DE19821954A1 - Verfahren zur Herstellung eines Epothilon-Derivats - Google Patents
Verfahren zur Herstellung eines Epothilon-DerivatsInfo
- Publication number
- DE19821954A1 DE19821954A1 DE19821954A DE19821954A DE19821954A1 DE 19821954 A1 DE19821954 A1 DE 19821954A1 DE 19821954 A DE19821954 A DE 19821954A DE 19821954 A DE19821954 A DE 19821954A DE 19821954 A1 DE19821954 A1 DE 19821954A1
- Authority
- DE
- Germany
- Prior art keywords
- group
- grouping
- epothilone
- radical
- optionally
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 150000003883 epothilone derivatives Chemical class 0.000 title claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 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 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000000468 ketone group Chemical group 0.000 claims abstract description 6
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical group 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 claims abstract description 5
- 238000005649 metathesis reaction Methods 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Chemical group 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 claims abstract description 3
- BEFZAMRWPCMWFJ-JRBBLYSQSA-N Epothilone C Chemical group 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 claims abstract description 3
- XOZIUKBZLSUILX-SDMHVBBESA-N Epothilone D Chemical group O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C(/C)=C/C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C XOZIUKBZLSUILX-SDMHVBBESA-N 0.000 claims abstract description 3
- BEFZAMRWPCMWFJ-UHFFFAOYSA-N desoxyepothilone A Chemical group 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 claims abstract description 3
- XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Chemical group 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 claims abstract description 3
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical group 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 claims abstract description 3
- BEFZAMRWPCMWFJ-QJKGZULSSA-N epothilone C Chemical group 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 claims abstract description 3
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical group 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 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229910052750 molybdenum Inorganic materials 0.000 claims description 5
- 239000011733 molybdenum Substances 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 3
- 238000006186 Bamford-Stevens reaction Methods 0.000 claims description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 239000010937 tungsten Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 229930013356 epothilone Natural products 0.000 description 2
- FQDXJYBXPOMIBX-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-ol Chemical compound FC(F)(F)C(O)(C)C(F)(F)F FQDXJYBXPOMIBX-UHFFFAOYSA-N 0.000 description 1
- KKJNNLOHMPIFLO-UHFFFAOYSA-N 1,2-dimethoxyethane trifluoromethanesulfonic acid Chemical compound C(OC)COC.FC(S(=O)(=O)O)(F)F.FC(S(=O)(=O)O)(F)F KKJNNLOHMPIFLO-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- 101100118680 Caenorhabditis elegans sec-61.G gene Proteins 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Epothilone A, B, C und D sind bekannt; vgl. beispielsweise
PCT/EP 96/05 080. Diese Epothilone tragen am C17-Kohlenstoffatom
einen heterozyklischen Rest. Es ist nun erwünscht, diesen Rest
durch einen anderen Rest zu ersetzen, der insbesondere für
pharmazeutische Wirkstoffe üblich oder vorteilhaft ist.
Zur Lösung dieser Aufgabe wird erfindungsgemäß ein Verfahren zur
Herstellung eines Epothilon-Derivats vorgesehen, das dadurch
gekennzeichnet ist, daß man
- (a) von einem Epothilon A, B, C oder D ausgeht,
- - wobei das C2- und das C3-Kohlenstoffatom durch die Gruppierung -CH2CHOH- oder -CH=CH- miteinander verbunden sein können und
- - wobei man bei der Ausgangsverbindung in 3- und 7-Stellung eine OH-Gruppe oder eine geschützte OH-Gruppe vorsieht,
- (b) in 16-Stellung zu einer Keto-Gruppierung oxidiert,
- (c1) das Sauerstoffatom der Keto-Gruppierung mit Hilfe von C6H5-P=CH2gegen eine =CH2-Gruppe austauscht und gegebenenfalls
- (d1) diese =CH2-Gruppe mit Hilfe einer Verbindung der Formel R-CH=CH2 katalytisch in eine =CH-R-Gruppe überführt, wobei R einen aliphatischen Rest, einen gegebenenfalls substituierten Phenylrest oder einen heterozyklischen Rest, insbesondere einen derartigen für pharmazeutische Wirkstoffe üblichen Rest darstellt; oder
- (c2) für die miteinander verbundenen Kohlenstoffatome C16 und C17 die Gruppierung -CH=CH2 vorsieht und gegebenenfalls
- (d2) diese Gruppierung mit Hilfe einer Metathese in die Gruppierung -CH=CH-R überführt, wobei R die vorstehend angegebenen Bedeutungen besitzt.
Bei Stufe (b) kann man mit Ozon oxidieren.
Bei Stufe (c2) kann man mit NaBH4 und danach mit
Tosylchlorid/Base arbeiten oder man kann eine Bamford-Stevens-
Reaktion gemäß Shapiro durchführen; vgl. Organic Reactions
(1976) 23, 405.
Bei Stufe (d) kann man mit einem Metathese-Katalysator arbeiten,
insbesondere einem derartigen Rhodium-, Ruthenium-, Wolfram-
oder Molybdän-Katalysator, beispielsweise mit
- - [RhCHPh)Cl2. (PCy3)2 gemäß Grubbs et al. in JACS, 118 (1996) 100-110; oder
- - RuCl2 (=CHPh)(PCy3)2; oder
- - RuCl2 (=CHCH=CPh2)(PCy3)2; oder
- - W(OAr¹)(OAr)(=CHtBu)(OEt2)Cl mit Ar1 = 2,6-diphenyl-C6H3 gemäß Basset et al. in Angew. Chem., Int. Ed., 32 (1993) 112; oder
- - Mo(C10H12)(C12H17N)(OC4H9)2, d. h. 2,6- Diisopropylphenylimidoneophyliden-molybdän-bis-(t-butoxid); oder
- - Mo(C10H12)(C12H17N)[OC(CH3)(CF3)2]2, d. h. 2,6- Diisopropylphenylimidoneophyliden-molybdän-bis-(hexafluoro-t butoxid); oder
- - Mo(C10H12)(C12H17N)(OSO2CF3)2(C4H10O2), d. h. 2,6- Diisopropylphenylimidoneophyliden-molybdän-bis- (trifluormethansulfonat)-dimethoxyethan-Addukt.
Für die genannten Molybdän-Katalysatoren sei verwiesen auf
US 4 681 956 und 4 727 215.
Claims (4)
1. Verfahren zur Herstellung eines Epothilon-Derivats, dadurch
gekennzeichnet, daß man
- (a) von Epothilon A, B, C oder D ausgeht,
- - wobei das C2- und das C3-Kohlenstoffatom durch die Gruppierung -CH2CHOH- oder -CH=CH- miteinander verbunden sein können und
- - wobei man bei der Ausgangsverbindung in 3- und 7-Stellung eine OH-Gruppe oder eine geschützte OH-Gruppe vorsieht,
- (b) in 16-Stellung zu einer Keto-Gruppierung oxidiert,
- (c1) das Sauerstoffatom der Keto-Gruppierung mit Hilfe von C6H5-P=CH2 gegen eine =CH2-Gruppe austauscht und gegebenenfalls
- (d1) diese =CH2-Gruppe mit Hilfe einer Verbindung der Formel R-CH=CH2 katalytisch in eine =CH2-R-Gruppe überführt, wobei R einen aliphatischen Rest, einen gegebenenfalls substituierten Phenylrest oder einen heterozyklischen Rest, insbesondere einen derartigen für pharmazeutische Wirkstoffe üblichen Rest dar stellt; oder
- (c2) für die unmittelbar miteinander verbundenen Kohlenstoffatome C16 und C17 an an sich bekannter Weise die Gruppierung -CH=CH2 vorsieht und gegebenenfalls
- (d2) diese Gruppierung mit Hilfe einer Metathese in die Gruppierung -CH=CH-R überführt, wobei R die vorstehend angegebenen Bedeutungen besitzt.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man
bei Stufe (b) mit Ozon oxidiert.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß
man bei Stufe (c2) mit NaBH4 und danach mit Tosylchlorid/Base
arbeitet oder eine Bamford-Stevens-Reaktion durchführt.
4. Verfahren nach einem der vorhergehenden Ansprüche, dadurch
gekennzeichnet, daß man bei Stufe (d) mit einem Metathese-
Katalysator arbeitet, insbesondere einem derartigen Rhodium-,
Ruthenium-, Wolfram- oder Molybdän-Katalysator.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19821954A DE19821954A1 (de) | 1997-05-15 | 1998-05-15 | Verfahren zur Herstellung eines Epothilon-Derivats |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19720250 | 1997-05-15 | ||
| DE19821954A DE19821954A1 (de) | 1997-05-15 | 1998-05-15 | Verfahren zur Herstellung eines Epothilon-Derivats |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19821954A1 true DE19821954A1 (de) | 1998-11-19 |
Family
ID=7829454
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19821954A Ceased DE19821954A1 (de) | 1997-05-15 | 1998-05-15 | Verfahren zur Herstellung eines Epothilon-Derivats |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE19821954A1 (de) |
Cited By (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6262094B1 (en) | 1999-02-22 | 2001-07-17 | Bristol-Myers Squibb Company | C-21 modified epothilones |
| US6288237B1 (en) | 1995-11-17 | 2001-09-11 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Epothilons C and D, preparation and compositions |
| US6291684B1 (en) | 1999-03-29 | 2001-09-18 | Bristol-Myers Squibb Company | Process for the preparation of aziridinyl epothilones from oxiranyl epothilones |
| US6320045B1 (en) | 1997-12-04 | 2001-11-20 | Bristol-Myers Squibb Company | Process for the reduction of oxiranyl epothilones to olefinic epothilones |
| US6365749B1 (en) | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
| US6380395B1 (en) | 1998-04-21 | 2002-04-30 | Bristol-Myers Squibb Company | 12, 13-cyclopropane epothilone derivatives |
| US6498257B1 (en) | 1998-04-21 | 2002-12-24 | Bristol-Myers Squibb Company | 2,3-olefinic epothilone derivatives |
| US6518421B1 (en) | 2000-03-20 | 2003-02-11 | Bristol-Myers Squibb Company | Process for the preparation of epothilone analogs |
| US6576651B2 (en) | 2001-01-25 | 2003-06-10 | Bristol-Myers Squibb Company | Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones |
| US6593115B2 (en) | 2000-03-24 | 2003-07-15 | Bristol-Myers Squibb Co. | Preparation of epothilone intermediates |
| US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US6670384B2 (en) | 2001-01-25 | 2003-12-30 | Bristol-Myers Squibb Company | Methods of administering epothilone analogs for the treatment of cancer |
| US6686380B2 (en) | 2001-02-20 | 2004-02-03 | Bristol-Myers Squibb Company | Treatment of refractory tumors using epothilone derivatives |
| US6689802B2 (en) | 2000-08-16 | 2004-02-10 | Bristol-Myers Squibb Company | Polymorphs of an epothilone analog |
| US6727276B2 (en) | 2001-02-20 | 2004-04-27 | Bristol-Myers Squibb Company | Epothilone derivatives for the treatment of refractory tumors |
| US6780620B1 (en) | 1998-12-23 | 2004-08-24 | Bristol-Myers Squibb Company | Microbial transformation method for the preparation of an epothilone |
| US6800653B2 (en) | 2001-06-01 | 2004-10-05 | Bristol-Myers Squibb Compnay | Epothilone derivatives |
| US6849651B2 (en) | 1996-12-03 | 2005-02-01 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| US6936628B2 (en) | 2002-04-04 | 2005-08-30 | Bristol-Myers Squibb Company | Oral administration of epothilones |
| US6965034B2 (en) | 1996-12-03 | 2005-11-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| 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 |
| US7022330B2 (en) | 2001-01-25 | 2006-04-04 | Bristol-Myers Squibb Company | Parenteral formulation for epothilone analogs |
| US7053069B2 (en) | 2002-05-15 | 2006-05-30 | Bristol-Myers Squibb Company | Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives |
| US7091226B2 (en) | 1998-02-25 | 2006-08-15 | Novartis Ag | Cancer treatment with epothilones |
| US7172884B2 (en) | 2002-09-23 | 2007-02-06 | Bristol-Myers Squibb Company | Methods for the preparation, isolation and purification of epothilone B, and x-ray crystal structures of epothilone B |
| US7211593B2 (en) | 2002-03-12 | 2007-05-01 | Bristol-Myers Squibb Co. | C12-cyano epothilone derivatives |
| US7312237B2 (en) | 2001-03-14 | 2007-12-25 | Bristol-Myers Squibb Co. | Combination of epothilone analogs and chemotherapeutic agents for the treatment of prolilferative diseases |
| US7649006B2 (en) | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US7816370B2 (en) | 2004-01-30 | 2010-10-19 | Institut National De La Sante Et De La Recherche Medicale | Use of epothilones in the treatment of neuronal connectivity defects such as schizophrenia and autism |
| US7846952B2 (en) | 1996-11-18 | 2010-12-07 | Helmholtz-Zentrum Fuer Infektionsforschung Gmbh | Epothilones C, D, E, and F, preparation and compositions |
| US7875638B2 (en) | 2002-08-23 | 2011-01-25 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
-
1998
- 1998-05-15 DE DE19821954A patent/DE19821954A1/de not_active Ceased
Cited By (65)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6613912B2 (en) | 1995-11-17 | 2003-09-02 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Epothilons C and D, preparation and compositions |
| US6288237B1 (en) | 1995-11-17 | 2001-09-11 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Epothilons C and D, preparation and compositions |
| US6831076B2 (en) | 1995-11-17 | 2004-12-14 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Epothilons C and D, preparation and compositions |
| US7846952B2 (en) | 1996-11-18 | 2010-12-07 | Helmholtz-Zentrum Fuer Infektionsforschung Gmbh | Epothilones C, D, E, and F, preparation and compositions |
| US8076490B2 (en) | 1996-11-18 | 2011-12-13 | Helmholtz-Zentrum Fuer Infektionsforschung Gmbh | Epothilones C, D, E, and F, preparation and compositions |
| US7750164B2 (en) | 1996-12-03 | 2010-07-06 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| US6972335B2 (en) | 1996-12-03 | 2005-12-06 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| US6965034B2 (en) | 1996-12-03 | 2005-11-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US6849651B2 (en) | 1996-12-03 | 2005-02-01 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| USRE41990E1 (en) | 1996-12-03 | 2010-12-07 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| US8481575B2 (en) | 1996-12-03 | 2013-07-09 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| USRE43003E1 (en) | 1997-07-08 | 2011-12-06 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US8536327B2 (en) | 1997-07-08 | 2013-09-17 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US7125899B2 (en) | 1997-07-08 | 2006-10-24 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US8921542B2 (en) | 1997-07-08 | 2014-12-30 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
| USRE41911E1 (en) | 1997-07-08 | 2010-11-02 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US7241755B2 (en) | 1997-07-08 | 2007-07-10 | Bristol-Myers Squibb Company | Epothilone derivatives |
| USRE41895E1 (en) | 1997-07-08 | 2010-10-26 | Bristol-Myers Squibb Company | Epothilone derivatives |
| USRE41893E1 (en) | 1997-07-08 | 2010-10-26 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US6365749B1 (en) | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
| US6320045B1 (en) | 1997-12-04 | 2001-11-20 | Bristol-Myers Squibb Company | Process for the reduction of oxiranyl epothilones to olefinic epothilones |
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