T3/da active
- 2003-09-12 PL PL03375039A patent/PL375039A1/xx not_active Application Discontinuation
- 2003-09-12 US US10/526,283 patent/US7470792B2/en not_active Expired - Fee Related
- 2003-09-12 EP EP03748015A patent/EP1539768B1/en not_active Expired - Lifetime
- 2003-09-12 RU RU2005110925/04A patent/RU2343155C2/ru not_active IP Right Cessation
- 2003-09-12 ES ES03748015T patent/ES2290489T3/es not_active Expired - Lifetime
- 2003-09-12 JP JP2004535499A patent/JP4628102B2/ja not_active Expired - Fee Related
- 2003-09-12 TW TW092125250A patent/TWI289563B/zh not_active IP Right Cessation
- 2003-09-12 NZ NZ538612A patent/NZ538612A/en not_active IP Right Cessation
- 2003-09-12 CA CA2497119A patent/CA2497119C/en not_active Expired - Fee Related
- 2003-09-12 CN CNB038215837A patent/CN100522968C/zh not_active Expired - Fee Related
- 2003-09-12 PT PT03748015T patent/PT1539768E/pt unknown
- 2003-09-12 KR KR1020057004237A patent/KR20050042500A/ko not_active Ceased
- 2003-09-12 MX MXPA05002785A patent/MXPA05002785A/es active IP Right Grant
- 2003-09-12 WO PCT/EP2003/010171 patent/WO2004024735A2/en not_active Ceased
- 2003-09-12 BR BR0314263-9A patent/BR0314263A/pt not_active IP Right Cessation
- 2003-09-12 DE DE60316456T patent/DE60316456T2/de not_active Expired - Lifetime
- 2003-09-12 AU AU2003267349A patent/AU2003267349B2/en not_active Ceased
- 2003-09-12 RU RU2008129613/04A patent/RU2404985C2/ru not_active IP Right Cessation
- 2003-09-13 MY MYPI20033494A patent/MY140442A/en unknown
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2005
- 2005-02-03 ZA ZA200501008A patent/ZA200501008B/xx unknown
- 2005-02-10 IL IL166829A patent/IL166829A/en not_active IP Right Cessation
- 2005-03-09 EC EC2005005652A patent/ECSP055652A/es unknown
- 2005-04-12 NO NO20051794A patent/NO20051794L/no not_active Application Discontinuation
-
2007
- 2007-11-08 CY CY20071101447T patent/CY1107794T1/el unknown
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2008
- 2008-08-01 AU AU2008203451A patent/AU2008203451A1/en not_active Abandoned
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998008849A1 (de) * | 1996-08-30 | 1998-03-05 | Novartis Aktiengesellschaft | Verfahren zur herstellung von epothilonen und zwischenprodukte innerhalb des verfahrens |
| WO1998025929A1 (en) * | 1996-12-13 | 1998-06-18 | Novartis Ag | Epothilone analogs |
| RU2201932C2 (ru) * | 1997-02-25 | 2003-04-10 | Гезелльшафт Фюр Биотехнологише Форшунг Мбх (Гбф) | Модифицированные в боковой цепи эпотилоны |
| US6387927B1 (en) * | 1998-12-22 | 2002-05-14 | Novatis Ag | Epothilone derivatives and their use as antitumor agents |
| WO2002030356A2 (en) * | 2000-10-13 | 2002-04-18 | The University Of Mississipi | Synthesis of epothilones and relates analogs |
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| Date | Code | Title | Description |
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| MM4A | The patent is invalid due to non-payment of fees |
Effective date: 20130913 |