WO2002092578A1 - Derives de quinazoline - Google Patents

Derives de quinazoline Download PDF

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Publication number
WO2002092578A1
WO2002092578A1 PCT/GB2002/002124 GB0202124W WO02092578A1 WO 2002092578 A1 WO2002092578 A1 WO 2002092578A1 GB 0202124 W GB0202124 W GB 0202124W WO 02092578 A1 WO02092578 A1 WO 02092578A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
group
hydroxy
formula
amino
Prior art date
Application number
PCT/GB2002/002124
Other languages
English (en)
Inventor
Laurent Francois Andre Hennequin
Patrick Ple
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
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 Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2002092578A1 publication Critical patent/WO2002092578A1/fr

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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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Non-receptor tyrosine kinases include the Src family such as the Src, Lyn, Fyn and Yes tyrosine kinases, the Abl family such as Abl and Arg and the Jak family such as Jak 1 and Tyk 2.
  • X 4 is a direct bond or is selected from O, N(R 8 ), CON(R 8 ), N(R 8 )CO and C(R 8 ) 2 O, wherein R 8 is hydrogen or (l-6C)alkyl, and Q 2 is heteroaryl, heteroaryl-(l-6C)alkyl, heterocyclyl or heterocyclyl-(l-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, hydroxy, amino, carbamoyl, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl and (2-6C
  • R 1 is hydrogen or methoxy and R 2 is a group of the formula : Q ⁇ X 1 - wherein X 1 is selected from O, NH, CONH, NHCO and OCH 2 and Q 1 is 2-thienyl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-
  • X 1 is selected from O, NH, CONH, NHCO and OCH 2 and Q 1 is 2-thienyl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 2-, 3- or 4-pyridyl, 2-imidazol-l-ylethyl, 3-imidazol-l-ylpropyl, 2-(l,2,3-triazolyl)ethyl, 3-(l,2,3-triazolyl)propyl, 2-(l,2,4-triazolyl)ethyl, 3-(l,2,4-triazolyl)propyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3- or 4-pyridyl)ethyl, 3-(2-, 3- or 4-pyridyl)propyl, 2-(2-, 3- or 4-pyridyloxy)ethyl, 3-(2-, 3- or 4-pyridyl,
  • R is methoxy and R is 3 -pyrrolidin- 1 -ylpropoxy, 2-hydroxy-3-pyrrolidin- 1 -ylpropoxy, 3-morpholinopropoxy, 2-hydroxy-3-morpholinopropoxy,
  • a suitable displaceable group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • the following assays can be used to measure the effects of the compounds of the present invention as c-Src tyrosine kinase inhibitors, as inhibitors in vitro of the proliferation of c-Src transfected fibroblast cells, as inhibitors in vitro of the migration of A549 human lung tumour cells and as inhibitors in vivo of the growth in nude mice of xenografts of A549 tissue.
  • This assay determines the ability of a test compound to inhibit the migration of adherent mammalian cell lines, for example the human tumour cell line A549.
  • N-tert-butoxycarbonyl-4-(4-toluenesulphonyloxymethyl)piperidine (76.7 g); NMR Spectrum: (CDC1 3 ) 1.0-1.2 (m, 2H), 1.45 (s, 9H), 1.65 (d, 2H), 1.75-1.9 (m, 2H), 2.45 (s, 3H), 2.55-2.75 (m, 2H), 3.85 (d, 1H), 4.0-4.2 (br s, 2H), 7.35 (d, 2H), 7.8 (d, 2H). A portion (40 g) of the material so obtained was added to a suspension of ethyl
  • Compound X the active ingredient being termed "Compound X"

Abstract

L'invention porte sur des dérivés de quinazoline représentés par la formule I dans laquelle R?1, R2, Ra et Rb¿ peuvent avoir n'importe quelle signification définie dans la description. L'invention porte aussi sur des procédés de préparation, sur des compositions pharmaceutiques les contenant et sur leur utilisation dans la fabrication d'un médicament utilisé en tant qu'agent anti-invasif dans le confinement et/ou le traitement des tumeurs solides.
PCT/GB2002/002124 2001-05-14 2002-05-08 Derives de quinazoline WO2002092578A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP01401222.3 2001-05-14
EP01401222 2001-05-14

Publications (1)

Publication Number Publication Date
WO2002092578A1 true WO2002092578A1 (fr) 2002-11-21

Family

ID=8182725

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/002124 WO2002092578A1 (fr) 2001-05-14 2002-05-08 Derives de quinazoline

Country Status (1)

Country Link
WO (1) WO2002092578A1 (fr)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004056801A1 (fr) * 2002-12-23 2004-07-08 Astrazeneca Ab Derives quinazoliniques
WO2004081000A1 (fr) * 2003-03-10 2004-09-23 Astrazeneca Ab Dérivés quinazoliniques
US6849625B2 (en) 2000-10-13 2005-02-01 Astrazeneca Ab Quinazoline derivatives with anti-tumour activity
WO2005026150A1 (fr) * 2003-09-16 2005-03-24 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de la tyrosine kinase
WO2005030757A1 (fr) * 2003-09-25 2005-04-07 Astrazeneca Ab Derives de quinazoline
US6939866B2 (en) 2000-10-13 2005-09-06 Astrazeneca Ab Quinazoline derivatives
WO2006044351A2 (fr) 2004-10-12 2006-04-27 Certain Teed Corporation Isolant fibreux presentant un fongicide
US7141577B2 (en) 2001-04-19 2006-11-28 Astrazeneca Ab Quinazoline derivatives
US7148230B2 (en) 2003-07-29 2006-12-12 Astrazeneca Ab Quinazoline derivatives
US7462623B2 (en) 2002-11-04 2008-12-09 Astrazeneca Ab Quinazoline derivatives as Src tyrosine kinase inhibitors
US7632840B2 (en) 2004-02-03 2009-12-15 Astrazeneca Ab Quinazoline compounds for the treatment of hyperproliferative disorders
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7772243B2 (en) 2004-05-06 2010-08-10 Warner-Lambert Company Llc 4-phenylamino-quinazolin-6-yl-amides
CN1882567B (zh) * 2003-09-16 2010-12-15 阿斯利康(瑞典)有限公司 用作酪氨酸激酶抑制剂的喹唑啉衍生物
US7910731B2 (en) 2002-03-30 2011-03-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US7998949B2 (en) 2007-02-06 2011-08-16 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
US8399461B2 (en) 2006-11-10 2013-03-19 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same
US8497369B2 (en) 2008-02-07 2013-07-30 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
WO2016016894A1 (fr) 2014-07-30 2016-02-04 Yeda Research And Development Co. Ltd. Milieux pour la culture de cellules souches pluripotentes
US9359332B2 (en) 2002-07-15 2016-06-07 Symphony Evolution, Inc. Processes for the preparation of substituted quinazolines
WO2020152686A1 (fr) 2019-01-23 2020-07-30 Yeda Research And Development Co. Ltd. Milieux de culture pour cellules souches pluripotentes
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11124482B2 (en) 2003-09-26 2021-09-21 Exelixis, Inc. C-met modulators and methods of use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999006378A1 (fr) * 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs irreversibles de tyrosines kinases
WO1999035146A1 (fr) * 1998-01-12 1999-07-15 Glaxo Group Limited Composes heteroaromatiques bicycliques agissant comme inhibiteurs de la tyrosine kinase
US5962458A (en) * 1995-12-18 1999-10-05 Zeneca Limited Substituted quinazolines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962458A (en) * 1995-12-18 1999-10-05 Zeneca Limited Substituted quinazolines
WO1999006378A1 (fr) * 1997-07-29 1999-02-11 Warner-Lambert Company Inhibiteurs irreversibles de tyrosines kinases
WO1999035146A1 (fr) * 1998-01-12 1999-07-15 Glaxo Group Limited Composes heteroaromatiques bicycliques agissant comme inhibiteurs de la tyrosine kinase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HENNEQUIN L F ET AL: "Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 42, 1999, pages 5369 - 5389, XP002164236, ISSN: 0022-2623 *

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6939866B2 (en) 2000-10-13 2005-09-06 Astrazeneca Ab Quinazoline derivatives
US6849625B2 (en) 2000-10-13 2005-02-01 Astrazeneca Ab Quinazoline derivatives with anti-tumour activity
USRE43098E1 (en) 2000-11-01 2012-01-10 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7141577B2 (en) 2001-04-19 2006-11-28 Astrazeneca Ab Quinazoline derivatives
US8343982B2 (en) 2002-03-30 2013-01-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds pharmaceutical compositions containing these compounds, their use and process for preparing the same
US7910731B2 (en) 2002-03-30 2011-03-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US10266518B2 (en) 2002-07-15 2019-04-23 Symphony Evolution, Inc. Solid dosage formulations of substituted quinazoline receptor-type kinase modulators and methods of use thereof
US9796704B2 (en) 2002-07-15 2017-10-24 Symphony Evolution, Inc. Substituted quinazolines as receptor-type kinase inhibitors
US9359332B2 (en) 2002-07-15 2016-06-07 Symphony Evolution, Inc. Processes for the preparation of substituted quinazolines
US7462623B2 (en) 2002-11-04 2008-12-09 Astrazeneca Ab Quinazoline derivatives as Src tyrosine kinase inhibitors
WO2004056801A1 (fr) * 2002-12-23 2004-07-08 Astrazeneca Ab Derives quinazoliniques
WO2004081000A1 (fr) * 2003-03-10 2004-09-23 Astrazeneca Ab Dérivés quinazoliniques
US7148230B2 (en) 2003-07-29 2006-12-12 Astrazeneca Ab Quinazoline derivatives
CN1882567B (zh) * 2003-09-16 2010-12-15 阿斯利康(瑞典)有限公司 用作酪氨酸激酶抑制剂的喹唑啉衍生物
KR101244524B1 (ko) * 2003-09-16 2013-03-19 아스트라제네카 아베 티로신 키나제 억제제로서의 퀴나졸린 유도체
WO2005026150A1 (fr) * 2003-09-16 2005-03-24 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de la tyrosine kinase
AU2004272348B2 (en) * 2003-09-16 2008-09-04 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
JP2007505872A (ja) * 2003-09-16 2007-03-15 アストラゼネカ アクチボラグ チロシンキナーゼ阻害剤としてのキナゾリン誘導体
JP4795952B2 (ja) * 2003-09-16 2011-10-19 アストラゼネカ アクチボラグ チロシンキナーゼ阻害剤としてのキナゾリン誘導体
JP2007506716A (ja) * 2003-09-25 2007-03-22 アストラゼネカ アクチボラグ キナゾリン誘導体
WO2005030757A1 (fr) * 2003-09-25 2005-04-07 Astrazeneca Ab Derives de quinazoline
US11124482B2 (en) 2003-09-26 2021-09-21 Exelixis, Inc. C-met modulators and methods of use
US7632840B2 (en) 2004-02-03 2009-12-15 Astrazeneca Ab Quinazoline compounds for the treatment of hyperproliferative disorders
US7772243B2 (en) 2004-05-06 2010-08-10 Warner-Lambert Company Llc 4-phenylamino-quinazolin-6-yl-amides
US8466165B2 (en) 2004-05-06 2013-06-18 Warner-Lambert Company Llc 4-phenylamino-quinazolin-6-yl-amides
US8623883B2 (en) 2004-05-06 2014-01-07 Warner-Lambert Company Llc 4-phenylamino-quinazolin-6-yl-amides
WO2006044351A2 (fr) 2004-10-12 2006-04-27 Certain Teed Corporation Isolant fibreux presentant un fongicide
US8399461B2 (en) 2006-11-10 2013-03-19 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same
US7998949B2 (en) 2007-02-06 2011-08-16 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
US8497369B2 (en) 2008-02-07 2013-07-30 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8772298B2 (en) 2008-02-07 2014-07-08 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
US9809549B2 (en) 2009-01-16 2017-11-07 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
US11091440B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)- N′-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide, and crystalline forms thereof for the treatment of cancer
US11091439B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US11098015B2 (en) 2009-01-16 2021-08-24 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11433064B2 (en) 2009-08-07 2022-09-06 Exelixis, Inc. Methods of using c-Met modulators
WO2016016894A1 (fr) 2014-07-30 2016-02-04 Yeda Research And Development Co. Ltd. Milieux pour la culture de cellules souches pluripotentes
WO2020152686A1 (fr) 2019-01-23 2020-07-30 Yeda Research And Development Co. Ltd. Milieux de culture pour cellules souches pluripotentes

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