WO1999065910A1 - Fused azepinone cyclin dependent kinase inhibitors - Google Patents

Fused azepinone cyclin dependent kinase inhibitors Download PDF

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Publication number
WO1999065910A1
WO1999065910A1 PCT/US1999/013579 US9913579W WO9965910A1 WO 1999065910 A1 WO1999065910 A1 WO 1999065910A1 US 9913579 W US9913579 W US 9913579W WO 9965910 A1 WO9965910 A1 WO 9965910A1
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WO
WIPO (PCT)
Prior art keywords
dihydro
benzazepin
indolo
bromo
group
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
PCT/US1999/013579
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English (en)
French (fr)
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WO1999065910A9 (en
Inventor
Daniel W. Zaharevitz
Rick Gussio
Ravi K. Jalluri
Edward A. Sausville
Conrad Kunick
Laurent Meijer
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US Department of Health and Human Services
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US Department of Health and Human Services
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 US Department of Health and Human Services filed Critical US Department of Health and Human Services
Priority to EP99928715A priority Critical patent/EP1086105B1/en
Priority to JP2000554735A priority patent/JP4555476B2/ja
Priority to CA002335115A priority patent/CA2335115C/en
Priority to DE69930120T priority patent/DE69930120T2/de
Priority to AU45714/99A priority patent/AU778735B2/en
Publication of WO1999065910A1 publication Critical patent/WO1999065910A1/en
Publication of WO1999065910A9 publication Critical patent/WO1999065910A9/en
Priority to US09/739,534 priority patent/US6610684B2/en
Anticipated expiration legal-status Critical
Priority to AU15009/01A priority patent/AU780528B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • cyclin dependent kinases cyclin dependent kinases
  • the regulatory subunit is necessary for activity and a number of proteins in this family have been described (cyclin A-cyclin H). Most cyclins can interact with more than one cdk and each known cyclin-cdk pair seems to have a distinct role in regulating the cell cycle.
  • Inhibitors of cdk5 should be useful in the treatment of the disease.
  • the potential role of cdk inhibitors in therapy of numerous diseases has led to efforts to find small molecules that inhibit all or some of the cdks.
  • Several small molecules have been discovered that inhibit cdks specifically. These include the purine analogs, olomoucine, roscovitine, and CVT-313; the flavonoid, flavopiridol; and butyrolactone I.
  • Other potent inhibitors of cdks are known, including staurosporine, UCN-01, and suramin, but these compounds also are potent inhibitors of other protein kinases.
  • CVT-313 is an effective inhibitor of neointimal proliferation in a rat restenosis model.
  • CVT-313 a Specific and Potent Inhibitor of CDK2 that Prevents Neointimal Proliferation, " J. Biol. Chem. , 272(46):29207-l l (1997).
  • Roscovitine has been reported to improve renal function in a rat model of glomerulonephritis, and to be an inhibitor of human cytomegalovirus replication in culture. Roscovitine also inhibits DNA synthesis in plasmodium falciparum, the malarial parasite.
  • [l]benzazepin-6(5H)-one is a known compound.
  • the effective amount should be as high as the subject can tolerate, but typically is from about 0.1 gram to about 3.0 grams of a compound, and from about 30 mg/kg of subject/dose to about 400 mg/kg of subject/dose, preferably from about 30 mg/kg of subject/dose to about 50 mg/kg of subject/dose.
  • FIG. 2 provides mean plots of data obtained by in vitro human tumor cell line screens for 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2- -f
  • FIG. 3 provides mean plots of data obtained by in vitro human tumor cell line screens for 9-bromo-7,12-dihydro-indolo[3,2-- ][l]benzazepin-6(5H)-one.
  • FIG. 5 provides mean plots of data obtained by in vitro human tumor cell line screens for 9-chloro-7,12-dihydro-indolo[3,2- ⁇ [l]benzazepin-6(5H)-one.
  • FIG. 10 provides mean plots of data obtained by in vitro human tumor cell line screens for 6-methylthio-7,12-dihydro-indolo[3,2-- ][l]benzazepine.
  • FIG. 17 provides mean plots of data obtained by in vitro human tumor cell line screens for 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2- d][l]benzazepin-2-yl)-acrylonitrile.
  • FIG. 27 provides mean plots of data obtained by in vitro human tumor cell line screens for 2-iodo-7,12-dihydro-indolo[3,2-t/][l]benzazepin-6(5H)-one.
  • FIG. 31 provides graphs illustrating in vitro time course assays for 9-nitro- 7 , 12-dihydro-indolo[3 , 2-d] [ 1 ]benzazepin-6(5H)-one .
  • A is oxygen or sulfur coupled to the B ring by a single bond or a double bond, generally a double bond.
  • R2 is selected from the group consisting of hydrogen, acyl, aliphatic substituents, particularly alkyl, alkenyl and alkinyl substituents, even more particularly lower alkyl substituents, cyano, nitro, aryl, and lower alkyl ester, preferably hydrogen.
  • the enzyme inhibition activity of compounds of the present invention have been assayed by Dr. Larent Meijer of CNRS, Roscoff, France, using his cdk inhibition assay.
  • the assay is described by V. Rialet's and L. Meijer's "A Screening Test for Antimitotic Compounds Using the Universal M Phase-specific Protein Kinase, p34 ⁇ - c2 /Cyclin b cdc13 , Affinity-Immobilized on ⁇ l3sucl-Coated Microtitration Plates, " Anticancer Res. , 11(4): 1581-90 (1991), which is incorporated herein by reference. The results of these assays are provided below in Table 1.
  • Example 23 This example describes the synthesis of 2-iodo-9-t ⁇ fluoromethy 1-7, 12- dihydro-indolo[3,2-d][l]benzazepin-6(5H)-one.
  • Example 26 This example describes the synthesis of 2- (3 -oxo- 1 -butenyl) -9- trifluoromethyl- 7, 12-dihydro-indolo[3, 2-d][l]benzazepin-6(5H)-one.
  • This example describes a method for treating humans with the compounds of the present invention.
  • Compounds satisfying Formulas 1 and/or 2 are obtained. These compounds are then administered orally or intravenously to humans at a dose of from about 30 mg/kg of subject/dose up to about 400 mg/Kg of subject/dose, but preferably between about 30 mg/Kg of subject/dose to about 50 mg/kg of subject/dose, or to provide a total amount of compound or compounds to the subject per treatment of from about 0.1 gram to about 3 grams.
  • compositions are administered to provide a total amount of compound or compounds to the subject of from about 30 mg/kg of subject/dose up to about 400 mg/Kg of subject/dose, but preferably between about 30 mg/Kg of subject/dose to about 50 mg/kg of subject/dose, or to provide a total amount of compound or compounds to the subject per treatment of from about 0.1 gram to about 3 grams.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
PCT/US1999/013579 1998-06-16 1999-06-16 Fused azepinone cyclin dependent kinase inhibitors Ceased WO1999065910A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP99928715A EP1086105B1 (en) 1998-06-16 1999-06-16 Fused azepinone cyclin dependent kinase inhibitors
JP2000554735A JP4555476B2 (ja) 1998-06-16 1999-06-16 縮合アゼピノン型サイクリン依存性キナーゼ阻害物質
CA002335115A CA2335115C (en) 1998-06-16 1999-06-16 Fused azepinone cyclin dependent kinase inhibitors
DE69930120T DE69930120T2 (de) 1998-06-16 1999-06-16 Annellierte azepinone als inhibitoren cyclin-abhängiger kinasen
AU45714/99A AU778735B2 (en) 1998-06-16 1999-06-16 Fused azepinone cyclin dependent kinase inhibitors
US09/739,534 US6610684B2 (en) 1998-06-16 2000-12-14 Fused azepinone cyclin dependent kinase inhibitors
AU15009/01A AU780528B2 (en) 1999-06-16 2001-01-16 Fused azepinone cyclin dependent kinase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8961998P 1998-06-16 1998-06-16
US60/089,619 1998-06-16

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/739,534 Continuation-In-Part US6610684B2 (en) 1998-06-16 2000-12-14 Fused azepinone cyclin dependent kinase inhibitors

Publications (2)

Publication Number Publication Date
WO1999065910A1 true WO1999065910A1 (en) 1999-12-23
WO1999065910A9 WO1999065910A9 (en) 2000-03-16

Family

ID=22218651

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/013579 Ceased WO1999065910A1 (en) 1998-06-16 1999-06-16 Fused azepinone cyclin dependent kinase inhibitors

Country Status (8)

Country Link
US (1) US6610684B2 (https=)
EP (1) EP1086105B1 (https=)
JP (1) JP4555476B2 (https=)
AT (1) ATE318818T1 (https=)
AU (1) AU778735B2 (https=)
CA (1) CA2335115C (https=)
DE (1) DE69930120T2 (https=)
WO (1) WO1999065910A1 (https=)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2804959A1 (fr) * 2000-02-15 2001-08-17 Centre Nat Rech Scient Utilisation de derives de paullones pour la fabrication de medicaments
DE10260618A1 (de) * 2002-12-23 2004-07-08 Faustus Forschungs Cie. Translational Cancer Research Gmbh Tumorhemmende annellierte Azepinonderivate
WO2005107471A1 (en) * 2004-05-12 2005-11-17 Bayer Cropscience Gmbh Plant growth regulation
WO2006089874A1 (en) * 2005-02-22 2006-08-31 Gpc Biotech Ag Benzo[2,3]azepino[4,5-b]indol-6-ones
EP1757607A1 (en) 2005-08-24 2007-02-28 Molisa GmbH N5-substituted benzo¬2,3|azepino¬4,5-b|indol-6-ones for treating tropical diseases
US7393953B2 (en) 2002-04-04 2008-07-01 Enzon, Inc. Polymeric acyl derivatives of indoles
WO2009010298A3 (en) * 2007-07-18 2009-06-18 Univ Braunschweig Tech Carolo Wilhelmina Paullone derivatives and its use
WO2010114902A1 (en) * 2009-03-31 2010-10-07 Arqule, Inc. Substituted tetrahydropyrazolo-pyrido-azepin compounds
WO2011003988A1 (en) 2009-07-08 2011-01-13 INSERM (Institut National de la Santé et de la Recherche Médicale) A method for inducing extended self-renewal of functionally differentiated somatic cells

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FR2899107B1 (fr) * 2006-03-30 2008-06-13 Neurokin Entpr Unipersonnelle Utilisation de la (s)-roscovitine pour la fabrication d'un medicament
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
JP2012504646A (ja) * 2008-10-01 2012-02-23 ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル 選択的サイクリン依存性キナーゼ４／６阻害剤を用いた化学療法化合物に対する造血系の防護
CN102231983A (zh) * 2008-10-01 2011-11-02 北卡罗来纳大学查珀尔希尔分校 使用选择性细胞周期蛋白依赖性激酶4/6抑制剂对抗电离辐射的造血防护
EP3406260B1 (en) 2009-05-13 2020-09-23 The University of North Carolina at Chapel Hill Cyclin dependent kinase inhibitors and methods of use
WO2011003012A1 (en) * 2009-07-01 2011-01-06 Albany Molecular Research, Inc. Azinone-substituted azapolycycle mch-1 antagonists, methods of making, and use thereof
US8637501B2 (en) * 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US9073925B2 (en) * 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) * 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
WO2011112635A1 (en) 2010-03-08 2011-09-15 Sloan-Kettering Institute For Cancer Research Cdc7 kinase inhibitors and uses thereof
EP2640394A4 (en) 2010-11-17 2015-02-25 Univ North Carolina PROTECTION OF KIDNEY TISSUE FROM ISCHEMIA BY THE INHIBITION OF PROLEVERATIVE KINASES CDK4 AND CDK6
WO2012088038A2 (en) 2010-12-21 2012-06-28 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline mch-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
HK1222766A1 (zh) 2013-03-15 2017-07-14 G1治疗公司 高效的抗赘生剂和抗增生剂
DK2968290T3 (da) 2013-03-15 2019-11-25 G1 Therapeutics Inc Transient beskyttelse af normale celler under kemoterapi
WO2015161285A1 (en) 2014-04-17 2015-10-22 G1 Therapeutics, Inc. Tricyclic lactams for use in the protection of hematopoietic stem and progenitor cells against ionizing radiation
WO2016040858A1 (en) 2014-09-12 2016-03-17 G1 Therapeutics, Inc. Combinations and dosing regimes to treat rb-positive tumors
WO2016040848A1 (en) 2014-09-12 2016-03-17 G1 Therapeutics, Inc. Treatment of rb-negative tumors using topoisomerase inhibitors in combination with cyclin dependent kinase 4/6 inhibitors
EA201891170A1 (ru) 2015-11-18 2018-11-30 Джензим Корпорейшн Биомаркер поликистозной болезни почек и варианты его применения
US10988479B1 (en) 2020-06-15 2021-04-27 G1 Therapeutics, Inc. Morphic forms of trilaciclib and methods of manufacture thereof
WO2022104206A1 (en) * 2020-11-13 2022-05-19 Neuron23, Inc. Kinase modulators and methods of use thereof
EP4277897A1 (en) * 2021-01-12 2023-11-22 Chengdu Anticancer Bioscience, Ltd. Fused azepine compounds and their use in the treatment of cancer
US12258345B1 (en) 2023-12-12 2025-03-25 King Faisal University Pyrrolo[3,2-c]isoquinoline-2,3-dione compounds as CK2 inhibitors

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7232814B2 (en) 2000-02-15 2007-06-19 Centre National De La Recherche Scientifique (C.N.R.S.) Use of paullone derivatives for making medicines
WO2001060374A1 (fr) * 2000-02-15 2001-08-23 Centre National De La Recherche Scientifique (C.N.R.S.) Utilisation de derives de paullones pour la fabrication de medicaments
JP2003522793A (ja) * 2000-02-15 2003-07-29 サントル ナショナル デ ラ ルシェルシュ シィアンティフィク （セ．エヌ．エール．エス．） 製薬におけるパウロン誘導体の使用
FR2804959A1 (fr) * 2000-02-15 2001-08-17 Centre Nat Rech Scient Utilisation de derives de paullones pour la fabrication de medicaments
US7393953B2 (en) 2002-04-04 2008-07-01 Enzon, Inc. Polymeric acyl derivatives of indoles
DE10260618A1 (de) * 2002-12-23 2004-07-08 Faustus Forschungs Cie. Translational Cancer Research Gmbh Tumorhemmende annellierte Azepinonderivate
WO2004058766A3 (de) * 2002-12-23 2004-08-26 Faustus Forschungs Cie Tumorhemmende annellierte azepinonderivate
DE10260618B4 (de) * 2002-12-23 2005-06-09 Faustus Forschungs Cie. Translational Cancer Research Gmbh Tumorhemmende annellierte Azepinonderivate
EA013072B1 (ru) * 2004-05-12 2010-02-26 Байер Кропсайенс Аг Применение конденсированных производных азепинона для регулирования роста растений, композиция для регулирования роста растений и ее применение и способ регулирования роста растений
WO2005107471A1 (en) * 2004-05-12 2005-11-17 Bayer Cropscience Gmbh Plant growth regulation
AU2005239811B2 (en) * 2004-05-12 2010-06-17 Bayer Cropscience Ag Plant growth regulation
US7767664B2 (en) 2004-05-12 2010-08-03 Bayer Cropscience Ag Plant growth regulation
WO2006089874A1 (en) * 2005-02-22 2006-08-31 Gpc Biotech Ag Benzo[2,3]azepino[4,5-b]indol-6-ones
EP1757607A1 (en) 2005-08-24 2007-02-28 Molisa GmbH N5-substituted benzo¬2,3|azepino¬4,5-b|indol-6-ones for treating tropical diseases
WO2009010298A3 (en) * 2007-07-18 2009-06-18 Univ Braunschweig Tech Carolo Wilhelmina Paullone derivatives and its use
WO2010114902A1 (en) * 2009-03-31 2010-10-07 Arqule, Inc. Substituted tetrahydropyrazolo-pyrido-azepin compounds
US8049005B2 (en) 2009-03-31 2011-11-01 Arqule, Inc. Substituted tetrahydropyrazolo-pyrido-azepine compounds
US8293892B2 (en) 2009-03-31 2012-10-23 Arqule, Inc. Substituted tetrahydropyrazolo-pyrido-azepine compounds
WO2011003988A1 (en) 2009-07-08 2011-01-13 INSERM (Institut National de la Santé et de la Recherche Médicale) A method for inducing extended self-renewal of functionally differentiated somatic cells

Also Published As

Publication number Publication date
EP1086105A1 (en) 2001-03-28
CA2335115C (en) 2009-01-27
CA2335115A1 (en) 1999-12-23
DE69930120D1 (de) 2006-04-27
US20020042412A1 (en) 2002-04-11
AU4571499A (en) 2000-01-05
EP1086105B1 (en) 2006-03-01
ATE318818T1 (de) 2006-03-15
US6610684B2 (en) 2003-08-26
JP4555476B2 (ja) 2010-09-29
WO1999065910A9 (en) 2000-03-16
JP2002518395A (ja) 2002-06-25
DE69930120T2 (de) 2006-11-02
AU778735B2 (en) 2004-12-16

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