WO2010120854A1 - Composés chimiques - Google Patents

Composés chimiques Download PDF

Info

Publication number
WO2010120854A1
WO2010120854A1 PCT/US2010/030996 US2010030996W WO2010120854A1 WO 2010120854 A1 WO2010120854 A1 WO 2010120854A1 US 2010030996 W US2010030996 W US 2010030996W WO 2010120854 A1 WO2010120854 A1 WO 2010120854A1
Authority
WO
WIPO (PCT)
Prior art keywords
dihydroindazolo
mmol
benzoxazepin
substituted
pyrimidinamine
Prior art date
Application number
PCT/US2010/030996
Other languages
English (en)
Inventor
Jeffrey Michael Axten
Gerald Patrick Brady, Jr.
Timothy Francis Gallagher
Dirk A. Heerding
Jesus Raul Medina
Stuart Paul Romeril
Original Assignee
Glaxosmithkline Llc
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 Glaxosmithkline Llc filed Critical Glaxosmithkline Llc
Publication of WO2010120854A1 publication Critical patent/WO2010120854A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • C07D487/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems

Definitions

  • R , R and R are each independently selected from: hydrogen, C-
  • 18 R is selected from: aryl, substituted aryl, heteroaryl, substituted heteroaryl,
  • R201 are eac h independently selected from: hydrogen, C-
  • Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R * , R * )-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Non-receptor tyrosine kinases which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases.
  • Non-receptor tyrosine kinases for use in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • Such non- receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S. J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15: 371-404.
  • C1 is the average control value obtained for DMSO only
  • the chemiluminescent signal was allowed to develop at room temperature for 10 minutes following which luminescence was measured using in an Envision plate reader (Wallac/ Perkin Elmer, Waltham, MA). Cell growth was expressed as a percentage of the cells in the DMSO control wells, and
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, suitably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular PDK1 inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.

Abstract

L'invention porte sur des dérivés d'indazole substitués. De façon spécifique, l'invention porte sur des composés représentés par la Formule I : dans laquelle R1 - R6 et X sont tels que définis dans la description. Les composés de l'invention sont des inhibiteurs de PDK1 et peuvent être utiles pour le traitement de troubles caractérisés par des ACG kinases à activation constitutive, tels que le cancer et, plus spécifiquement, la leucémie et les cancers du sein, du côlon et du poumon. En conséquence, l'invention porte également sur des compositions pharmaceutiques comprenant un composé de l'invention. L'invention porte également sur des procédés d'inhibition de l'activité PDK1 et le traitement de troubles associés à celle-ci à l'aide d'un composé de l'invention ou d'une composition pharmaceutique comprenant un composé de l'invention.
PCT/US2010/030996 2009-04-15 2010-04-14 Composés chimiques WO2010120854A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16947709P 2009-04-15 2009-04-15
US61/169,477 2009-04-15

Publications (1)

Publication Number Publication Date
WO2010120854A1 true WO2010120854A1 (fr) 2010-10-21

Family

ID=42982826

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/030996 WO2010120854A1 (fr) 2009-04-15 2010-04-14 Composés chimiques

Country Status (1)

Country Link
WO (1) WO2010120854A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015069752A1 (fr) * 2013-11-05 2015-05-14 The Regents Of The University Of California Ligands de protéine de liaison à l'acétylcholine, modulateurs nachr coopérants et procédés de fabrication et d'utilisation
CN104725322A (zh) * 2015-02-16 2015-06-24 同济大学 一种2-胺基嘧啶类化合物及其制备方法
US9072731B2 (en) 2011-02-23 2015-07-07 Lupin Limited Heteroaryl derivatives as alpha7 nAChR modulators
CN105732516A (zh) * 2016-03-09 2016-07-06 哈尔滨医科大学 一种合成mth1蛋白抑制剂th287的方法
US9388196B2 (en) 2012-03-06 2016-07-12 Lupin Limited Thiazole derivatives as alpha 7 nAChR modulators
WO2017015152A1 (fr) 2015-07-17 2017-01-26 Memorial Sloan-Kettering Cancer Center Thérapie combinée utilisant des inhibiteurs de pdk1 et de pi3k
CN107721991A (zh) * 2017-11-17 2018-02-23 南方医科大学中西医结合医院 一种6‑(嘧啶‑4‑基)‑1h‑吲唑衍生物及其制备方法和应用
WO2018065768A1 (fr) * 2016-10-05 2018-04-12 Mission Therapeutics Limited Hétérocycles cyano-substitués présentant une activité en tant qu'inhibiteurs de l'usp30
WO2020028482A1 (fr) * 2018-07-31 2020-02-06 The Trustees Of The University Of Pennsylvania Petites molécules qui sensibilisent des cellules infectées par le vih-1 à une cytotoxicité cellulaire dépendante des anticorps
CN114702453A (zh) * 2022-03-29 2022-07-05 江西师范大学 11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3505315A (en) * 1968-04-12 1970-04-07 American Home Prod 5,7-dihydro-6-oxo-6h-indazolo(2,3-d)(1,4) benzodiazepines-12-sulfonamides
US5958953A (en) * 1996-06-27 1999-09-28 Pfizer Inc Substituted indazole derivatives
US20060004043A1 (en) * 2003-11-19 2006-01-05 Bhagwat Shripad S Indazole compounds and methods of use thereof
US7041687B2 (en) * 2002-01-25 2006-05-09 Vertex Pharmaceuticals Incorporated Indazole compounds useful as protein kinase inhibitors
US20070129404A1 (en) * 2003-10-15 2007-06-07 Masahiko Hagihara Novel indazole derivatives
US20070281933A1 (en) * 2004-06-24 2007-12-06 Smithkline Beecham Corporation Novel Indazole Carboxamides And Their Use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3505315A (en) * 1968-04-12 1970-04-07 American Home Prod 5,7-dihydro-6-oxo-6h-indazolo(2,3-d)(1,4) benzodiazepines-12-sulfonamides
US5958953A (en) * 1996-06-27 1999-09-28 Pfizer Inc Substituted indazole derivatives
US7041687B2 (en) * 2002-01-25 2006-05-09 Vertex Pharmaceuticals Incorporated Indazole compounds useful as protein kinase inhibitors
US20070129404A1 (en) * 2003-10-15 2007-06-07 Masahiko Hagihara Novel indazole derivatives
US20060004043A1 (en) * 2003-11-19 2006-01-05 Bhagwat Shripad S Indazole compounds and methods of use thereof
US20070281933A1 (en) * 2004-06-24 2007-12-06 Smithkline Beecham Corporation Novel Indazole Carboxamides And Their Use

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9072731B2 (en) 2011-02-23 2015-07-07 Lupin Limited Heteroaryl derivatives as alpha7 nAChR modulators
US9393247B2 (en) 2011-02-23 2016-07-19 Lupin Limited Heteroaryl derivatives as alpha7 nAChR modulators
US9388196B2 (en) 2012-03-06 2016-07-12 Lupin Limited Thiazole derivatives as alpha 7 nAChR modulators
WO2015069752A1 (fr) * 2013-11-05 2015-05-14 The Regents Of The University Of California Ligands de protéine de liaison à l'acétylcholine, modulateurs nachr coopérants et procédés de fabrication et d'utilisation
CN104725322A (zh) * 2015-02-16 2015-06-24 同济大学 一种2-胺基嘧啶类化合物及其制备方法
WO2017015152A1 (fr) 2015-07-17 2017-01-26 Memorial Sloan-Kettering Cancer Center Thérapie combinée utilisant des inhibiteurs de pdk1 et de pi3k
US11696924B2 (en) 2015-07-17 2023-07-11 Memorial Sloan-Kettering Cancer Center Combination therapy using PDK1 and PI3K inhibitors
CN105732516A (zh) * 2016-03-09 2016-07-06 哈尔滨医科大学 一种合成mth1蛋白抑制剂th287的方法
WO2018065768A1 (fr) * 2016-10-05 2018-04-12 Mission Therapeutics Limited Hétérocycles cyano-substitués présentant une activité en tant qu'inhibiteurs de l'usp30
CN109803963A (zh) * 2016-10-05 2019-05-24 特殊治疗有限公司 具有usp30抑制剂活性的氰基取代的杂环
CN109803963B (zh) * 2016-10-05 2022-04-26 特殊治疗有限公司 具有usp30抑制剂活性的氰基取代的杂环
US11370784B2 (en) 2016-10-05 2022-06-28 Mission Therapeutics Limited Cyano-substituted heterocycles with activity as inhibitors of USP30
CN107721991A (zh) * 2017-11-17 2018-02-23 南方医科大学中西医结合医院 一种6‑(嘧啶‑4‑基)‑1h‑吲唑衍生物及其制备方法和应用
WO2020028482A1 (fr) * 2018-07-31 2020-02-06 The Trustees Of The University Of Pennsylvania Petites molécules qui sensibilisent des cellules infectées par le vih-1 à une cytotoxicité cellulaire dépendante des anticorps
CN114702453A (zh) * 2022-03-29 2022-07-05 江西师范大学 11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物及其制备方法
CN114702453B (zh) * 2022-03-29 2024-02-02 江西师范大学 11-(三氟甲基)-二苯并[b,e][1,4]二氮杂卓系列化合物及其制备方法

Similar Documents

Publication Publication Date Title
EP2549868B1 (fr) Composés chimiques
JP5634995B2 (ja) 化学化合物
AU2010306653B2 (en) Combination
JP5743897B2 (ja) 化合物
WO2010120854A1 (fr) Composés chimiques
US8598156B2 (en) Chemical compounds
EP2173354A1 (fr) Dérivés des quinoxalines utilisés comme inhibiteurs des pi3-kinases
WO2005011700A1 (fr) Inhibiteurs de l'activite de akt
WO2012061557A2 (fr) Composés chimiques
WO2013028263A1 (fr) Dérivés pyrazolopyrimidines en tant qu'inhibiteurs de pi3 kinase
US9084794B2 (en) Fatty acid synthase inhibitors
WO2013095761A1 (fr) Dérivés d'imidizopyridine comme inhibiteurs de la pi3 kinase
EP2663311A2 (fr) Dérivés de pyrimidinone en tant qu'inhibiteurs de l'acide gras synthase
WO2015056180A1 (fr) Dérivés d'indoline utilisés comme inhibiteurs de perk
AU2013334599A1 (en) Combination
JP5554833B2 (ja) Ｐｉ３キナーゼ阻害剤としてのチアゾロピリミジノン誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10765068

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10765068

Country of ref document: EP

Kind code of ref document: A1