BG105802A - 16-халоген-епотилонови производни, метод за тяхното получаване и фармацевтичното им използване - Google Patents

16-халоген-епотилонови производни, метод за тяхното получаване и фармацевтичното им използване Download PDF

Info

Publication number: BG105802A
Authority: BG; Bulgaria
Prior art keywords: ethenyl; dione; dihydroxy; hydrogen; methyl
Prior art date: 1999-02-18

Application number

BG105802A

Other languages

Bulgarian (bg)

English (en)

Inventor

Ulrich Klar

Werner Skuballa

Bernd Buchmann

Wolfgang Schwede

Michael Schirner

Original Assignee

Schering Aktiengesellschaft

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1999-02-18

Filing date

2001-08-09

Publication date

2002-03-29

1999-02-18 Priority claimed from DE19908765A external-priority patent/DE19908765A1/de

1999-11-04 Priority claimed from DE19954230A external-priority patent/DE19954230A1/de

2001-08-09 Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft

2002-03-29 Publication of BG105802A publication Critical patent/BG105802A/bg

Links

238000004519 manufacturing process Methods 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 329
150000003883 epothilone derivatives Chemical class 0.000 claims abstract description 20
229910052801 chlorine Inorganic materials 0.000 claims abstract description 18
229910052731 fluorine Inorganic materials 0.000 claims abstract description 16
239000011737 fluorine Substances 0.000 claims abstract description 11
239000003814 drug Substances 0.000 claims abstract description 9
125000005843 halogen group Chemical group 0.000 claims abstract description 9
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
-1 2-methyl-4-thiazolyl Chemical group 0.000 claims description 178
229910052739 hydrogen Inorganic materials 0.000 claims description 106
239000001257 hydrogen Substances 0.000 claims description 100
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 72
125000000217 alkyl group Chemical group 0.000 claims description 47
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 31
LZWPOLSJFGLQCE-UHFFFAOYSA-N heptadecane-5,9-dione Chemical compound CCCCCCCCC(=O)CCCC(=O)CCCC LZWPOLSJFGLQCE-UHFFFAOYSA-N 0.000 claims description 28
150000002431 hydrogen Chemical class 0.000 claims description 26
125000003118 aryl group Chemical group 0.000 claims description 24
GESONPPMDAXJEH-UHFFFAOYSA-N cyclohexadec-9-ene-1,5-dione Chemical compound O=C1CCCCCCC=CCCCC(=O)CCC1 GESONPPMDAXJEH-UHFFFAOYSA-N 0.000 claims description 22
229910052757 nitrogen Inorganic materials 0.000 claims description 22
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
125000004430 oxygen atom Chemical group O* 0.000 claims description 19
125000003710 aryl alkyl group Chemical group 0.000 claims description 18
238000002360 preparation method Methods 0.000 claims description 18
125000006239 protecting group Chemical group 0.000 claims description 18
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 16
239000000460 chlorine Substances 0.000 claims description 15
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
229910052736 halogen Inorganic materials 0.000 claims description 14
150000002367 halogens Chemical class 0.000 claims description 13
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 11
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
229910052794 bromium Inorganic materials 0.000 claims description 10
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
229910052740 iodine Inorganic materials 0.000 claims description 10
125000004076 pyridyl group Chemical group 0.000 claims description 10
125000003545 alkoxy group Chemical group 0.000 claims description 9
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
125000002252 acyl group Chemical group 0.000 claims description 8
125000002947 alkylene group Chemical group 0.000 claims description 7
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 6
229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
239000000543 intermediate Substances 0.000 claims description 5
GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 claims description 5
SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical group C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 claims description 5
239000001301 oxygen Substances 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 4
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
125000004093 cyano group Chemical group *C#N 0.000 claims description 4
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 3
125000003277 amino group Chemical group 0.000 claims description 3
MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical group [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 claims description 3
101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims description 2
239000008194 pharmaceutical composition Substances 0.000 claims description 2
XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 2
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 3
FMGNVEVLMGMCNQ-UHFFFAOYSA-N 15-oxabicyclo[14.1.0]heptadecane-8,12-dione Chemical compound O1CCC(=O)CCCC(=O)CCCCCCC2CC21 FMGNVEVLMGMCNQ-UHFFFAOYSA-N 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
125000001424 substituent group Chemical group 0.000 abstract description 5
125000001309 chloro group Chemical group Cl* 0.000 abstract description 4
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 183
239000000243 solution Substances 0.000 description 132
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
238000005160 1H NMR spectroscopy Methods 0.000 description 122
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 114
239000012230 colorless oil Substances 0.000 description 49
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
229910052938 sodium sulfate Inorganic materials 0.000 description 33
235000011152 sodium sulphate Nutrition 0.000 description 33
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 29
239000000741 silica gel Substances 0.000 description 29
229910002027 silica gel Inorganic materials 0.000 description 29
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
238000004587 chromatography analysis Methods 0.000 description 26
238000000746 purification Methods 0.000 description 26
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
229940126062 Compound A Drugs 0.000 description 22
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 22
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 22
239000012634 fragment Substances 0.000 description 22
238000000034 method Methods 0.000 description 22
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
239000000203 mixture Substances 0.000 description 20
208000008884 Aneurysmal Bone Cysts Diseases 0.000 description 18
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 17
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
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 16
239000002904 solvent Substances 0.000 description 16
239000012074 organic phase Substances 0.000 description 15
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
239000007983 Tris buffer Substances 0.000 description 14
238000001704 evaporation Methods 0.000 description 14
230000008020 evaporation Effects 0.000 description 14
239000011541 reaction mixture Substances 0.000 description 14
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
229910052786 argon Inorganic materials 0.000 description 13
239000000284 extract Substances 0.000 description 13
230000004048 modification Effects 0.000 description 13
238000012986 modification Methods 0.000 description 13
230000036961 partial effect Effects 0.000 description 13
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
238000004440 column chromatography Methods 0.000 description 12
238000001914 filtration Methods 0.000 description 12
239000003921 oil Substances 0.000 description 12
HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 10
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
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 9
239000012300 argon atmosphere Substances 0.000 description 9
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
230000000694 effects Effects 0.000 description 9
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 8
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 8
230000015572 biosynthetic process Effects 0.000 description 8
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 8
238000003786 synthesis reaction Methods 0.000 description 8
229930012538 Paclitaxel Natural products 0.000 description 7
125000004432 carbon atom Chemical group C* 0.000 description 7
229930013356 epothilone Natural products 0.000 description 7
HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical compound 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 7
239000000706 filtrate Substances 0.000 description 7
229960001592 paclitaxel Drugs 0.000 description 7
239000000126 substance Substances 0.000 description 7
239000000725 suspension Substances 0.000 description 7
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 7
KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 6
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VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
239000012043 crude product Substances 0.000 description 6
XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC1C(C)=CC1=CSC(C)=N1 XOZIUKBZLSUILX-UHFFFAOYSA-N 0.000 description 6
XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
239000002244 precipitate Substances 0.000 description 6
238000007670 refining Methods 0.000 description 6
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
150000001299 aldehydes Chemical class 0.000 description 5
210000004027 cell Anatomy 0.000 description 5
238000006243 chemical reaction Methods 0.000 description 5
238000001816 cooling Methods 0.000 description 5
239000013078 crystal Substances 0.000 description 5
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
150000004714 phosphonium salts Chemical class 0.000 description 5
239000012312 sodium hydride Substances 0.000 description 5
229910000104 sodium hydride Inorganic materials 0.000 description 5
239000007858 starting material Substances 0.000 description 5
FHUDAMLDXFJHJE-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-one Chemical compound CC(=O)C(F)(F)F FHUDAMLDXFJHJE-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
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 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
230000032050 esterification Effects 0.000 description 4
238000005886 esterification reaction Methods 0.000 description 4
239000004615 ingredient Substances 0.000 description 4
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
238000003756 stirring Methods 0.000 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 description 3
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
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BEFZAMRWPCMWFJ-JRBBLYSQSA-N Epothilone C Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C=C\C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C BEFZAMRWPCMWFJ-JRBBLYSQSA-N 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
150000001336 alkenes Chemical class 0.000 description 3
235000019270 ammonium chloride Nutrition 0.000 description 3
239000012298 atmosphere Substances 0.000 description 3
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
210000000481 breast Anatomy 0.000 description 3
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
BEFZAMRWPCMWFJ-UHFFFAOYSA-N desoxyepothilone A Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC=CCC1C(C)=CC1=CSC(C)=N1 BEFZAMRWPCMWFJ-UHFFFAOYSA-N 0.000 description 3
238000011161 development Methods 0.000 description 3
229940043279 diisopropylamine Drugs 0.000 description 3
229940079593 drug Drugs 0.000 description 3
BEFZAMRWPCMWFJ-QJKGZULSSA-N epothilone C Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 BEFZAMRWPCMWFJ-QJKGZULSSA-N 0.000 description 3
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DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
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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
229960001278 teniposide Drugs 0.000 description 1
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 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
150000003557 thiazoles Chemical class 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
229960000303 topotecan Drugs 0.000 description 1
125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
210000004881 tumor cell Anatomy 0.000 description 1
230000004614 tumor growth Effects 0.000 description 1
239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
238000005292 vacuum distillation Methods 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
239000000341 volatile oil Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- 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
- 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
- C07D493/08—Bridged systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- 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)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Veterinary Medicine (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Oncology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Saccharide Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

BG105802A 1999-02-18 2001-08-09 16-халоген-епотилонови производни, метод за тяхното получаване и фармацевтичното им използване BG105802A (bg)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
DE19908765A DE19908765A1 (de)	1999-02-18	1999-02-18	16-Halogen-Epothilon-Derivate, Verfahren zu deren Herstellung und ihre pharmazeutische Verwendung
DE19954230A DE19954230A1 (de)	1999-11-04	1999-11-04	16-Halogen-Epothilon-Derivate, Verfahren zu deren Herstellung und ihre pharmazeutische Verwendung
PCT/EP2000/001333 WO2000049021A2 (de)	1999-02-18	2000-02-18	16-halogen-epothilon-derivate, verfahren zu deren herstellung und ihre pharmazeutische verwendung

Publications (1)

Publication Number	Publication Date
BG105802A true BG105802A (bg)	2002-03-29

Family

ID=26052117

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG105802A BG105802A (bg)	1999-02-18	2001-08-09	16-халоген-епотилонови производни, метод за тяхното получаване и фармацевтичното им използване

Country Status (27)

Country	Link
US (3)	US6610736B1 (no)
EP (1)	EP1150980B1 (no)
JP (1)	JP2002537301A (no)
KR (1)	KR100718616B1 (no)
CN (1)	CN1209360C (no)
AR (1)	AR022636A1 (no)
AT (1)	ATE370946T1 (no)
AU (1)	AU3156700A (no)
BG (1)	BG105802A (no)
BR (1)	BR0008331A (no)
CA (1)	CA2361278A1 (no)
CZ (1)	CZ20012951A3 (no)
DE (1)	DE50014587D1 (no)
EA (1)	EA009206B1 (no)
EE (1)	EE200100431A (no)
ES (1)	ES2291194T3 (no)
HR (1)	HRP20010677A2 (no)
HU (1)	HUP0105478A3 (no)
IL (1)	IL144519A0 (no)
MX (1)	MXPA01008328A (no)
NO (1)	NO20014013L (no)
NZ (1)	NZ513268A (no)
PL (1)	PL349863A1 (no)
SK (1)	SK11852001A3 (no)
TW (1)	TWI285645B (no)
WO (1)	WO2000049021A2 (no)
YU (1)	YU59001A (no)

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EP1340498A1 (en) *	2002-03-01	2003-09-03	Schering Aktiengesellschaft	Use of epothilones in the treatment of brain diseases associated with proliferative processes
ATE452896T1 (de)	2002-03-12	2010-01-15	Bristol Myers Squibb Co	C3-cyanoepothilonderivate
US7211593B2 (en)	2002-03-12	2007-05-01	Bristol-Myers Squibb Co.	C12-cyano epothilone derivatives
TW200403994A (en)	2002-04-04	2004-03-16	Bristol Myers Squibb Co	Oral administration of EPOTHILONES
TW200400191A (en)	2002-05-15	2004-01-01	Bristol Myers Squibb Co	Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives
US7008936B2 (en)	2002-06-14	2006-03-07	Bristol-Myers Squibb Company	Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
US7649006B2 (en)	2002-08-23	2010-01-19	Sloan-Kettering Institute For Cancer Research	Synthesis of epothilones, intermediates thereto and analogues thereof
NZ538522A (en) *	2002-08-23	2008-03-28	Sloan Kettering Inst Cancer	Synthesis of epothilones, intermediates thereto, analogues and uses thereof
RU2311415C2 (ru) *	2002-08-23	2007-11-27	Слоан-Кеттеринг Инститьют Фор Кэнсер Рисерч	Синтез эпотилонов, их промежуточных продуктов, аналогов и их применения
TWI291464B (en)	2002-09-23	2007-12-21	Bristol Myers Squibb Co	Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
EP1559447A1 (en)	2004-01-30	2005-08-03	Institut National De La Sante Et De La Recherche Medicale (Inserm)	Use of epothilones in the treatment of neuronal connectivity defects such as schizophrenia and autism
WO2006055742A1 (en) *	2004-11-18	2006-05-26	Bristol-Myers Squibb Company	Enteric coated bead comprising epothilone or epothilone analog, and preparation and administration thereof
CA2588400A1 (en) *	2004-11-18	2006-05-26	Bristol-Myers Squibb Company	Enteric coated bead comprising ixabepilone, and preparation thereof
EP1674098A1 (en)	2004-12-23	2006-06-28	Schering Aktiengesellschaft	Stable and tolerable parental formulations of highly reactive organic drug substances with low or no solubility in water
WO2007086879A2 (en)	2005-02-11	2007-08-02	University Of Southern California	Method of expressing proteins with disulfide bridges
JP4954983B2 (ja)	2005-05-18	2012-06-20	ファーマサイエンス・インコーポレイテッド	Ｂｉｒドメイン結合化合物
US20070014978A1 (en) *	2005-07-18	2007-01-18	Anthony Poloso	Method of flame blocking and articles made therefrom
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2000
- 2000-02-18 AT AT00909205T patent/ATE370946T1/de not_active IP Right Cessation
- 2000-02-18 HR HR20010677A patent/HRP20010677A2/hr not_active Application Discontinuation
- 2000-02-18 CA CA002361278A patent/CA2361278A1/en not_active Abandoned
- 2000-02-18 IL IL14451900A patent/IL144519A0/xx unknown
- 2000-02-18 BR BR0008331-3A patent/BR0008331A/pt not_active Application Discontinuation
- 2000-02-18 NZ NZ513268A patent/NZ513268A/en unknown
- 2000-02-18 EA EA200100826A patent/EA009206B1/ru unknown
- 2000-02-18 KR KR1020017010455A patent/KR100718616B1/ko not_active Expired - Fee Related
- 2000-02-18 ES ES00909205T patent/ES2291194T3/es not_active Expired - Lifetime
- 2000-02-18 MX MXPA01008328A patent/MXPA01008328A/es active IP Right Grant
- 2000-02-18 YU YU59001A patent/YU59001A/sh unknown
- 2000-02-18 HU HU0105478A patent/HUP0105478A3/hu unknown
- 2000-02-18 SK SK1185-2001A patent/SK11852001A3/sk unknown
- 2000-02-18 PL PL00349863A patent/PL349863A1/xx not_active Application Discontinuation
- 2000-02-18 EP EP00909205A patent/EP1150980B1/de not_active Expired - Lifetime
- 2000-02-18 CZ CZ20012951A patent/CZ20012951A3/cs unknown
- 2000-02-18 CN CNB008039763A patent/CN1209360C/zh not_active Expired - Fee Related
- 2000-02-18 DE DE50014587T patent/DE50014587D1/de not_active Expired - Fee Related
- 2000-02-18 US US09/913,495 patent/US6610736B1/en not_active Expired - Fee Related
- 2000-02-18 EE EEP200100431A patent/EE200100431A/xx unknown
- 2000-02-18 WO PCT/EP2000/001333 patent/WO2000049021A2/de not_active Ceased
- 2000-02-18 JP JP2000599760A patent/JP2002537301A/ja active Pending
- 2000-02-18 AU AU31567/00A patent/AU3156700A/en not_active Abandoned
- 2000-02-21 AR ARP000100714A patent/AR022636A1/es unknown
- 2000-04-19 TW TW089102834A patent/TWI285645B/zh not_active IP Right Cessation
2001
- 2001-08-09 BG BG105802A patent/BG105802A/bg unknown
- 2001-08-17 NO NO20014013A patent/NO20014013L/no not_active Application Discontinuation
2003
- 2003-02-12 US US10/364,337 patent/US6930102B2/en not_active Expired - Fee Related
2005
- 2005-03-25 US US11/090,841 patent/US20050187270A1/en not_active Abandoned

Also Published As

Publication number	Publication date
CN1341115A (zh)	2002-03-20
US6610736B1 (en)	2003-08-26
IL144519A0 (en)	2002-05-23
CA2361278A1 (en)	2000-08-24
DE50014587D1 (de)	2007-10-04
US6930102B2 (en)	2005-08-16
US20050187270A1 (en)	2005-08-25
EE200100431A (et)	2002-12-16
JP2002537301A (ja)	2002-11-05
NO20014013D0 (no)	2001-08-17
EP1150980B1 (de)	2007-08-22
HUP0105478A2 (en)	2002-06-29
WO2000049021A2 (de)	2000-08-24
KR20010102215A (ko)	2001-11-15
CN1209360C (zh)	2005-07-06
EP1150980A2 (de)	2001-11-07
HK1044945A1 (en)	2002-11-08
PL349863A1 (en)	2002-09-23
EA200100826A1 (ru)	2002-02-28
AU3156700A (en)	2000-09-04
KR100718616B1 (ko)	2007-05-16
TWI285645B (en)	2007-08-21
HUP0105478A3 (en)	2002-08-28
AR022636A1 (es)	2002-09-04
ES2291194T3 (es)	2008-03-01
EA009206B1 (ru)	2007-12-28
HRP20010677A2 (en)	2005-06-30
ATE370946T1 (de)	2007-09-15
SK11852001A3 (sk)	2002-04-04
WO2000049021A3 (de)	2000-12-28
NO20014013L (no)	2001-10-18
YU59001A (sh)	2005-07-19
US20040014978A1 (en)	2004-01-22
CZ20012951A3 (cs)	2001-11-14
MXPA01008328A (es)	2002-06-04
BR0008331A (pt)	2002-01-29
NZ513268A (en)	2004-05-28

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BG105802A (bg)	2002-03-29	16-халоген-епотилонови производни, метод за тяхното получаване и фармацевтичното им използване
KR100721488B1 (ko)	2007-05-23	6-알케닐-,6-알키닐- 및 6-에폭시-에포틸론 유도체, 그의제조 방법 및 제약 제제로서 그의 용도
US7407975B2 (en)	2008-08-05	Epothilone derivatives, method for producing same and their pharmaceutical use
RS59001B1 (sr)	2019-08-30	Miš sa zajedničkim lakim lancem
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ZA200107648B (en)	2003-01-07	16-Halogen-epothilone derivatives, method for producing them and their pharmaceutical use.
UA74542C2 (en)	2006-01-16	Epothilone 16-halogen derivatives, a pharmaceutical agent based thereon, intermediary compounds (variants)
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AU2004200949A1 (en)	2004-04-01	16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use
DE19954229A1 (de)	2001-05-10	Epothilon-Derivate, Verfahren zu deren Herstellung und ihre pharmazeutische Verwendung
AU2004200948A1 (en)	2004-04-01	Epothilon derivatives, method for the production and the use thereof as pharmaceuticals
DE19907480A1 (de)	2000-08-17	Epothilon-Derivate, Verfahren zu deren Herstellung und ihre pharmazeutische Verwendung