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WO2007051333A1 - Inhibiteurs de beta-secretase a base de triazine - Google Patents

Inhibiteurs de beta-secretase a base de triazine Download PDF

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Publication number
WO2007051333A1
WO2007051333A1 PCT/CH2006/000607 CH2006000607W WO2007051333A1 WO 2007051333 A1 WO2007051333 A1 WO 2007051333A1 CH 2006000607 W CH2006000607 W CH 2006000607W WO 2007051333 A1 WO2007051333 A1 WO 2007051333A1
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WO
WIPO (PCT)
Prior art keywords
cooh
compound
alkyl
optionally substituted
formula
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/CH2006/000607
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English (en)
Other versions
WO2007051333A8 (fr
Inventor
Urs LÜTHI
Danzhi Huang
Peter Kolb
Marco Cecchini
Nicolas Majeux
Fabian Dey
Stephan Valentin Audétat
Amedeo Caflisch
Alcide Barberis
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.)
Oncalis AG
Original Assignee
Oncalis AG
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
Priority claimed from EP05023893A external-priority patent/EP1790345A1/fr
Application filed by Oncalis AG filed Critical Oncalis AG
Publication of WO2007051333A1 publication Critical patent/WO2007051333A1/fr
Publication of WO2007051333A8 publication Critical patent/WO2007051333A8/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
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms

Definitions

  • This invention relates to compounds acting as beta-secretase inhibitors.
  • AD Alzheimer's disease
  • a characteristic of this disease is the presence of extracellular senile plaque, the major component of which is the ⁇ -amyloid peptide (A ⁇ ) .
  • a ⁇ amyloid precursor protein
  • APP amyloid precursor protein
  • AD Alzheimer's disease
  • X ⁇ and X 2 independently from each other are selected from 0 or S or N-R 2 or N-R4 r and in particular X]_ is N-R 2 and X 2 is N-R4 ,
  • R 2 and R4 are independently from each other selected from the group comprising hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenoxy, C1-C3 thioalkyl, wherein preferred C1-C3 alkyl is methyl, preferred C1-C3 alkoxy is methoxy, and preferred C1-C3 thioalkyl is -S-CH 3 , or Ri and R 2 and/or R3 and R4 form together with the N to which R2 and/or R4, respectively, are bound a 5 or 6 membered heterocycle comprising 1 or 2 heteroatoms , the second heteroatom being N or O, in particular
  • R 5 is selected from the group comprising -H 7 - OH 7 -CH 3 , -CH 2 OH, -CH 2 CH 37 -CH 2 CH 2 CH 37 -NH-CH 2 CH 3 f
  • R5 / is selected from the group comprising -H 7 -OH, -CH 3 -, ---CH 2 OH 7 -CH 2 CH 37 -CH 2 CH 2 CH 3 , -NH-CH 2 CH 3 f -0- CH 2 CH 3 , -0-phenyl, -CH 2 -phenyl, -NH-phenyl , -F, -Cl, -Br 7 -I, and much preferred is -H 7 Rg is selected from the group comprising -H, -
  • R7 is selected from the group comprising -H, - OH 7 -CH 3 , -CH 2 OH, -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -NH-CH 2 CH 3 t -0- CH 2 CH 3 , -0-phenyl, -CH 2 -phenyl, -NH-phenyl, R Q is selected from the group comprising -H, -
  • R 9 is selected from the group comprising -H, - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , phenyl, -CH 2 -phenyl, -0-phenyl, -NH-phenyl , Br 7 R]_ 0 is selected from the group comprising -H,
  • -CH 3 -CH 2 CH 3 , -CH 2 CH 2 CH 3 , phenyl, -CH 2 -phenyl, -0-phenyl, -NH-phenyl, Br, R ⁇ i is selected from the group comprising -
  • R ⁇ 2 is selected from the group comprising -H, halogen selected from -Cl, -Br, -I, in particular -Cl, C1-C3 alkyl, in particular -CH3., -OH, Cl- C3 alkoxy, in particular methoxy,
  • R2 . 3 is selected from the group comprising -H, -OH, -NO 2 , -Cl, -Br, -I, in particular -Cl, C1-C3 alkyl, in particular -CH3, C1-C3 alkoxy, in particular methoxy, R ⁇ 4 is selected from the group comprising -H,
  • At least one of the below mentioned preferences is present, preferably two or more of them, most preferred all of them.
  • X]_ is N-R 2 and X 2 is N-R4.
  • at least one of R ⁇ and R3 are optionally substituted phenyl with the substituents being independent from each other selected from 1 or 2 of C1-C3 alkyl, in particular methyl; halogen selected from chlorine, bromine and iodine, in particular fluorine and chlorine; C1-C3 alkyloxy, in particular methoxy, and R 2 and R4 are hydrogen;
  • R ⁇ and R 2 and/or R3 and R4 form together with the N to which R2 and/or R4, respectively, are bound a 5 or 6 membered heterocycle comprising 1 or 2 heteroatoms, the second heteroatom being N or 0, in particular piperidinyl, morpholinyl, pyrrolinyl;
  • Ri or R 3 is Cl-C3-alkoxy, in particular methoxy
  • R 5 is -H or -OH
  • Rg is selected from the group comprising -H
  • R 7 is -H or -OH
  • Rg is selected from the group comprising H, Cl, Br, or I,
  • R 12 is selected from the group comprising -H, -Cl, -CH 3 ,
  • R 13 is selected from the group comprising -H, -OH, -Cl, -NO 2
  • R 14 is selected from the group comprising -H
  • RN and R Q are both -H.
  • X ⁇ is N- R2
  • ⁇ 2 is N-R4
  • R ⁇ and R ⁇ are both -H, and which additionally have at least one of the preferences below, namely
  • Ri and R3 are optionally substituted phenyl with the substituents being independent from each other selected from 1 or 2 of methyl, fluorine, chlorine, and methoxy, and
  • R2 and R4 are hydrogen
  • R j _ and R2 , and R3 and R4 form together with the N to which R2 and R4 are bound a heterocycle selected from the group consisting of piperidinyl, morpholinyl , pyrrolinyl ;
  • Ri is optionally substituted phenyl with the substituents being independent from each other selected from 1 or 2 of .methyl, fluorine, chlorine, and methoxy, and R2 is hydrogen, and R3 and R4 form together with the N to which R4 is bound a heterocycle selected from the group consisting of piperidinyl, morpholinyl, pyrrolinyl;
  • Ri is as defined in (i) or (ii) and R3 is methoxy;
  • Rg and R ⁇ are Cl, Br, I, preferably both, and much preferred both are the same;
  • R5 to R 3 are not hydrogen, preferably at least R 8 and much preferred R 8 and
  • Rg are Cl, Br or I , in particular R 8 and R 6 are the same;
  • R 14 is -COOH
  • R 14 is -COOH and R 13 is -OH or -Cl;
  • VUi R 13 is -OH or -Cl or -NO2.
  • the invention relates to a compound of formula (I-B)
  • X 1 represents 0, S or N-R 2 ;
  • X 2 represents 0, S or N-R 4 .
  • R N - represents hydrogen, hydroxy, formyl or amino
  • RQ represents hydrogen, hydroxy, formyl or amino
  • R 1 represents C1-C6 alkyl , 3- to 8-membered aliphatic cycles or 3- to 8-membered heteroaliphatic cycles, optionally substituted 5- or 6-membered heteroaryl or optionally substituted aryl, in particular optionally substituted phenyl, with the substituents of the phenyl being independent from each other selected from 1 to 5, preferably from 1 or 2, of C1-C6 alkyl, halogen selected from fluorine, chlorine, bromine, iodine, C1-C6 alkyloxy, hydroxy, C1-C6 alkene;
  • R2 represents hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenoxy, C1-C3 thioalkyl;
  • R3 represents C1-C6 alkoxy, 3- to 8-membered aliphatic cycles or 3- to 8-membered heteroaliphatic cycles, optionally substituted 5- or 6-membered heteroaryl or optionally substituted aryl, in particular optionally substituted phenyl, with the substituents of the phenyl being independent from each other selected from 1 to 5, preferably from 1 or 2 , of C1-C6 alkyl, fluorine, chlorine, bromine, iodine, C1-C6 alkyloxy, hydroxy, C1-C6 alkene; and
  • R4 represents hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenoxy, C1-C3 thioalkyl; or R 1 and R2 and/or R3 and R4 form together with the N to which R2 and/or R4 , respectively, are bound a 5 or 6 membered heterocycle comprising 1 or 2 heteroatoms, the second heteroatom being N or O;
  • R 9 represents -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , phenyl, benzyl, phenoxy, -NH-phenyl, Br;
  • R 10 represents -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , phenyl, benzyl, phenoxy, -NH-phenyl, Br;
  • R ⁇ represents methyl, optionally substituted phenyl with the substituents being independent from each other selected from 1 or 2 of methyl, fluorine, chlorine, methoxy;
  • R 2 represents hydrogen, methoxy;
  • R3 represents methoxy, optionally substituted phenyl with the substituents being independent from each other selected from 1 or 2 of methyl, fluorine, chlorine, methoxy;
  • R4 represents hydrogen, methoxy; and / or
  • R ⁇ and R 2 and/or R3 and R4 form together with the N to which R 2 and/or R4, respectively, are bound a 5 or 6 membered heterocycle selected from pyrrolidinyl, piperidinyl, morpholinyl.
  • R ⁇ i represents
  • R 11 represents -CH 2 CH 2 CH 2 COOH, -CH 2 CH 2 COOH 7 -NH- CH 2 CH 2 COOH, -NH-CH 2 COOH, -0-CH 2 CH 2 COOH, -0-CH 2 COOH, S-CH 2 CH 2 COOH, -S-CH 2 COOH, -Br, or
  • R 12 represents -H, -Cl, -Br, -I, -CH3, -OH, -OCH 3 ;
  • R 13 represents -H, -OH, -NO 2 , -Cl, -Br, -I, -CH 3 , OCH 3 and
  • R 1 represents optionally substituted phenyl with the substituents being independent from each other selected from 1 or 2 of C1-C3 alkyl (in particular methyl) , halogen (in particular fluorine and chlorine) .
  • C1-C3 alkyloxy in particular methoxy
  • R 3 represents optionally substituted phenyl with the substituents being independent from each other selected from 1 or 2 of C1-C3 alkyl (in particular methyl) , halogen (in particular fluorine and chlorine) . C1-C3 alkyloxy (in particular methoxy) .
  • R 2 and R4 represent hydrogen
  • R 1 and R 2 and/or R 3 and R4 form together with the N to which R 2 and/or R4, respectively, are bound a 5 or 6 membered heterocycle comprising 1 or 2 heteroatoms, the second heteroatom being N or 0.
  • R]_2 represents -H, -Cl, -CH 3 ,
  • R 13 represents -H, -OH, -Cl, -NO 2 ,
  • R ⁇ 4 represents -H, -COOH, -NO2 , Cl.
  • (xi) A compound of formula (I -B) , wherein R ⁇ 4 represents -
  • the invention relates to a compound of formula (I-C)
  • R ⁇ represents optionally substituted phenyl, with the substituents being independently from each other selected from 1 to 5, in particular 1 or 2, of C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxy and C2-C6 alkene, wherein preferred alkyls are C1-C3 alkyl, in particular methyl, the halogens are selected from fluorine, chlorine, bromine and iodine, in particular from fluorine and chlorine, preferred alkoxy are C1-C3 alkyloxy, in particular methoxy, and preferred alkene are vinyl or allyl and
  • RJJ, Rc/ R5, R5"/ R6/ R 7/ R 8 are as defined above.
  • the invention further relates to compounds of formula (I) as pharmaceutical.
  • the invention further relates to compounds of formula (I-B) as pharmaceutical.
  • the invention further relates to compounds of formula (I-C) as pharmaceutical.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof as described herein, together with a pharmaceutically acceptable carrier and optionally one or more adjuvants.
  • the invention further relates to the manufacture of a compound of formula (I) comprising the step of reacting a compound of formula (II)
  • substituents are as defined above, optionally in the presence of a solvent, such as an alcohol (e.g. methanol) and optionally in the presence of an reaction auxiliary, such as a water-removing agent (e.g. molecular sieve).
  • a solvent such as an alcohol (e.g. methanol)
  • an reaction auxiliary such as a water-removing agent (e.g. molecular sieve).
  • the invention further relates to the manufacture of a compound of formula (I-B) comprising the step of reacting a compound of formula (II-B)
  • substituents are as defined above, optionally in the presence of a solvent, such as an alcohol (e.g. methanol) and optionally in the presence of an reaction auxiliary, such as a water-removing agent (e.g. molecular sieve) .
  • a solvent such as an alcohol (e.g. methanol)
  • an reaction auxiliary such as a water-removing agent (e.g. molecular sieve)
  • the invention further relates to the manufacture of a compound of formula (I-C) comprising the step of reacting a compound of formula (II-C)
  • HI-C wherein the substituents are as defined above, optionally in the presence of a solvent, such as an alcohol (e.g. methanol) and optionally in the presence of an reaction auxiliary, such as a water-removing agent (e.g. molecular sieve).
  • a solvent such as an alcohol (e.g. methanol)
  • an reaction auxiliary such as a water-removing agent (e.g. molecular sieve).
  • the starting materials used in these reactions are known or available by using known manufacturing steps.
  • (II-B) and (II-C) are available from the reaction of hydrazine with the corresponding chlorine-derivatives .
  • the invention relates to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the ⁇ -secretase activity or diseases related to the deposition of amyloid beta-protein (such as the production and/or the accumulation of amyloid beta-protein) mammals, in particular human beings.
  • the invention relates to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Alzheimer's disease and / or Down's syndrome and / or aging of brain.
  • the invention also relates to a method of prevention, treatment or delay of progression of a disease involving an abnormal ⁇ -secretase activity or a disease related to the deposition of amyloid beta-protein (such as the production and/or the accumulation of amyloid beta- protein) , in a subject in need thereof comprising the step of administering an effective amount of a compound as described herein.
  • the invention relates to method of prevention, treatment or delay of progression of a disease selected from the group consisting of Alzheimer's disease (AD) , Down's syndrome , aging of brain, in a subject in need thereof comprising the step of administering an effective amount of a compound as described herein.
  • AD Alzheimer's disease
  • Down's syndrome aging of brain
  • AD as used in this specification includes all stages of this disease, its mild, moderate and severe form.
  • the compounds are administered to a host already suffering from the disease.
  • the compounds will be administered in an amount sufficient to inhibit further deposition of senile plaques.
  • the specific dose of compound (s) administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances, such as the specific compound administered, the condition being treated, etc.
  • a daily dose will contain a dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound, preferably from about 0.05 mg/kg to about 20 mg/kg, for example from about 0.1 mg/kg to about 120 mg/kg.
  • the compound can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal either as such, but preferable in a formulation comprising carriers adjuvants etc.
  • Suitable pharmaceutically acceptable solid and liquid carriers and/or pharmaceutically acceptable adjuvants, such as stabilizing agents, emulsifyers, etc. are known in the art.
  • a typical pharmaceutical composition for intramuscular injection would contain about one ⁇ g to one mg of the compound in from one to four milliliters of sterile buffered water.
  • the typical pharmaceutical composition for intravenous infusion would contain about one to one hundred milligrams of the compound in from one hundred to five hundred milliliters of sterile Ringer's solution.
  • the pharmaceutical formulations are prepared by known procedures using known and readily available ingredients.
  • the compounds investigated were the compounds with the following formulas :
  • the tests performed were a) A ⁇ l-40 (Sw) bioassay, which measures the amount of the amyoid peptide A ⁇ l-40 in the supernatant of Swedish APP695 transgenic HEK293 cells in the presence of the various BACE inhibitors via ELISA (enzyme-linked immunosorbent assay) .
  • IC50 inhibitory concentration that reduces A ⁇ l-40 secretion to 50 %
  • FRET fluorescence resonance energy transfer

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

Abstract

L'invention concerne des composés de formule (I) dans laquelle, selon des modes de réalisation préférés, X1 et X2 représentent N-H ou N-R3 ou N-R4, RN et RC représentent tous les deux H, R1 et R3 représentent indépendamment l'un de l'autre un phényle éventuellement substitué, ou R1 et R2 et/ou R3 et R4 forment ensemble, avec le N auquel R2 et/ou R4 sont respectivement liés, un hétérocycle à 5 ou 6 éléments comprenant 1 ou 2 hétéroatomes, et A représente un phényle substitué de préférence par un halogène ou un furanyle substitué de préférence par un phényle, lesdits composés étant de bons inhibiteurs de β-secrétase et étant utiles pour le traitement de la maladie d'Alzheimer.
PCT/CH2006/000607 2005-11-02 2006-10-30 Inhibiteurs de beta-secretase a base de triazine Ceased WO2007051333A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP05023893.0 2005-11-02
EP05023893A EP1790345A1 (fr) 2005-11-02 2005-11-02 Inibiteurs de beta-sécrétase a base de triazine
US73438405P 2005-11-08 2005-11-08
US60/734,384 2005-11-08

Publications (2)

Publication Number Publication Date
WO2007051333A1 true WO2007051333A1 (fr) 2007-05-10
WO2007051333A8 WO2007051333A8 (fr) 2007-09-13

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010040661A1 (fr) 2008-10-09 2010-04-15 F. Hoffmann-La Roche Ag Modulateurs pour l'amyloïde bêta
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8288403B2 (en) 2008-11-10 2012-10-16 Hoffmann-La Roche Inc. Heterocyclic gamma secretase modulators
US8399663B2 (en) 2009-04-03 2013-03-19 Astellas Pharma Inc. Salt of 1,3,5-triazine-2,4,6-triamine derivative
CN103052628A (zh) * 2010-07-20 2013-04-17 韦斯塔隆公司 三嗪类和嘧啶类杀虫剂
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
US8962834B2 (en) 2008-02-22 2015-02-24 Hoffmann-La Roche Inc. Modulators of amyloid beta
WO2017106367A1 (fr) * 2015-12-15 2017-06-22 D.E. Shaw Research, Llc Méthode de traitement de troubles neurodégénératifs par récupération de la toxicité de l'alpha-synucléine
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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GB2397301A (en) * 2003-01-14 2004-07-21 Novo Pharmaceuticals Ltd De Substituted 1,3,5-triazine derivatives
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US6335339B1 (en) * 1998-01-13 2002-01-01 Scriptgen Pharmaceuticals, Inc. Triazine antiviral compounds
GB2397301A (en) * 2003-01-14 2004-07-21 Novo Pharmaceuticals Ltd De Substituted 1,3,5-triazine derivatives
US20060223812A1 (en) * 2004-07-17 2006-10-05 Max-Planck-Gesellschaft Zur Forderungder Wissenschaften, E.V. Treating neurodegenerative conditions

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8962834B2 (en) 2008-02-22 2015-02-24 Hoffmann-La Roche Inc. Modulators of amyloid beta
WO2010040661A1 (fr) 2008-10-09 2010-04-15 F. Hoffmann-La Roche Ag Modulateurs pour l'amyloïde bêta
JP2012504575A (ja) * 2008-10-09 2012-02-23 エフ．ホフマン−ラ ロシュ アーゲー アミロイドβのモジュレーター
US8389717B2 (en) 2008-10-09 2013-03-05 Hoffmann-La Roche Inc. Modulators for amyloid beta
US8288403B2 (en) 2008-11-10 2012-10-16 Hoffmann-La Roche Inc. Heterocyclic gamma secretase modulators
US8399663B2 (en) 2009-04-03 2013-03-19 Astellas Pharma Inc. Salt of 1,3,5-triazine-2,4,6-triamine derivative
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
CN103052628A (zh) * 2010-07-20 2013-04-17 韦斯塔隆公司 三嗪类和嘧啶类杀虫剂
JP2013532659A (ja) * 2010-07-20 2013-08-19 ベスタロン コーポレイション トリアジン系およびピリミジン系殺虫剤
US8785630B2 (en) 2010-07-20 2014-07-22 Vestaron Corporation Insecticidal triazines and pyrimidines
CN103052628B (zh) * 2010-07-20 2016-05-18 韦斯塔隆公司 三嗪类和嘧啶类杀虫剂
WO2017106367A1 (fr) * 2015-12-15 2017-06-22 D.E. Shaw Research, Llc Méthode de traitement de troubles neurodégénératifs par récupération de la toxicité de l'alpha-synucléine
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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