WO2009137499A1 - Inhibiteurs de l'histone désacétylase - Google Patents

Inhibiteurs de l'histone désacétylase Download PDF

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Publication number
WO2009137499A1
WO2009137499A1 PCT/US2009/042869 US2009042869W WO2009137499A1 WO 2009137499 A1 WO2009137499 A1 WO 2009137499A1 US 2009042869 W US2009042869 W US 2009042869W WO 2009137499 A1 WO2009137499 A1 WO 2009137499A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
independently selected
oxazepin
cycloalkyl
Prior art date
Application number
PCT/US2009/042869
Other languages
English (en)
Inventor
Richard Chesworth
Gideon Shapiro
Patrick Beaulieu
Yves Chantigny
John Mancuso
Robert Deziel
Silvana Leit
Pierre Tessier
David Smil
Original Assignee
Envivo Pharmaceuticals, Inc.
Methylgene Inc.
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 Envivo Pharmaceuticals, Inc., Methylgene Inc. filed Critical Envivo Pharmaceuticals, Inc.
Publication of WO2009137499A1 publication Critical patent/WO2009137499A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/16—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
    • C07D498/04—Ortho-condensed systems

Definitions

  • Compounds of the invention may be formulated by any method known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • compounds of the invention are administered intravenously in a hospital setting.
  • administration may preferably be by the oral route.
  • the compositions may be in any form, including but not limited to, liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops or aerosols.
  • the compositions of the may be administered systemically or locally.
  • the disclosure provides compound of the formula (II)
  • the disclosure provides a composition comprising a compound according to the first aspect or a preferred embodiment thereof and a pharmaceutically acceptable carrier.
  • D 3 is -O-.
  • D la -D 2a is ;
  • D 3 is -O-
  • D la -D 2a is ! or / &, or ; Where * indicates the point of attachment to Q and B 1 the point of attachment to
  • DD laa --DD 2aa i iss 1 K ⁇
  • V ⁇ -- WW i iss pyridyl and is phenyl, wherein the phenyl and pyridyl are independently optionally and substituted.
  • R 150 and R 160 are independently selected from the group consisting of H, OH, halo, -CN, -CF 3 , -OCF 3 , -Ci-C 4 alkyl, -Ci-C 4 alkoxyl, -O-C 2 -C 4 alkyl-O-R 53 , -OR 53 , -C 0 - C 4 alkyl-S(0)o- 2 -R 53 , -Co-Cealkyl-cycloalkyl, -NH 2 , -NR 50 R 51 , -C r C 4 alkyl- NR 50 R 51 and -O-C 2 -C 4 alkyl-NR 50 R 51 .
  • hydrocarbyl refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein.
  • a “Co” hydrocarbyl is used to refer to a covalent bond.
  • “Co-C 3 -hydrocarbyl” includes a covalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.
  • cycloalkyl is intended to mean a saturated or unsaturated mono-, bi, tri- or poly-cyclic hydrocarbon group having about 3 to 15 carbons, preferably having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons. In certain preferred embodiments, the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group.
  • Preferred cycloalkyl groups include, without limitation, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • the heterocyclic group is a bridged heterocyclic group, preferably a C 6 -CiO bridged bicyclic group, wherein one or more carbon atoms are independently replaced by a heteroatom selected from the group consisting of N, O and S.
  • the bridged heterocyclic group is a C 6 bridged bicyclic group.
  • the bridged heterocyclic group is a C 7 bridged bicyclic group.
  • the bridged heterocyclic group is a Cs bridged bicyclic group.
  • the bridged heterocyclic group is a C9 bridged bicyclic.
  • heterocyclic groups include l,2,3,4-tetrahydro-2,6-naphthyridyl, 1,2,3,4-tetrahydro- 2,7-naphthyridyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridyl, 4,5,6,7-tetrahydro- lH-pyrazolo[3,4-c]pyridyl , 4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridyl , 4,5,6,7- tetrahydro-lH-pyrrolo[2,3-c]pyridyl , 4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridyl , 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl , 4,5,6,7-tetrahydrofuro
  • hydrocarbyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aromatic polycycle, non- aromatic polycycle, polyheteroaryl, non-aromatic polyheterocyclic and mixed aryl and non-aryl polyheterocycle groups are substituted with from 1 to 3 independently selected substituents.
  • substituents on ring groups such as aryl, heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy and alkyl.
  • Preferred substituents on aromatic polycycles include, but are not limited to, oxo, Ci-C ⁇ alkyl, cycloalkylalkyl (e.g.
  • Step 2 ethyl 4-(1OJ l-dihydrodibenzo
  • Title compound 4 was dissolved in ethanol (25 niL) and THF (5 niL).
  • Platinum (IV) oxide (0.075 g, 10% wt) was added. The mixture was stirred at room temperature for 3 h under 1 atmosphere of hydrogen. The catalyst was filtered and the filtrate was concentrated under reduced pressure to one third volume. The precipitate was filtered to afford title compound 5 (510 mg, 67%) as a white solid.
  • Step 1 ethyl 4-(10-methyl-10,l l-dihvdrodibenzorb,firi,41oxazepin-l l-yl)benzoate (7)
  • Step 6 (Z)-ethyl 4-(2-hydroxydibenzo
  • BBr 3 IM in DCM, 13.0 mL, 13.0 mmol
  • Ethanol (20 mL) was added and the mixture was stirred at room temperature for 30 min. Enough MeOH to get everything soluble was added and this mixture was poured into ethyl acetate (600 mL).
  • Step 3 (E)-methyl 4-(dibenzorb.firi.41oxazepin-l l-yl)-3-fluorobenzoate (103)
  • the resulting crude residue was purified on ISCO (0-100% EtOAc in Hexanes) to afford title compound 103 (0.364 g, 56%) as a yellow solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des composés inhibiteurs de l'histone désacétylase et sur leur utilisation pour traiter différents troubles dont la maladie d'Alzheimer.
PCT/US2009/042869 2008-05-05 2009-05-05 Inhibiteurs de l'histone désacétylase WO2009137499A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5050108P 2008-05-05 2008-05-05
US61/050,501 2008-05-05

Publications (1)

Publication Number Publication Date
WO2009137499A1 true WO2009137499A1 (fr) 2009-11-12

Family

ID=41264955

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/042869 WO2009137499A1 (fr) 2008-05-05 2009-05-05 Inhibiteurs de l'histone désacétylase

Country Status (1)

Country Link
WO (1) WO2009137499A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012135097A1 (fr) * 2011-03-26 2012-10-04 Envivo Pharmaceuticals, Inc. Méthodes de traitement ciblé de la dégénérescence lobaire fronto-temporale
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9115096B2 (en) 2011-05-10 2015-08-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9193694B2 (en) 2011-07-01 2015-11-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
CN112500395A (zh) * 2020-12-02 2021-03-16 吉林奥来德光电材料股份有限公司 一种二苯并含氮七元杂环类有机化合物、其制备方法及有机电致发光器件
CN112592355A (zh) * 2020-12-23 2021-04-02 吉林奥来德光电材料股份有限公司 一种有机磷发光化合物及其制备方法和有机电致发光器件
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
US20230277551A1 (en) * 2022-03-04 2023-09-07 National Taiwan University Antibacterial chemical compound, its manufacturing method and its use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018045A1 (fr) * 1999-09-08 2001-03-15 Sloan-Kettering Institute For Cancer Research Structure cristalline d'une deacetylase et ses inhibiteurs
WO2006123121A1 (fr) * 2005-05-19 2006-11-23 Chroma Therapeutics Ltd Inhibiteurs de l’histone desacetylase
WO2007118137A1 (fr) * 2006-04-07 2007-10-18 Methylgene Inc. Dérivés de benzamide utilisés en tant qu'inhibiteurs de l'histone désacétylase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018045A1 (fr) * 1999-09-08 2001-03-15 Sloan-Kettering Institute For Cancer Research Structure cristalline d'une deacetylase et ses inhibiteurs
WO2006123121A1 (fr) * 2005-05-19 2006-11-23 Chroma Therapeutics Ltd Inhibiteurs de l’histone desacetylase
WO2007118137A1 (fr) * 2006-04-07 2007-10-18 Methylgene Inc. Dérivés de benzamide utilisés en tant qu'inhibiteurs de l'histone désacétylase

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9371329B2 (en) 2009-07-27 2016-06-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
JP2017019826A (ja) * 2011-03-26 2017-01-26 フォルム ファーマシューティカルズ、インコーポレイテッド 前頭側頭葉変性症の標的治療の方法
WO2012135097A1 (fr) * 2011-03-26 2012-10-04 Envivo Pharmaceuticals, Inc. Méthodes de traitement ciblé de la dégénérescence lobaire fronto-temporale
JP2014511848A (ja) * 2011-03-26 2014-05-19 エンビボ ファーマシューティカルズ インコーポレイテッド 前頭側頭葉変性症の標的治療の方法
CN103561747A (zh) * 2011-03-26 2014-02-05 英维沃医药有限公司 靶向治疗额颞叶变性的方法
US9115096B2 (en) 2011-05-10 2015-08-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9403782B2 (en) 2011-05-10 2016-08-02 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9676760B2 (en) 2011-07-01 2017-06-13 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9193694B2 (en) 2011-07-01 2015-11-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
CN112500395A (zh) * 2020-12-02 2021-03-16 吉林奥来德光电材料股份有限公司 一种二苯并含氮七元杂环类有机化合物、其制备方法及有机电致发光器件
CN112500395B (zh) * 2020-12-02 2022-03-08 吉林奥来德光电材料股份有限公司 一种二苯并含氮七元杂环类有机化合物、其制备方法及有机电致发光器件
CN112592355A (zh) * 2020-12-23 2021-04-02 吉林奥来德光电材料股份有限公司 一种有机磷发光化合物及其制备方法和有机电致发光器件
US20230277551A1 (en) * 2022-03-04 2023-09-07 National Taiwan University Antibacterial chemical compound, its manufacturing method and its use thereof
US11925650B2 (en) * 2022-03-04 2024-03-12 National Taiwan University Antibacterial chemical compound, its manufacturing method and its use thereof
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

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