Title:
CYCLOPROPYL AND CYCLOBUTYL EPOTHILONE ANALOGS
Document Type and Number:
WIPO Patent Application WO2003018002
Kind Code:
A3
Abstract:
The invention relates to cis- and trans-12, 13-cyclopropyl and 12, 13-cyclobutyl epothilones of formula (I) to (IV), wherein Ar is a radical represented by the following structure:, and the other radicals and symbols have the meanings as defined herein; to their chemical synthesis and biological evaluation; their use in the treatment of neoplastic diseases and to pharmaceutical preparations containing such compounds. The compounds described herein are potent tubulin polymerization promoters and cytotoxic agents.
Inventors:
NICOLAOU KYRIACOS COSTA (US)
NAMOTO KENJI (US)
RITZEN ANDREAS (DK)
ULVEN TROND (DK)
SHOJI MUTSURU (JP)
ALTMANN KARL-HEINZ (CH)
NAMOTO KENJI (US)
RITZEN ANDREAS (DK)
ULVEN TROND (DK)
SHOJI MUTSURU (JP)
ALTMANN KARL-HEINZ (CH)
Application Number:
PCT/EP2002/009407
Publication Date:
September 04, 2003
Filing Date:
August 22, 2002
Export Citation:
Assignee:
NOVARTIS AG (CH)
NOVARTIS PHARMA GMBH (AT)
SCRIPPS RESEARCH INST (US)
NICOLAOU KYRIACOS COSTA (US)
NAMOTO KENJI (US)
RITZEN ANDREAS (DK)
ULVEN TROND (DK)
SHOJI MUTSURU (JP)
ALTMANN KARL-HEINZ (CH)
NOVARTIS PHARMA GMBH (AT)
SCRIPPS RESEARCH INST (US)
NICOLAOU KYRIACOS COSTA (US)
NAMOTO KENJI (US)
RITZEN ANDREAS (DK)
ULVEN TROND (DK)
SHOJI MUTSURU (JP)
ALTMANN KARL-HEINZ (CH)
International Classes:
A61K31/427; A61K31/4427; A61P35/00; A61P35/02; C07D313/00; C07D405/06; C07D405/12; C07D417/06; C07D417/12; C07D495/08; (IPC1-7): A61K31/365; C07D313/00; C07D417/06; C07D407/06; C07D493/04; A61P35/02
Domestic Patent References:
| WO1998025929A1 | 1998-06-18 | |||
| WO2000047584A2 | 2000-08-17 | |||
| WO1999054318A1 | 1999-10-28 |
Other References:
ALTMANN K-H ET AL: "Synthesis and biological evaluation of highly potent analogues of epothilones B and D", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 10, no. 24, 18 December 2000 (2000-12-18), pages 2765 - 2768, XP004225345, ISSN: 0960-894X
NICOLAOU K C ET AL: "Total synthesis of 16-desmethylepothilone B, epothilone B10, epothilone F, and related side chain modified epothilone B analogues.", CHEMISTRY (WEINHEIM AN DER BERGSTRASSE, GERMANY) GERMANY 4 AUG 2000, vol. 6, no. 15, 4 August 2000 (2000-08-04), pages 2783 - 2800, XP002223256, ISSN: 0947-6539
NICOLAOU K C ET AL: "DESIGNED EPOTHILONES: COMBINATORIAL SYNTHESIS, TUBULIN ASSEMBLY PROPERTIES, AND CYTOTOXIC ACTION AGAINST TAXOL.RESISTANT TUMOR CELLS", ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, VERLAG CHEMIE. WEINHEIM, DE, vol. 36, no. 19, 1997, pages 2097 - 2103, XP002064441, ISSN: 0570-0833
NICOLAOU K C ET AL: "Chemical Biology of Epothilones", ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, VERLAG CHEMIE. WEINHEIM, DE, vol. 37, no. 15, August 1998 (1998-08-01), pages 2014 - 2045, XP002131418, ISSN: 0570-0833
NICOLAOU K C ET AL: "SYNTHESIS AND BIOLOGICAL PROPERTIES OF C12,13-CYCLOPROPYL-EPOTHILONE A AND RELATED EPOTHILONES", CHEMISTRY AND BIOLOGY, CURRENT BIOLOGY, LONDON, GB, vol. 5, no. 7, July 1998 (1998-07-01), pages 365 - 372, XP008010169, ISSN: 1074-5521
JOHNSON J ET AL: "Synthesis, structure proof, and biological activity of epothilone cyclopropanes.", ORGANIC LETTERS. UNITED STATES 1 JUN 2000, vol. 2, no. 11, 1 June 2000 (2000-06-01), pages 1537 - 1540, XP002235574, ISSN: 1523-7060
NICOLAOU K C ET AL: "Synthesis and biological evaluation of 12,13-cyclopropyl and 12,13-cyclobutyl epothilones.", CHEMBIOCHEM: A EUROPEAN JOURNAL OF CHEMICAL BIOLOGY. GERMANY 8 JAN 2001, vol. 2, no. 1, 8 January 2001 (2001-01-08), pages 69 - 75, XP002235575, ISSN: 1439-4227
NICOLAOU K C ET AL: "Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. UNITED STATES 26 SEP 2001, vol. 123, no. 38, 26 September 2001 (2001-09-26), pages 9313 - 9323, XP002235576, ISSN: 0002-7863
NICOLAOU K C ET AL: "Total synthesis of 16-desmethylepothilone B, epothilone B10, epothilone F, and related side chain modified epothilone B analogues.", CHEMISTRY (WEINHEIM AN DER BERGSTRASSE, GERMANY) GERMANY 4 AUG 2000, vol. 6, no. 15, 4 August 2000 (2000-08-04), pages 2783 - 2800, XP002223256, ISSN: 0947-6539
NICOLAOU K C ET AL: "DESIGNED EPOTHILONES: COMBINATORIAL SYNTHESIS, TUBULIN ASSEMBLY PROPERTIES, AND CYTOTOXIC ACTION AGAINST TAXOL.RESISTANT TUMOR CELLS", ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, VERLAG CHEMIE. WEINHEIM, DE, vol. 36, no. 19, 1997, pages 2097 - 2103, XP002064441, ISSN: 0570-0833
NICOLAOU K C ET AL: "Chemical Biology of Epothilones", ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, VERLAG CHEMIE. WEINHEIM, DE, vol. 37, no. 15, August 1998 (1998-08-01), pages 2014 - 2045, XP002131418, ISSN: 0570-0833
NICOLAOU K C ET AL: "SYNTHESIS AND BIOLOGICAL PROPERTIES OF C12,13-CYCLOPROPYL-EPOTHILONE A AND RELATED EPOTHILONES", CHEMISTRY AND BIOLOGY, CURRENT BIOLOGY, LONDON, GB, vol. 5, no. 7, July 1998 (1998-07-01), pages 365 - 372, XP008010169, ISSN: 1074-5521
JOHNSON J ET AL: "Synthesis, structure proof, and biological activity of epothilone cyclopropanes.", ORGANIC LETTERS. UNITED STATES 1 JUN 2000, vol. 2, no. 11, 1 June 2000 (2000-06-01), pages 1537 - 1540, XP002235574, ISSN: 1523-7060
NICOLAOU K C ET AL: "Synthesis and biological evaluation of 12,13-cyclopropyl and 12,13-cyclobutyl epothilones.", CHEMBIOCHEM: A EUROPEAN JOURNAL OF CHEMICAL BIOLOGY. GERMANY 8 JAN 2001, vol. 2, no. 1, 8 January 2001 (2001-01-08), pages 69 - 75, XP002235575, ISSN: 1439-4227
NICOLAOU K C ET AL: "Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. UNITED STATES 26 SEP 2001, vol. 123, no. 38, 26 September 2001 (2001-09-26), pages 9313 - 9323, XP002235576, ISSN: 0002-7863
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