WO2008145398A1 - Dérivés de la 2-indoline substituée par 4-arylpyrrole, actifs en tant qu'inhibiteurs de protéine kinase - Google Patents

Dérivés de la 2-indoline substituée par 4-arylpyrrole, actifs en tant qu'inhibiteurs de protéine kinase Download PDF

Info

Publication number
WO2008145398A1
WO2008145398A1 PCT/EP2008/004342 EP2008004342W WO2008145398A1 WO 2008145398 A1 WO2008145398 A1 WO 2008145398A1 EP 2008004342 W EP2008004342 W EP 2008004342W WO 2008145398 A1 WO2008145398 A1 WO 2008145398A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
oxo
dihydro
carboxamide
indol
Prior art date
Application number
PCT/EP2008/004342
Other languages
English (en)
Inventor
Tiziano Bandiera
Andrea Lombardi Borgia
Paolo Paolucci
Christian Orrenius
Arturo Galvani
Original Assignee
Pfizer Italia S.R.L.
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 Pfizer Italia S.R.L. filed Critical Pfizer Italia S.R.L.
Publication of WO2008145398A1 publication Critical patent/WO2008145398A1/fr

Links

Classifications

    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • R 14 is hydrogen
  • R 3 is -(CH 2 ) n -CH(R 6 )-(CH 2 ) m R ⁇ ;
  • alkyl indicates a saturated aliphatic hydrocarbon radical, including straight chain and branched chain groups of 1 to 6 carbon atoms More preferably, an alkyl group has 1 to 4 carbon atoms
  • alkyl are, for instance, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, and tert-butyl 0
  • cycloalkyl indicates a 3 to 6-membered all-carbon monocyclic ring, which may contain one or more double bonds but does not have a completely conjugated ⁇ -electron system
  • Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, and cyclohexadiene.
  • trihalomethyl indicates a -CX 3 group wherein X is a halogen atom, as defined above
  • a compound of formula (VIIl) can be obtained from a compound of formula (X),
  • Starved cells were treated for 1 hour with desired doses of compounds and then stimulated for a further 2 hours with either 10 nM IGF-1 (Invitrogen Corp , CA, USA), 10 nM EGF (Gibco BRL 1 USA) or 1 nM PDGF-B/B (Roche Diagnostics GmbH, Germany) Cells were then fixed in PBS/37% paraformaldehyde for 20 minutes at room temperature, washed X2 with PBS, and permeabilized with PBS/0 3% Triton X-100 for 15 minutes Wells were then saturated with PBS/1% non-fat dry milk (Bio-Rad Laboratories, Hercules, CA 1 USA) for 1 hour, and then probed for 1 hour at 37°C with anti-phospho-S6 (Ser 235/236) antibody (Cell Signaling Technology, Beverly, MA, USA, cat #2211) at 1/200 dilution in PBS/1% milk/03% Tween 20 Wells were then washed twice with PBS, and in
  • the substrate used in the assay was a peptide of the following sequence: K V V E E I0 N G N N Y V Y I D P T Q L P Y D H K W E F P R N R
  • the peptide was obtained in batches of >95% peptide purity from American Peptide Company, lnc (Sunnyvale, CA, USA).
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e g , sterile water, olive oil, ethyl oleate, glycols, e g , propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e g , sterile water, olive oil, ethyl oleate, glycols, e g , propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.
  • the title compound can be obtained starting from 1-tert-butyl 3- ethyl 5-formyl-4-(2-methoxyphenyl)-2-methyl-1H-pyrrole-1 ,3-dicarboxylate according to the following procedure: A mixture of 1-tert-butyl 3-ethyl 5-formyl-4-(2-methoxyphenyl)-2-methyl- 1H-pyrrole-1,3-dicarboxylate (75 3 mg, 0 194 mmol ) in ethanol (1 mL) and 20% KOH (10 mL) was refiuxed for 1h The cooled reaction mixture was acidified to pH 3 with 2N HCI 1 and extracted with AcOEt (3x15 mL) The organic phases were combined, washed with water (2x15 mL), dried on anhydrous Na 2 SCi 1 filtered and evaporated to dryness to give 59 mg (85% yield) of the desired product as white solid ESI(+) MS: m/z 519 (2M+H),

Abstract

La présente invention porte sur certains composés de la formule (I) de 2-indolinone substituée par 4-arylpyrrole, qui modulent l'activité de protéine kinase (PK). Les composés de cette invention s'utilisent par conséquent dans le traitement de troubles associés à une activité de PK dérégulée. La présente invention porte également sur des procédés pour préparer ces composés, sur des compositions pharmaceutiques comportant ces composés, et sur des procédés de traitement de maladies utilisant des compositions pharmaceutiques comportant ces composés.
PCT/EP2008/004342 2007-06-01 2008-05-31 Dérivés de la 2-indoline substituée par 4-arylpyrrole, actifs en tant qu'inhibiteurs de protéine kinase WO2008145398A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US93260207P 2007-06-01 2007-06-01
US60/932,602 2007-06-01

Publications (1)

Publication Number Publication Date
WO2008145398A1 true WO2008145398A1 (fr) 2008-12-04

Family

ID=39739660

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/004342 WO2008145398A1 (fr) 2007-06-01 2008-05-31 Dérivés de la 2-indoline substituée par 4-arylpyrrole, actifs en tant qu'inhibiteurs de protéine kinase

Country Status (1)

Country Link
WO (1) WO2008145398A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010098866A1 (fr) 2009-02-27 2010-09-02 Supergen, Inc. Inhibiteurs cyclopentathiophène/cyclohexathiophène de l'adn méthyltransférase
US8906900B2 (en) 2012-12-21 2014-12-09 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8940726B2 (en) 2012-12-21 2015-01-27 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8993555B2 (en) 2012-12-21 2015-03-31 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9221794B2 (en) 2012-12-21 2015-12-29 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9365555B2 (en) 2012-12-21 2016-06-14 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10653693B2 (en) 2014-08-04 2020-05-19 Epizyme, Inc. PRMT5 inhibitors and uses thereof
IT202100019526A1 (it) * 2021-07-22 2023-01-22 Simona Rapposelli Modulatori di proteine 14-3-3 come agenti antitumorali

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060814A2 (fr) * 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2002066463A1 (fr) * 2001-02-15 2002-08-29 Pharmacia & Upjohn Company Derives de 3-(4-amidopyrrol-2-ylmethlidene)-2-indolinone utilises comme inhibiteurs de la proteine kinase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060814A2 (fr) * 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2002066463A1 (fr) * 2001-02-15 2002-08-29 Pharmacia & Upjohn Company Derives de 3-(4-amidopyrrol-2-ylmethlidene)-2-indolinone utilises comme inhibiteurs de la proteine kinase

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010098866A1 (fr) 2009-02-27 2010-09-02 Supergen, Inc. Inhibiteurs cyclopentathiophène/cyclohexathiophène de l'adn méthyltransférase
US9732072B2 (en) 2012-12-21 2017-08-15 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10980794B2 (en) 2012-12-21 2021-04-20 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8993555B2 (en) 2012-12-21 2015-03-31 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9221794B2 (en) 2012-12-21 2015-12-29 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9266836B2 (en) 2012-12-21 2016-02-23 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9365555B2 (en) 2012-12-21 2016-06-14 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9365519B2 (en) 2012-12-21 2016-06-14 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9388173B2 (en) 2012-12-21 2016-07-12 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9604930B2 (en) 2012-12-21 2017-03-28 Epizyme, Inc. Tetrahydro- and dihydro-isoquinoline PRMT5 inhibitors and uses thereof
US9611257B2 (en) 2012-12-21 2017-04-04 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9675614B2 (en) 2012-12-21 2017-06-13 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US8940726B2 (en) 2012-12-21 2015-01-27 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9777008B2 (en) 2012-12-21 2017-10-03 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9765068B2 (en) 2012-12-21 2017-09-19 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US9745291B2 (en) 2012-12-21 2017-08-29 Epizyme, Inc. PRMT5 inhibitors containing a dihydro- or tetrahydroisoquinoline and uses thereof
US9908887B2 (en) 2012-12-21 2018-03-06 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10118918B2 (en) 2012-12-21 2018-11-06 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10150758B2 (en) 2012-12-21 2018-12-11 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10307413B2 (en) 2012-12-21 2019-06-04 Epizyme, Inc. Tetrahydro- and dihydro-isoquinoline PRMT5 inhibitors and uses thereof
US10391089B2 (en) 2012-12-21 2019-08-27 Epizyme, Inc. PRMT5 inhibitors and uses therof
US8906900B2 (en) 2012-12-21 2014-12-09 Epizyme, Inc. PRMT5 inhibitors and uses thereof
US10653693B2 (en) 2014-08-04 2020-05-19 Epizyme, Inc. PRMT5 inhibitors and uses thereof
IT202100019526A1 (it) * 2021-07-22 2023-01-22 Simona Rapposelli Modulatori di proteine 14-3-3 come agenti antitumorali
WO2023001942A1 (fr) * 2021-07-22 2023-01-26 Simona Rapposelli Modulateurs de la protéine 14-3-3 à titre d'agents antitumoraux

Similar Documents

Publication Publication Date Title
WO2008145398A1 (fr) Dérivés de la 2-indoline substituée par 4-arylpyrrole, actifs en tant qu'inhibiteurs de protéine kinase
JP5506674B2 (ja) キナーゼ阻害剤として活性な置換インダゾール誘導体
US8592463B2 (en) Hedgehog pathway antagonists and therapeutic applications thereof
JP5065034B2 (ja) キナーゼ阻害剤として適しているｎ，ｎ’−ジフェニル尿素誘導体
AU2006326063B2 (en) Substituted pyrrolo-pyrazole derivatives active as kinase inhibitors
US20090318446A1 (en) 4-(1H-Indol-3-yl)-Pyrimidin-2-Ylamine Derivatives and Their Use in Therapy
US8835648B2 (en) Hedgehog pathway antagonists and therapeutic applications thereof
JP2003532635A (ja) キナーゼ阻害薬
WO2008074749A9 (fr) Dérivés de l'indazole en tant qu'inhibiteurs des kinases pour le traitement du cancer
MX2007000735A (es) Derivados de urea ciclicos sustituidos con heterociclo, preparacion de los mismos y uso farmaceutico de los mismos como inhibidores de quinasa.
WO2010069966A1 (fr) Dérivés d'indazole substitués actifs en tant qu'inhibiteurs de kinases
AU2006278862A1 (en) Pyrazole derivatives having tyrosinkinase activity
JP5250432B2 (ja) キナーゼ阻害剤として活性なビシクロピラゾール
KR20080087851A (ko) 신규한 시클릭 우레아 유도체, 그의 제조법 및 키나제억제제로서의 그의 제약 용도
JP2023513854A (ja) 大環状化合物およびその使用
JP7066644B2 (ja) がんの処置のための化合物および組成物
EA030564B1 (ru) СОЕДИНЕНИЯ, СОДЕРЖАЩИЕ СИСТЕМУ 1,1',2,5'-ТЕТРАГИДРОСПИРО[ИНДОЛ-3,2'-ПИРРОЛ]-2,5'-ДИОНА В КАЧЕСТВЕ ИНГИБИТОРОВ БЕЛОК-БЕЛКОВОГО ВЗАИМОДЕЙСТВИЯ p53-Mdm2
JP5730855B2 (ja) イミダゾリジン−２，４−ジオン誘導体及びそれらの医薬製造のための利用
KR20060132965A (ko) 타이로신 키나아제 억제제로서의 이미다졸 유도체
WO2020224607A1 (fr) Inhibiteur d'ezh2 et son utilisation
MX2011007054A (es) Derivados de 2-il-pirazol-3(2h)-ona, su preparacion y su aplicacion en terapeutica como activadores de hif.
US7943654B2 (en) 1H-thieno[2,3-c]pyrazole compounds useful as kinase inhibitors
KR102467724B1 (ko) Brd4억제제
BRPI1015913A2 (pt) derivados de (6-oxo-1,6-di-hidro-pirimidin-2-il)-amida, o respectivo preparo e a respectiva utilização farmacêutica como inibidores de fosforilação de akt (pkb)
VARELIO et al. eT TTTTT

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: 08758912

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: 08758912

Country of ref document: EP

Kind code of ref document: A1