WO2006083692A3 - Methods of identifying modulators of bromodomains - Google Patents

Methods of identifying modulators of bromodomains Download PDF

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Publication number
WO2006083692A3
WO2006083692A3 PCT/US2006/002840 US2006002840W WO2006083692A3 WO 2006083692 A3 WO2006083692 A3 WO 2006083692A3 US 2006002840 W US2006002840 W US 2006002840W WO 2006083692 A3 WO2006083692 A3 WO 2006083692A3
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WO
WIPO (PCT)
Prior art keywords
aralkyl
ch2coch3
ococh3
ch2ch3
och3
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PCT/US2006/002840
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French (fr)
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WO2006083692A2 (en
Inventor
Ming-Ming Zhou
Lei Zeng
Zhiyong Wang
Original Assignee
Mount Sinai Schoool Of Medicin
Ming-Ming Zhou
Lei Zeng
Zhiyong Wang
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Application filed by Mount Sinai Schoool Of Medicin, Ming-Ming Zhou, Lei Zeng, Zhiyong Wang filed Critical Mount Sinai Schoool Of Medicin
Publication of WO2006083692A2 publication Critical patent/WO2006083692A2/en
Publication of WO2006083692A3 publication Critical patent/WO2006083692A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/16—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/53—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having the nitrogen atom of at least one of the amino groups further bound to a hydrocarbon radical substituted by amino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7

Abstract

The present invention features compounds of the following general formula (I) wherein R1 is selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl; substituted aralkyl, heteroaryl; substituted heteroaryl, phenyl, SO2, NH2, NO2, SO2, CH2, CH2CH3, OCH3, OCOCH3, CH2COCH3, and OH, CN and halogen; R2 is selected from the group consisting of hydrogen; lower alkyl, aryl, phenyl, aralkyl; substituted aralkyl, heteroaryl; substituted heteroaryl, SO2 NH2NH3+NO2, SO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, and OH, halogen, carboxy, and alkoxy; X is selected from the group consisting of lower alkyl, SO2, NH, NO2, , CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, and OH, carboxy, and alkoxy; and n is an integer from O to 10 and their pharmaceutically acceptable salts of acids or bases as well as pharmaceutical compositions comprising these compounds. The invention further provides methods for preventing or inhibiting the binding of bromodomains to acetyl-lysine residues of proteins and methods for treating HIV infection and HW related disease. The present invention also features compounds of the following general formula (II) wherein: R1R2 and R3 are independently selected from the group consisting of hydrogen; lower alkyl, aryl, phenyl, aralkyl; substituted aralkyl, heteroaryl; substituted heteroaryl, SO2, NH2, NH3+ NO2, SO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, SH, halogen, carboxy; and R4 is selected from the group consisting of lower alkyl, aryl, SO2, NH, NO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OH, carboxy, and alkoxy as well as pharmaceutical compositions comprising these compounds. The invention further provides methods for preventing or inhibiting the binding of bromodomains to acetyl-lysine residues of proteins and methods f treating HW infection and HIY related disease. The present invention also features compounds of formula (III) wherein R1, R2, R3, R4 R5, and R6 are independently selected from the group consisting of hydrogen; lower alkyl, aryl, phenyl, aralkyl; substituted aralkyl, heteroaryl, substituted heteroaryl, SO2 NH2, NH3+, NO2, SO2, CH3, CH2CH3, OCH3, OCOCH3, CH2COCH3, OCH2CH3, OCH(CH3)2, OCH2COOH, OCHCH3COOH, OCH2COCH3, OCH2CONH2, OCOCH(CH3)2, OCH2CH2OH, OCH2CH2CH3, O(CH2)3CH3, OCHCH3COOCH3, OCH2CON(CH3)2,NH(CH2)3N(CH3)2, NH(CH2)2N(CH3)2, NH(CH2)2OH, NH(CH2)3CH3, NHCH3, SH, halogen, carboxy, and alkoxy as well as pharmaceutical compositions comprising these compounds. The invention further provides methods for preventing or inhibiting the binding of bromodomains to acetyl-lysine residues of proteins and methods for treating HIV infection and HIV related disease.
PCT/US2006/002840 2005-01-28 2006-01-27 Methods of identifying modulators of bromodomains WO2006083692A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US64803205P 2005-01-28 2005-01-28
US60/648,032 2005-01-28

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WO2006083692A3 true WO2006083692A3 (en) 2007-01-11

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US7745646B2 (en) 2006-07-07 2010-06-29 Kalypsys, Inc. Bicyclic heteroaryl inhibitors of PDE4
JP5479105B2 (en) * 2007-11-05 2014-04-23 国立大学法人佐賀大学 Novel ubiquitin-binding small molecule
GB0919434D0 (en) * 2009-11-05 2009-12-23 Glaxosmithkline Llc Novel compounds
CN103347517B (en) 2010-08-11 2018-10-02 德雷克塞尔大学 Treat the D of dyskinesia in Parkinson's disease3Dopamine-receptor stimulant
EP2677865A4 (en) * 2011-02-23 2015-04-22 Icahn School Med Mount Sinai Inhibitors of bromodomains as modulators of gene expression
GB201107325D0 (en) * 2011-05-04 2011-06-15 Glaxosmithkline Llc Novel compounds
CA2843643A1 (en) * 2011-07-29 2013-02-07 The Children's Hospital Of Philadelphia Compositions and methods for the treatment of hiv
WO2013033268A2 (en) 2011-08-29 2013-03-07 Coferon, Inc. Bivalent bromodomain ligands, and methods of using same
WO2013033269A1 (en) 2011-08-29 2013-03-07 Coferon, Inc. Bioorthogonal monomers capable of dimerizing and targeting bromodomains and methods of using same
WO2013044118A2 (en) * 2011-09-23 2013-03-28 Merial Limited Indirect modeling of new repellent molecules active against insects, acarids, and other arthropods
CN104370824A (en) * 2013-01-29 2015-02-25 韩冰 Intraocular tension reducing compound and preparation method and use thereof
US9861594B2 (en) 2013-10-28 2018-01-09 Drexel University Treatments for attention and cognitive disorders, and for dementia associated with a neurodegenerative disorder
CN105708836B (en) * 2014-12-04 2019-01-15 复旦大学 Coumarin kind compound is preparing the application in the latent therapeutic agent of AntiHIV1 RT activity
GB201514021D0 (en) 2015-08-07 2015-09-23 Arner Elias Set Jeno Novel Pyridines and their use in the treatment of cancer
CA3051644A1 (en) 2017-02-07 2018-08-16 Oblique Therapeutics Ab Sulfinylpyridines and their use in the treatment of cancer
EP3580215A1 (en) 2017-02-07 2019-12-18 Oblique Therapeutics AB Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer
MX2019009354A (en) 2017-02-07 2019-09-19 Oblique Therapeutics Ab Heterocyclylsulfonyl-substituted pyridines and their use in the treatment of cancer.
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