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WO2007112922A1 - Composés trimères d'aminopyrazole hydrosolubles à action contre des maladies neurodégénératives - Google Patents

Composés trimères d'aminopyrazole hydrosolubles à action contre des maladies neurodégénératives Download PDF

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Publication number
WO2007112922A1
WO2007112922A1 PCT/EP2007/002782 EP2007002782W WO2007112922A1 WO 2007112922 A1 WO2007112922 A1 WO 2007112922A1 EP 2007002782 W EP2007002782 W EP 2007002782W WO 2007112922 A1 WO2007112922 A1 WO 2007112922A1
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
aminopyrazole
soluble
sup
water
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/EP2007/002782
Other languages
German (de)
English (en)
Inventor
Thomas Schrader
Detlev Riesner
Luitgard Nagel-Steger
Frank Biesemeier
Katrin Hochdörffer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Philipps Universitaet Marburg
Original Assignee
Philipps Universitaet Marburg
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 Philipps Universitaet Marburg filed Critical Philipps Universitaet Marburg
Publication of WO2007112922A1 publication Critical patent/WO2007112922A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms

Definitions

  • the invention relates to novel, non-peptide aminopyrazole-based active compounds and to processes for their preparation. These drugs are able to prevent the de novo aggregation of Alzheimer's peptide, prion protein, ⁇ -synuclein and huntingtin as well as to dissolve existing aggregates.
  • Alzheimer's disease which is associated with a serious impairment of cognitive abilities.
  • Neurobiological characteristics of Alzheimer's disease are the conversion of normal ⁇ -helical protein structures to abnormal ⁇ -sheet structures ( ⁇ -amyloid patches, ⁇ -AP), excessive loading of cytoskeletal ⁇ proteins with phosphate groups, and muscarinic degeneration, cholinergic neurons.
  • ß-AP are deposited between the nerve cells, so that the oxygen and energy supply of the brain is impaired and the nerve cells eventually die.
  • ⁇ proteins are normal components of the cytoskeleton.
  • acetylcholine esterase inhibitors which slow down and prevent the breakdown of acetylcholine.
  • phytotherapeutics cat's claw, St. John's wort, etc., as well as some non-steroidal anti-inflammatory drugs such as I-buprofen used, the mode of action of these preparations is unknown.
  • DE 102 21 052 A1 already describes heterocyclic active substances which bind to proteins or peptides having a ⁇ -sheet structure and are present at least as dimers.
  • the active substances mentioned there also contain amino pyrazole groups and can be used for the treatment, diagnosis and prophylaxis of diseases that are associated with the formation of a ⁇ -sheet structure and subsequent abnormal protein aggregation.
  • the interest in the active ingredients described there is considerable and has given rise to the search for further, pharmacologically interesting agents whose structures differ from those of DE 102 21 052 A1 and which are better than the previously known agents for dissolving pathogenic protein fibrils.
  • the invention therefore trimeric, water-soluble aminopyrazole compound of the formula I.
  • R 1 for H 1 is a straight-chain or branched alkyl group having up to 10 carbon atoms or an amino acid or polyamino acid residue
  • R 2 is an OH, OR 3 or NHR 3 group in which R 3 is a straight-chain or branched alkyl group 1 to 10 carbon atoms or an amino acid or polyamino acid residue.
  • R 3 is a straight-chain or branched alkyl group 1 to 10 carbon atoms or an amino acid or polyamino acid residue.
  • aminopyrazole derivatives according to the invention can be prepared by a surprisingly simple preparation process: the iterative coupling of ⁇ / -PMB-protected nitropyrazolecarboxylic esters with the aid of the coupling reagent PyClop followed by reduction of the nitro group with H 2 / Pd-C leads directly to oligomers, possibly after attachment of further solubility or affinity-mediating groups such as lysine building blocks be transferred by acidic deprotection in the finished active ingredients.
  • the manufacturing process used comprises the following steps:
  • the PMB-protected pyrazole component (with or without peptidically linked amino acid units) is treated with trifluoroacetic acid (about 1 mL per 0.01 g of compound to be deprotected). Optionally, it is largely dissolved in the ultrasonic bath. After 6-24 h at 60-70 0 C, the reaction mixture is cooled in an ice bath and mixed with the 5-10-fold volume of diethyl ether. The precipitate is collected by centrifugation, washed with a little diethyl ether and dried in an oil pump vacuum.
  • the active compounds according to the invention can be used for the treatment of Parkinson's disease, Alzheimer's disease and prion diseases and show their superior pharmacological properties in the following experiments:

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention a pour objet des composés trimères d'aminopyrazole hydrosolubles de formule (I), dans laquelle R<SUP>1</SUP> désigne H, un groupe alkyle à chaîne linéaire ou ramifiée renfermant jusqu'à 10 atomes de carbone, ou un reste aminoacide ou polyaminoacide, et R<SUP>2</SUP> désigne un groupe OH, OR<SUP>3</SUP> ou NHR<SUP>3</SUP>, dans lequel R<SUP>3</SUP> désigne un groupe alkyle à chaîne linéaire ou ramifiée de 1 à 10 atomes de carbone, ou un reste aminoacide ou polyaminoacide.
PCT/EP2007/002782 2006-03-31 2007-03-29 Composés trimères d'aminopyrazole hydrosolubles à action contre des maladies neurodégénératives Ceased WO2007112922A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006015140A DE102006015140A1 (de) 2006-03-31 2006-03-31 Heterozyklische Verbindungen mit Wirkung gegen neurodegenerative Erkrankungen
DE102006015140.2 2006-03-31

Publications (1)

Publication Number Publication Date
WO2007112922A1 true WO2007112922A1 (fr) 2007-10-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/002782 Ceased WO2007112922A1 (fr) 2006-03-31 2007-03-29 Composés trimères d'aminopyrazole hydrosolubles à action contre des maladies neurodégénératives

Country Status (2)

Country Link
DE (1) DE102006015140A1 (fr)
WO (1) WO2007112922A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011050864A1 (fr) 2009-10-26 2011-05-05 Universität Duisburg-Essen Nouveaux composés pour le traitement de maladies liées à un mauvais repliement de protéines
DE102010017130A1 (de) 2010-05-28 2011-12-01 Forschungszentrum Jülich GmbH Hybrid-Verbindung, deren Verwendung und Verfahren zu deren Herstellung
US20120270795A1 (en) * 2009-10-26 2012-10-25 Thomas Schrader Compounds for the treatment of diseases related to protein misfolding

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102012102998B4 (de) * 2012-04-05 2013-12-05 Forschungszentrum Jülich GmbH Polymere, enthaltend multivalente Amyloid-Beta-bindende D-Peptide und deren Verwendung
JP2015518474A (ja) 2012-04-05 2015-07-02 フォルシュングスツェントルム ユーリッヒ ゲゼルシャフト ミット ベシュレンクテル ハフツングＦｏｒｓｃｈｕｎｇｓｚｅｎｔｒｕｍ Ｊｕｅｌｉｃｈ ＧｍｂＨ 血液、血液生産物及び器官を処置する方法
DK2834644T3 (da) 2012-04-05 2019-11-04 Forschungszentrum Juelich Gmbh Polymerer, indeholdende multivalente amyloid-beta-bindende d-peptider og deres anvendelse
DE102014003262A1 (de) 2014-03-12 2015-09-17 Forschungszentrum Jülich GmbH Amyloid-Beta-bindende Peptide und deren Verwendung für die Therapie und die Diagnose der Alzheimerschen Demenz
CN105745219B (zh) 2013-09-26 2020-10-09 于利奇研究中心有限公司 结合β淀粉状蛋白的肽及其用于治疗和诊断阿尔茨海默痴呆症的用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0835659A1 (fr) * 1996-10-14 1998-04-15 Hoechst Marion Roussel Deutschland GmbH Utilisation d'antagonistes non peptidiques de la bradykinine dans la préparation de médicaments pour le traitement et la prévention de la maladie d'Alzheimer
WO2003095429A1 (fr) * 2002-05-10 2003-11-20 TransMIT Gesellschaft für Technologietransfer mbH Principes actifs utilises dans le traitement, le diagnostic et la prophylaxie de pathologies dans lesquelles interviennent des structures proteiques anormales
WO2004099155A2 (fr) * 2003-05-02 2004-11-18 Elan Pharmaceuticals, Inc. Utilisation de derives de pyrazole substitues selectionnes et de composes associes en tant qu'antagonistes du recepteur b1 a la bradykinine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020002239A1 (en) * 1999-12-29 2002-01-03 Tanaka Richard D. Binding of polyamides to proteins having SH3 or WW domains

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0835659A1 (fr) * 1996-10-14 1998-04-15 Hoechst Marion Roussel Deutschland GmbH Utilisation d'antagonistes non peptidiques de la bradykinine dans la préparation de médicaments pour le traitement et la prévention de la maladie d'Alzheimer
WO2003095429A1 (fr) * 2002-05-10 2003-11-20 TransMIT Gesellschaft für Technologietransfer mbH Principes actifs utilises dans le traitement, le diagnostic et la prophylaxie de pathologies dans lesquelles interviennent des structures proteiques anormales
WO2004099155A2 (fr) * 2003-05-02 2004-11-18 Elan Pharmaceuticals, Inc. Utilisation de derives de pyrazole substitues selectionnes et de composes associes en tant qu'antagonistes du recepteur b1 a la bradykinine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RZEPECKI, PETRA ET AL: "Synthesis and Binding Studies of Alzheimer Ligands on Solid Support", JOURNAL OF ORGANIC CHEMISTRY , 72(10), 3614-3624 CODEN: JOCEAH; ISSN: 0022-3263, 2007, XP002446684 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011050864A1 (fr) 2009-10-26 2011-05-05 Universität Duisburg-Essen Nouveaux composés pour le traitement de maladies liées à un mauvais repliement de protéines
US20120270795A1 (en) * 2009-10-26 2012-10-25 Thomas Schrader Compounds for the treatment of diseases related to protein misfolding
US8481494B2 (en) * 2009-10-26 2013-07-09 Thomas Schrader Compounds for the treatment of diseases related to protein misfolding
DE102010017130A1 (de) 2010-05-28 2011-12-01 Forschungszentrum Jülich GmbH Hybrid-Verbindung, deren Verwendung und Verfahren zu deren Herstellung
WO2011147797A2 (fr) 2010-05-28 2011-12-01 Forschungszentrum Jülich GmbH Composé hybride, son utilisation et son procédé de préparation
DE102010017130B4 (de) 2010-05-28 2018-11-29 Forschungszentrum Jülich GmbH Hybrid-Verbindung, deren Verwendung und Verfahren zu deren Herstellung

Also Published As

Publication number Publication date
DE102006015140A1 (de) 2007-10-11

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