DE69433146T2 - Delta 6,7-Taxol Derivate antineoplastische Verbindungen und diese enthaltende pharmazeutische Zusammenstellungen - Google Patents

Delta 6,7-Taxol Derivate antineoplastische Verbindungen und diese enthaltende pharmazeutische Zusammenstellungen Download PDF

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DE69433146T2
DE69433146T2 DE69433146T DE69433146T DE69433146T2 DE 69433146 T2 DE69433146 T2 DE 69433146T2 DE 69433146 T DE69433146 T DE 69433146T DE 69433146 T DE69433146 T DE 69433146T DE 69433146 T2 DE69433146 T2 DE 69433146T2
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nhc
phenyl
substd
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alkyl
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DE69433146D1 (de
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Robert C. Augusta Kelly
Roy A. Kalamazoo Johnson
Harvey I. Kalamazoo Skulnick
Eldon G. Kalamazoo Nidy
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Pharmacia and Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • 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
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 System
    • 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

Description

  • Gebiet der Erfindung
  • Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von 10-Desacetyltaxol, Taxotere und Analoga derselben.
  • Hintergrund der Erfindung
  • Taxol und Taxotere sind stark wirkende Antikrebsmittel.
  • Die US-A-5 248 796 betrifft 10-Desacetoxy-11,12-dihydrotaxol-10,12(18)-dienderivate und die Herstellung von 10-Desacetoxytaxol.
  • Samaranayake et al., J. Org. Chem., 1991, 56, 5114 offenbart ein Verfahren zur Entfernung der Acylgruppe von der 10-Position von Taxol und Baccatinstrukturen unter Verwendung von Zinkbromid in Methanol. Dieses Verfahren ergibt eine Zahl anderer Produkte zusätzlich zu dem gewünschten Deacylierungsprodukt.
  • Zusammenfassung der Erfindung
  • Die vorliegende Erfindung ist ein Deacetylierungsverfahren unter Verwendung von Hydrazin, das in den Ansprüchen definiert ist.
  • Beschreibung der Erfindung
  • In einer Ausführungsform der Erfindung umfasst die Reaktion von Taxol und Taxolanaloga 1
    Figure 00020001
    worin R15 Acetyl ist, Baccatin III oder Baccatin-III-Analoga 2
    Figure 00020002
    worin R6 Acetyl ist, mit Hydrazin ein besonders vorteilhaftes Verfahren zur Herstellung von 10-Desacetyltaxol, 10-Desacyltaxolanaloga (1, R15 = H), 10-Desacetylbaccatin III und 10-Desacylbaccatin-III-Analoga (2, R6 = H). Die Reaktion mit Hydrazin ergibt fast ausschließlich das gewünschte Deacylierungsprodukt. Die Reaktion kann bei Raumtemperatur in einem organischen Lösemittel durchgeführt werden und erfordert üblicherweise nur 15 min oder bis zu 24 h in Abhängigkeit vom Substrat. Das bevorzugte Lösemittel für die Reaktion ist 95%iges Ethanol, und 98%iges Hydrazin ist die bevorzugte Form des Reagens.
  • Die folgenden Beispiele erläutern die Erfindung.
  • Beispiel 1: Taxotere
  • 25 mg (0,029 mM) 10-Acetyltaxotere wird bei Raumtemperatur unter Stickstoff in 1,0 ml 95%igem Ethanol gerührt. Zwei Tropfen wasserfreies Hydrazin werden zugegeben und das Ganze wird 1,5 h lang reagieren gelassen, wonach DC zeigte, dass die Reaktion fast vollständig war. Das Reaktionsgemisch wird zwischen Wasser und Methylenchlorid verteilt. Die wässrige Schicht wird mit Methylenchlorid rückextrahiert. Die organischen Schichten werden vereinigt, über Natriumsulfat getrocknet und unter Vakuum eingedampft.
  • Das rohe Produkt wird über 3 g Silicagel unter Elution mit 70-30 Ethylacetat-Hexan chromatographiert. 1-ml-Fraktionen werden gewonnen und mittels DC analysiert. Die Fraktionen 14-28 enthalten das Produkt und sie werden vereinigt und unter Vakuum eingedampft.
  • DC: Silicagel 60; 70-30 EtOAc-Hexan; Rf: 0,33.
  • 1H-NMR (CDCl3, TMS): δ 1, 12 (s, 3H); 1, 23 (s, 3H); 1, 34 (s, 9H); 1,74 (s, 3H); 1,85 (s, 3H) 2,37 (s, 3H); 2,56 (m, 1H); 3,53 (bs, 1H); 3,90 (d, 1H), 4,18 (d, 1H), 4,21 (m; 1H); 4,30 (d, 1H); 4,32 (s, 1H); 4,62 (bs, 1H); 4,94 (d, 1H); 5,23 (s, 1H); 5,28 (bs, 1H); 5,52 (d, 1H); 5,66 (d, 1H); 6,20 (t, 1H); 6,20 (t, 1H); 7,25-7,45 (m, 6H); 7,50 (t, 2H); 7,61 (t, 1H); 8,11 (d, 2H).
  • Beispiel 2: 10-Desacetyltaxol
  • Eine Lösung von Taxol (0,026 g, 0,030 mmol) und 98%igem Hydrazin (0,035 g, 1,1 mmol) in 95%igem Ethanol (1,0 ml) wird 2 h lang bei Raumtemperatur gerührt. Die Lösung wird in Wasser und Ether gegossen, das Gemisch wird gut geschüttelt und die Schichten werden getrennt. Die wässrige Schicht wird mit weiterem Ether extrahiert. Die vereinigten Etherextrakte werden über Na2SO4 getrocknet, filtriert und eingeengt, wobei 0,021 g der Titelverbindung erhalten werden; deren 1H-NMR-Spektrum in CDCl3 ist mit dem für 10-Desacetyltaxol berichteten Spektrum (I. Ringel, S.B. Horwitz, J. Pharmacol. Exp. Ther., 1987, 242, 692) identisch und mit dem Spektrum einer authentischen Probe identisch.
  • Beispiel 3: 10-Desacetylbaccatin III
  • Eine Lösung von Baccatin III (0,024 g, 0,041 mmol) in 95%igem Ethanol (1,0 ml) wird durch Erwärmen des Gemischs hergestellt. Die Lösung wird auf Raumtemperatur gekühlt, mit 98%igem Hydrazin (0,035 g, 1,1 mmol) versetzt und 24 h lang bei Raumtemperatur gerührt. Die Lösung wird in Wasser/Ether gegossen, gut geschüttelt, und die Schichten werden getrennt. Die Etherschicht wird mit Wasser gewaschen, getrocknet (Na2SO4), filtriert und eingeengt, wobei 0,010 g der Titelverbindung erhalten werden; deren 1H-NMR-Spektrum in CDCl3 (kaum löslich) ist mit dem einer authentischen Probe von 10-Deacetylbaccatin III identisch.

Claims (2)

  1. Verfahren zur Herstellung einer Verbindung der Formel:
    Figure 00050001
    worin R1 ausgewählt ist aus der Gruppe von -CH3, -C6HS oder Phenyl, das mit 1, 2 oder 3 Resten von C1-C4-Alkyl, C1-C3-Alkoxy, Halogen, C1-C3-Alkylthio, Trifluormethyl, C2-C6-Dialkylamino, Hydroxy, oder Nitro substituiert ist, -2-Furyl, 2-Thienyl, 1-Naphthyl, 2-Naphthyl oder 3,4-Methylendioxyphenyl; R2 ausgewählt ist aus der Gruppe von -H, -NHC(O)H, -NHC(O)-C1-C10-Alkyl, -NHC(O)Phenyl, -NHC(O)Phenyl, das substituiert ist mit 1, 2 oder 3 Resten von C1-C4-Alkyl, C1-C3-Alkoxy, Halogen, C1-C3-Alkylthio, Trifluormethyl, C2-C6-Dialkylamino, Hydroxy oder Nitro, -NHC(O)C(CH3)=CHCH3, -NHC(O)OC(CH3)3, -NHC(O)OCH2-Phenyl, -NH2, -NHSO2-4-Methylphenyl, -NHC(O)(CH2)3COOH, -NHC(O)-4-(SO3H)Phenyl, -OH, -NHC(O)-1-Adamantyl, -NHC(O)O-3-Tetrahydrofuranyl, -NHC(O)O-4-Tetrahydropyranyl, -NHC(O)CH2C(CH3)3, -NHC(O)C(CH3)3, -NHC(O)O-C1-C10-Alkyl, -NHC(O)NH-C1-C10-Alkyl, -NHC(O)NHPh, -NHCO(O)NHPh, das substituiert ist mit 1, 2 oder 3 Resten von C1-C4-Alkyl, C1-C3-Alkoxy, Halogen, C1-C3-Alkylthio, Trifluormethyl, C2-C6-Dialkylamino oder Nitro, -NHC(O)-C3-C8-Cycloalkyl, -NHC(O)C(CH2CH3)2CH3, -NHC(O)C(CH3)2CH2Cl, -NHC(O)C(CH3)2CH2CH3, Phthalimido, -NHC(O)-1-Phenyl-1-cyclopentyl, -NHC(O)-1-Methyl-l-cyclohexyl, -NHC(S)NHC(CH3)3 oder -NHC(O)NHC(CH3)3; R3 ausgewählt ist aus der Gruppe von -H, -NHC(O)Phenyl oder -NHC(O)OC(CH3)3, unter dem allgemeinen Vorbehalt, dass einer der Reste R2 und R3 -H ist, jedoch R2 und R3 nicht beide -H sind; Bz -C(O)Phenyl ist; und Ac C(O)CH3 ist; wobei das Verfahren die Reaktion einer Verbindung der Formel:
    Figure 00060001
    worin R1, R2, R3, Bz und Ac wie im vorhergehenden definiert sind; mit Hydrazin umfasst.
  2. Verfahren zur Herstellung einer Verbindung der Formel:
    Figure 00070001
    worin Bz C(O)Phenyl ist und Ac C(O)CH3 ist; wobei das Verfahren die Reaktion einer Verbindung der Formel:
    Figure 00070002
    mit Hydrazin umfasst.
DE69433146T 1993-06-11 1994-06-03 Delta 6,7-Taxol Derivate antineoplastische Verbindungen und diese enthaltende pharmazeutische Zusammenstellungen Expired - Fee Related DE69433146T2 (de)

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US7633793A 1993-06-11 1993-06-11
US76337 1993-06-11
US12297493A 1993-09-17 1993-09-17
US122974 1993-09-17
WOPCT/US93/11827 1993-12-13
PCT/US1993/011827 WO1994013655A1 (en) 1992-12-15 1993-12-13 7-HALO- AND 7β,8β-METHANO-TAXOLS, ANTINEOPLASTIC USE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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DE69433146D1 DE69433146D1 (de) 2003-10-16
DE69433146T2 true DE69433146T2 (de) 2004-06-09

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DE69424166T Expired - Fee Related DE69424166T2 (de) 1993-06-11 1994-06-03 Delta 6, 7-taxolen, antineoplastische verwendung und diese enthaltende pharmazeutische zusammenstellungen
DE69433715T Expired - Fee Related DE69433715T2 (de) 1993-06-11 1994-06-03 Delta 6,7-Taxol Derivate antineoplastische Verwendung und diese enthaltende pharmazeutische Zusammenstellungen
DE69433146T Expired - Fee Related DE69433146T2 (de) 1993-06-11 1994-06-03 Delta 6,7-Taxol Derivate antineoplastische Verbindungen und diese enthaltende pharmazeutische Zusammenstellungen

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DE69424166T Expired - Fee Related DE69424166T2 (de) 1993-06-11 1994-06-03 Delta 6, 7-taxolen, antineoplastische verwendung und diese enthaltende pharmazeutische zusammenstellungen
DE69433715T Expired - Fee Related DE69433715T2 (de) 1993-06-11 1994-06-03 Delta 6,7-Taxol Derivate antineoplastische Verwendung und diese enthaltende pharmazeutische Zusammenstellungen

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US (2) US5965739A (de)
EP (3) EP0982301B1 (de)
JP (1) JPH09511212A (de)
AT (3) ATE192147T1 (de)
AU (1) AU7138894A (de)
CA (1) CA2161328A1 (de)
DE (3) DE69424166T2 (de)
DK (3) DK0703909T3 (de)
ES (3) ES2145829T3 (de)
GR (1) GR3033836T3 (de)
IL (1) IL109957A (de)
LV (2) LV12692B (de)
NZ (2) NZ268475A (de)
PT (3) PT982302E (de)
SI (2) SI0703909T1 (de)
TW (1) TW401407B (de)
WO (1) WO1994029288A1 (de)
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DK0703909T3 (da) 2000-09-11
LV12692A (lv) 2001-07-20
CA2161328A1 (en) 1994-12-22
ATE192147T1 (de) 2000-05-15
EP0982301A2 (de) 2000-03-01
DE69433715T2 (de) 2005-03-24
LV12692B (lv) 2001-09-20
PT982301E (pt) 2004-02-27
NZ268475A (en) 1998-08-26
IL109957A0 (en) 1994-10-07
EP0982301A3 (de) 2000-11-08
US5556878A (en) 1996-09-17
ZA944034B (en) 1995-12-08
IL109957A (en) 2001-01-11
EP0703909A1 (de) 1996-04-03
TW401407B (en) 2000-08-11
DE69433715D1 (de) 2004-05-19
AU7138894A (en) 1995-01-03
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EP0982302A3 (de) 2000-07-19
ES2145829T3 (es) 2000-07-16
EP0703909B1 (de) 2000-04-26
SI0982302T1 (en) 2004-08-31
ES2219968T3 (es) 2004-12-01
PT982302E (pt) 2004-07-30
DE69424166D1 (de) 2000-05-31
NZ330671A (en) 2000-01-28
SI0703909T1 (en) 2000-08-31
ATE249448T1 (de) 2003-09-15
DE69424166T2 (de) 2000-10-05
DK0982302T3 (da) 2004-08-02
ES2205663T3 (es) 2004-05-01
ATE264316T1 (de) 2004-04-15
EP0982301B1 (de) 2003-09-10
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EP0982302B1 (de) 2004-04-14
US5965739A (en) 1999-10-12
JPH09511212A (ja) 1997-11-11
LV13319B (en) 2005-08-20
DK0982301T3 (da) 2003-12-08
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PT703909E (pt) 2000-10-31

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