DE19821954A1 - Preparation of epothilone derivatives - Google Patents

Preparation of epothilone derivatives

Info

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
Application number
DE19821954A
Other languages
German (de)
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GESELLSCHAFT fur BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) 38124 BRAUNSCHWEIG DE
Original Assignee
GESELLSCHAFT fur BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) 38124 BRAUNSCHWEIG DE
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.)
Filing date
Publication date
Application filed by GESELLSCHAFT fur BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) 38124 BRAUNSCHWEIG DE filed Critical GESELLSCHAFT fur BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) 38124 BRAUNSCHWEIG DE
Priority to DE19821954A priority Critical patent/DE19821954A1/en
Publication of DE19821954A1 publication Critical patent/DE19821954A1/en
Ceased legal-status Critical Current

Links

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

Abstract

Preparation of epothilone derivatives comprises: (a) substituting epothilone A, B, C or D at carbons 2 and 3 with -CH2CHOH- or -CH=CH-, where an OH group or protected OH group is provided at positions 3 and 7; (b) oxidising position 16 into a keto group; (c1) exchanging the oxygen in the keto group using C6H5-P=CH2 into a =CH2- group, and optionally (d1) reacting the =CH2- with a catalyst and R-CH=CH2 to give =CH2-R-, where R = an aliphatic residue, phenyl residue or a heterocyclic residue, especially a pharmaceutical residue, or (c2) exchanging carbon 16 and 17 for a -CH=CH2 group, and optionally (d2) reacting this group using a metathesis to give -CH=CH-R-.

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.Epothilones A, B, C and D are known; see. for example PCT / EP 96/05 080. These epothilones have a heterocyclic radical on the C 17 carbon atom. It is now desirable to replace this radical with another radical which is customary or advantageous in particular for active pharmaceutical ingredients.

Zur Lösung dieser Aufgabe wird erfindungsgemäß ein Verfahren zur Herstellung eines Epothilon-Derivats vorgesehen, das dadurch gekennzeichnet ist, daß man
To achieve this object, a method for producing an epothilone derivative is provided according to the invention, which is characterized in that

  • (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,
    (a) starts from an epothilone A, B, C or D,
    • - The C2 and the C3 carbon atom can be connected to one another by the grouping -CH 2 CHOH- or -CH = CH- and
    • an OH group or a protected OH group is provided in the 3- and 7-position of the starting compound,
  • (b) in 16-Stellung zu einer Keto-Gruppierung oxidiert,(b) oxidized to a keto group in the 16-position,
  • (c1) das Sauerstoffatom der Keto-Gruppierung mit Hilfe von C6H5-P=CH2gegen eine =CH2-Gruppe austauscht und gegebenenfalls(c1) the oxygen atom of the keto group is replaced with a = CH 2 group using C 6 H 5 -P = CH 2 and, if appropriate
  • (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(d1) this = CH 2 group is catalytically converted into a = CH-R group with the aid of a compound of the formula R-CH = CH 2 , where R is an aliphatic radical, an optionally substituted phenyl radical or a heterocyclic radical, in particular such a radical represents rest usual for pharmaceutical active substances; or
  • (c2) für die miteinander verbundenen Kohlenstoffatome C16 und C17 die Gruppierung -CH=CH2 vorsieht und gegebenenfalls(c2) for the interconnected carbon atoms C16 and C17 provides the grouping -CH = CH 2 and optionally
  • (d2) diese Gruppierung mit Hilfe einer Metathese in die Gruppierung -CH=CH-R überführt, wobei R die vorstehend angegebenen Bedeutungen besitzt.(d2) this grouping with the help of a metathesis into the Grouping -CH = CH-R transferred, where R is the above has the meanings given.

Bei Stufe (b) kann man mit Ozon oxidieren.Step (b) can be oxidized with ozone.

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.In step (c2), one can work with NaBH 4 and then with tosyl chloride / base or one can carry out a Bamford-Stevens reaction according to Shapiro; see. 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
In step (d) it is possible to work with a metathesis catalyst, in particular with such a rhodium, ruthenium, tungsten or molybdenum catalyst, for example with

  • - [RhCHPh)Cl2. (PCy3)2 gemäß Grubbs et al. in JACS, 118 (1996) 100-110; oder- [RhCHPh) Cl 2 . (PCy 3 ) 2 according to Grubbs et al. in JACS, 118 (1996) 100-110; or
  • - RuCl2 (=CHPh)(PCy3)2; oder- RuCl 2 (= CHPh) (PCy 3 ) 2 ; or
  • - RuCl2 (=CHCH=CPh2)(PCy3)2; oder- RuCl 2 (= CHCH = CPh 2 ) (PCy 3 ) 2 ; or
  • - 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- W (OAr¹) (OAr) (= CHtBu) (OEt 2 ) Cl with Ar 1 = 2,6-diphenyl-C 6 H 3 according to Basset et al. in Angew. Chem., Int. Ed., 32 (1993) 112; or
  • - Mo(C10H12)(C12H17N)(OC4H9)2, d. h. 2,6- Diisopropylphenylimidoneophyliden-molybdän-bis-(t-butoxid); oderMo (C 10 H 12 ) (C 12 H 17 N) (OC 4 H 9 ) 2 , ie 2,6-diisopropylphenylimidoneophylidene-molybdenum bis (t-butoxide); or
  • - Mo(C10H12)(C12H17N)[OC(CH3)(CF3)2]2, d. h. 2,6- Diisopropylphenylimidoneophyliden-molybdän-bis-(hexafluoro-t butoxid); oderMo (C 10 H 12 ) (C 12 H 17 N) [OC (CH 3 ) (CF 3 ) 2 ] 2 , ie 2,6-diisopropylphenylimidoneophylidene-molybdenum-bis (hexafluorot-butoxide); or
  • - Mo(C10H12)(C12H17N)(OSO2CF3)2(C4H10O2), d. h. 2,6- Diisopropylphenylimidoneophyliden-molybdän-bis- (trifluormethansulfonat)-dimethoxyethan-Addukt.- Mo (C 10 H 12 ) (C 12 H 17 N) (OSO 2 CF 3 ) 2 (C 4 H 10 O 2 ), ie 2,6-diisopropylphenylimidoneophylidene-molybdenum bis (trifluoromethanesulfonate) dimethoxyethane adduct.

Für die genannten Molybdän-Katalysatoren sei verwiesen auf US 4 681 956 und 4 727 215.For the molybdenum catalysts mentioned, reference is made to U.S. 4,681,956 and 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.
1. A method for producing an epothilone derivative, characterized in that
  • (a) starts from epothilone A, B, C or D,
    • - The C2 and the C3 carbon atom can be connected to one another by the grouping -CH 2 CHOH- or -CH = CH- and
    • an OH group or a protected OH group is provided in the 3- and 7-position of the starting compound,
  • (b) oxidized to a keto group in the 16-position,
  • (c1) the oxygen atom of the keto group is replaced with a = CH 2 group using C 6 H 5 -P = CH 2 and, if appropriate
  • (d1) this = CH 2 group is catalytically converted into a = CH 2 -R group using a compound of the formula R-CH = CH 2 , where R is an aliphatic radical, an optionally substituted phenyl radical or a heterocyclic radical, in particular one represents such usual rest for active pharmaceutical ingredients; or
  • (c2) for the directly connected carbon atoms C16 and C17 provides the grouping -CH = CH 2 in a manner known per se and optionally
  • (d2) this grouping is converted into the grouping -CH = CH-R by means of a metathesis, where R has the meanings given above.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man bei Stufe (b) mit Ozon oxidiert.2. The method according to claim 1, characterized in that one oxidized with ozone at step (b). 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.3. The method according to claim 1 or 2, characterized in that one works in step (c2) with NaBH 4 and then with tosyl chloride / base or carries out a Bamford-Stevens reaction. 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.4. The method according to any one of the preceding claims, characterized characterized in that at step (d) with a metathesis Catalyst works, especially such a rhodium, Ruthenium, tungsten or molybdenum catalyst.
DE19821954A 1997-05-15 1998-05-15 Preparation of epothilone derivatives Ceased DE19821954A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE19821954A DE19821954A1 (en) 1997-05-15 1998-05-15 Preparation of epothilone derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19720250 1997-05-15
DE19821954A DE19821954A1 (en) 1997-05-15 1998-05-15 Preparation of epothilone derivatives

Publications (1)

Publication Number Publication Date
DE19821954A1 true DE19821954A1 (en) 1998-11-19

Family

ID=7829454

Family Applications (1)

Application Number Title Priority Date Filing Date
DE19821954A Ceased DE19821954A1 (en) 1997-05-15 1998-05-15 Preparation of epothilone derivatives

Country Status (1)

Country Link
DE (1) DE19821954A1 (en)

Cited By (30)

* Cited by examiner, † Cited by third party
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
US6936628B2 (en) 2002-04-04 2005-08-30 Bristol-Myers Squibb Company Oral administration of epothilones
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
US7750164B2 (en) 1996-12-03 2010-07-06 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses 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

Cited By (62)

* Cited by examiner, † Cited by third party
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
US8481575B2 (en) 1996-12-03 2013-07-09 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
US7750164B2 (en) 1996-12-03 2010-07-06 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
USRE41893E1 (en) 1997-07-08 2010-10-26 Bristol-Myers Squibb Company Epothilone derivatives
USRE41911E1 (en) 1997-07-08 2010-11-02 Bristol-Myers Squibb Company Epothilone derivatives
US6605599B1 (en) 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
US7125899B2 (en) 1997-07-08 2006-10-24 Bristol-Myers Squibb Company Epothilone derivatives
US8536327B2 (en) 1997-07-08 2013-09-17 Bristol-Myers Squibb Company Epothilone derivatives
US7241755B2 (en) 1997-07-08 2007-07-10 Bristol-Myers Squibb Company Epothilone derivatives
USRE43003E1 (en) 1997-07-08 2011-12-06 Bristol-Myers Squibb Company Epothilone derivatives
US8921542B2 (en) 1997-07-08 2014-12-30 Bristol-Myers Squibb Company Epothilone derivatives
USRE41895E1 (en) 1997-07-08 2010-10-26 Bristol-Myers Squibb Company Epothilone derivatives
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
US7091226B2 (en) 1998-02-25 2006-08-15 Novartis Ag Cancer treatment with epothilones
US6399638B1 (en) 1998-04-21 2002-06-04 Bristol-Myers Squibb Company 12,13-modified epothilone derivatives
US6498257B1 (en) 1998-04-21 2002-12-24 Bristol-Myers Squibb Company 2,3-olefinic epothilone derivatives
US6831090B2 (en) 1998-04-21 2004-12-14 Bristol-Myers Squibb Company 2,3-olefinic epothilone derivatives
US6380395B1 (en) 1998-04-21 2002-04-30 Bristol-Myers Squibb Company 12, 13-cyclopropane epothilone derivatives
US6780620B1 (en) 1998-12-23 2004-08-24 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US7244594B2 (en) 1998-12-23 2007-07-17 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US6262094B1 (en) 1999-02-22 2001-07-17 Bristol-Myers Squibb Company C-21 modified epothilones
US6291684B1 (en) 1999-03-29 2001-09-18 Bristol-Myers Squibb Company Process for the preparation of aziridinyl epothilones from oxiranyl epothilones
USRE39356E1 (en) * 2000-03-20 2006-10-17 Bristol-Myers Squibb Co. Process for the preparation of epothilone analogs
US6518421B1 (en) 2000-03-20 2003-02-11 Bristol-Myers Squibb Company Process for the preparation of epothilone analogs
US6593115B2 (en) 2000-03-24 2003-07-15 Bristol-Myers Squibb Co. Preparation of epothilone intermediates
US7153879B2 (en) 2000-08-16 2006-12-26 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
USRE39251E1 (en) * 2000-08-16 2006-08-29 Bristol-Myers Squibb Co. Polymorphs of an epothilone analog
US6689802B2 (en) 2000-08-16 2004-02-10 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
US6982276B2 (en) 2000-08-16 2006-01-03 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
US7022330B2 (en) 2001-01-25 2006-04-04 Bristol-Myers Squibb Company Parenteral formulation for 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
US8632788B2 (en) 2001-01-25 2014-01-21 Bristol-Myers Squibb Company Parenteral formulation for epothilone analogs
US6670384B2 (en) 2001-01-25 2003-12-30 Bristol-Myers Squibb Company Methods of administering epothilone analogs for the treatment of cancer
USRE40387E1 (en) * 2001-01-25 2008-06-17 Bristol-Myers Squibb Company Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones
USRE41393E1 (en) 2001-02-20 2010-06-22 Bristol-Myers Squibb Company Treatment of refractory tumors using epothilone derivatives
US6686380B2 (en) 2001-02-20 2004-02-03 Bristol-Myers Squibb Company Treatment of refractory tumors using epothilone derivatives
US6727276B2 (en) 2001-02-20 2004-04-27 Bristol-Myers Squibb Company Epothilone derivatives for the treatment of refractory tumors
US8598215B2 (en) 2001-03-14 2013-12-03 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
US8569347B2 (en) 2001-03-14 2013-10-29 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
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
US6800653B2 (en) 2001-06-01 2004-10-05 Bristol-Myers Squibb Compnay Epothilone derivatives
US7211593B2 (en) 2002-03-12 2007-05-01 Bristol-Myers Squibb Co. C12-cyano epothilone derivatives
US6936628B2 (en) 2002-04-04 2005-08-30 Bristol-Myers Squibb Company Oral administration of epothilones
US7053069B2 (en) 2002-05-15 2006-05-30 Bristol-Myers Squibb Company 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
US7759374B2 (en) 2002-08-23 2010-07-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US8110590B2 (en) 2002-08-23 2012-02-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US8513429B2 (en) 2002-08-23 2013-08-20 Sloan-Kettering Insitute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7875638B2 (en) 2002-08-23 2011-01-25 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
USRE42191E1 (en) 2002-09-23 2011-03-01 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
US7767432B2 (en) 2002-09-23 2010-08-03 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and x-ray crystal structures of epothilone B
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
US7241899B2 (en) 2002-09-23 2007-07-10 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
US8513280B2 (en) 2004-01-30 2013-08-20 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
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

Similar Documents

Publication Publication Date Title
DE19821954A1 (en) Preparation of epothilone derivatives
DE60130640T2 (en) 2-ALKYLIDENE-19-NOR-VITAMIN D COMPOUNDS AND ITS THERAPEUTIC USES
DE69832699T2 (en) CYCLIC ETHERIC VITAMIN D3 COMPOUNDS, 1ALFA (OH) 3-EPI-VITAMIN D3 COMPOUNDS AND ITS USES
DE3024855C2 (en)
WO1994007853A1 (en) 25-carboxylic acid derivatives in the vitamin d series, method of producing them, intermediate products for this method, pharmaceutical preparations containing these derivatives and their use in the manufacture of medicines
Abel et al. Eine einfache und flexible Synthese von Pyrrolen aus α, β‐ungesättigten Sulfonen
EP1654266B1 (en) Novel metathesis catalysts
CH648554A5 (en) GLYCIDYLISOCYANURIC ACID COMPOUNDS.
DE3490636T1 (en) Hydroxyvitamin D? 2? Isomers
DE3133814A1 (en) 2- (2-HYDROXY-3 '- (1,1-DIMETHYLPROPYLAMINO) -PROPOXY) -W-PHENYLPROPIOPHENONE, THEIR PRODUCTION AND I.V. AND ORAL TO BE ADMINISTRATED AGAINST HEART RHYTHMAL DISORDERS
DE69907681T2 (en) 24,24-DIFLUORED ANALOGS OF 1-ALPHA, 25-DIHYDROXY VITAMIN D3
EP1086077B1 (en) Novel antiestrogens, a method for the production thereof, and their pharmaceutical application
EP0435902B1 (en) 2-hydroxy-3-phenoxy-propyl-substituted piperazines, their manufacture and use
DE3590488T (en) Vitamin D derivatives and processes for their preparation
WO1991012238A1 (en) Side-chain-homologous vitamin d derivatives, process for producing them, pharmaceutical preparations containing these derivatives and their use as medicaments
DE60311779T2 (en) Steroidal quinols as prodrugs of antioxidants
DE3590021C2 (en) Alpha-hydroxyvitamin D derivative and medicinal product containing the same
EP0075165B1 (en) 9,10-substituted 2-mesitylimino-3-alkyl-3,4,6,7-tetrahydro-2h-pyrimido(6,1-a)isoquinolin-4-ones, process for their preparation and their use as medicaments
AT349481B (en) METHOD FOR PRODUCING NEW MORPHOLINE DERIVATIVES, THEIR N-OXIDES AND SALTS
DE3590080C2 (en)
DE2222478A1 (en) Alkanolamine derivatives
DE60110069T2 (en) 16,17-CARBOCYCLICALLY CONDENSED STEROID COMPOUNDS WITH SELECTIVE ESTROGENIC EFFICACY
DE2418877A1 (en) METHOD OF CYCLIZING A SUBSTRATE
EP3470401B1 (en) Method for photoredox catalytic addition of sulphur hexafluoride to unsaturated carbon-carbon bonds
DE3026601A1 (en) HALOGEN-14-OXO-15-HYDROXY-E-HOMOEBURN OTHER DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM

Legal Events

Date Code Title Description
8181 Inventor (new situation)

Free format text: HOEFLE, GERHARD, PROF. DR., 38124 BRAUNSCHWEIG, DE LEIBOLD, THOMAS, DR., 38124 BRAUNSCHWEIG, DE

8110 Request for examination paragraph 44
R016 Response to examination communication
R002 Refusal decision in examination/registration proceedings
R071 Expiry of right
R003 Refusal decision now final