WO2017159484A1 - DÉRIVÉ 2,4-DIAMINOPHÉNOL, ET AGENT D'INHIBITION DE L'AGRÉGATION DE TAU ET/OU DE L'AMYLOÏDE β - Google Patents

DÉRIVÉ 2,4-DIAMINOPHÉNOL, ET AGENT D'INHIBITION DE L'AGRÉGATION DE TAU ET/OU DE L'AMYLOÏDE β Download PDF

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WO2017159484A1
WO2017159484A1 PCT/JP2017/009189 JP2017009189W WO2017159484A1 WO 2017159484 A1 WO2017159484 A1 WO 2017159484A1 JP 2017009189 W JP2017009189 W JP 2017009189W WO 2017159484 A1 WO2017159484 A1 WO 2017159484A1
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group
synthesis
piperidyl
formula
yield
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Japanese (ja)
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知宏 宮坂
井上　善一
八郎 杉本
康夫 井原
真子 高見
美香 延原
有紀 藤田
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学校法人同志社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Patent Document 1 describes a drug mainly composed of a naphthoquinone type compound for improving AD symptoms. According to this drug, intracellular tau aggregation is suppressed to some extent, and thus, the symptoms of AD are alleviated by suppressing the formation of NFT.
  • senile plaques found in the AD patient's brain are an important pathological feature, mainly formed by the accumulation and aggregation of A ⁇ in the brain parenchyma.
  • the metabolism of A ⁇ in the brain is abnormal for some reason, and amyloid fibers formed by accumulation and aggregation of A ⁇ are thought to cause neuronal cell death, and more recently, A ⁇ oligomers formed in the process of A ⁇ aggregation Has been attracting attention as exhibiting neurotoxicity, and inhibition of the A ⁇ aggregation process is expected to be effective as an AD treatment.
  • the present invention has been made in view of such a problem, and is a 2,4-diaminophenol derivative, and a tau and / or A ⁇ aggregation inhibitor capable of sufficiently inhibiting the aggregation of intracellular tau and / or A ⁇ .
  • the purpose is to provide.
  • the compound according to the present invention is a compound consisting of the following formula (I) or a salt thereof.
  • Q is (i) a hydrogen atom, (ii) a lower alkyl group, an aryl group, an aralkyl group, or an alkoxyalkyl group that may have a heteroatom composed of N, O, or S, (iii) —R 5 — Y, R 5 is (i) a chemical bond, (ii) a heteroatom composed of O or S, (iii) a carbonyl group or a carboxyl group, (iv) a C1-6 alkyl group or a C2-6 alkenyl group, and Y represents (i) hydrogen, (ii) one or a plurality of independent substituents (this substituent is a lower alkyl, lower alkenyl, lower alkynyl, halogen atom to which one or more fluorine atoms may be bonded).
  • a substituent (this substituent) Is an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkoxyalkyl group, an ester group, an ester alkyl group, or a phenyl group, a pyridyl group, an amino group, a hydroxyl group, a thiol group, a fluorine atom, or a chlorine atom.
  • a linear or branched alkyl group having 1 to 6 carbon atoms which may have one or more heteroatoms (iv) an NR 11 R 11 ′ group (wherein R 11 and R 11 ′ are independently Hydrogen field , Substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted aryl group.
  • R 1 and R 2 are both hydrogen atoms, or when R 1 and R 2 are not both hydrogen atoms, they are bonded via several atoms so that R 1 and R 2 are monocyclic or polycyclic Form a ring of formula
  • R 3 and R 4 are both hydrogen atoms, or when R 3 and R 4 are not both hydrogen atoms, they are bonded via several atoms so that R 3 and R 4 are monocyclic or polycyclic Form a ring of formula X is written as -R 10 -Y
  • R 10 is (i) a chemical bond, (ii) a heteroatom comprising N, O or S, (iii) a carbonyl group, a carboxyl group, an amide group, or an ester group, (iv) a C1-6 alkyl group or C2— A 6 alkenyl group, (v) a C1-4 alkylidene group
  • Y represents (i) hydrogen, (ii) one or a plurality of independent substituents (this substitu
  • a substituent (this substituent) Is an alkyl group having 1 to 4 carbon atoms, an alkoxy group, an alkoxyalkyl group, an ester group, an ester alkyl group, or a phenyl group, a pyridyl group, an amino group, a hydroxyl group, a thiol group, a fluorine atom, or a chlorine atom.
  • intracellular tau aggregation can be sufficiently inhibited. For this reason, patients who suffered from tauopathy, such as AD, for whom there was no effective treatment, have been remedied, and in the current aging society, many societies have been improved by improving the lives of the elderly, reducing the burden of care, and reducing medical expenses. Contribution can be made.
  • a compound comprising the following formula (I) or a salt thereof has a tau aggregation inhibitory action and / or an A ⁇ aggregation inhibitory action, and is caused by the aggregation of tauopathy and / or A ⁇ .
  • the present inventors have found a new finding that it is useful for the prevention and treatment of amyloidosis, and based on this fact, the present invention has been completed.
  • Q is (i) a hydrogen atom, (ii) an alkyl group, an aryl group, an aralkyl group, or an alkoxyalkyl group that may have a heteroatom composed of N, O, or S, and (iii) R 5 -Y Written, R 5 is (i) a chemical bond, (ii) a heteroatom composed of O or S, (iii) a carbonyl group or a carboxyl group, (iv) a C1-6 alkyl group or a C2-6 alkenyl group, and Y is (i) hydrogen, (ii) one or a plurality of independent substituents (the substituent of Y is a lower alkyl, lower alkenyl, lower alkynyl, to which one or more fluorine atoms may be bonded, A halogen atom, a hydroxyl group, an homocycle or a heterocycle that may have one or more fluorine atoms to which one or a plurality of fluor
  • R 11 and R 11 'and bonded to may form a ring.
  • a heteroatom, a double bond, a bridge, or one or two substituents X in each ring substituted with substituents X in each ring.
  • substituent X in (III) may be the same or different, and when there are two substituents X in each ring of formula (II) or formula (III), these substituents X may be the same And when there are two substituents X in each ring of formula (II) or formula (III), these substituents X may be bonded to each other to form a ring).
  • the formula (II) or (III) can be any of the following functional groups, for example.
  • the formula (II) or (III) can be any of the following functional groups, for example.
  • the formula (II) or (III) can be any of the following functional groups, for example.
  • Metal for example, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.
  • alkali metal hydrogen carbonate for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.
  • alkali metal hydroxide for example, sodium hydroxide
  • Salts of inorganic bases such as trimethylamine, triethylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkyl-morpholine, DBN, Salts of organic bases such as DBU; hydrochlorides, water bromide Salts of inorganic acids such as acid, hydroiodide, sulfate, nitrate, phosphate; formate, acetate, propionate, oxalate, malonate, succinate, fumarate, Organic acids such as maleate, lactate, malate, citrate, tartrate, citrate, carbonate, picrate, methanesulfonate,
  • pH adjusters include sulfuric acid, hydrochloric acid, acetic acid, lactic acid, calcium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, etc. can do.
  • Example 1-3 Synthesis of 2,4-dimorpholinophenol dihydrochloride (KT-413)
  • Example 1-3-1 Synthesis of 4- (2-benzyloxy-5-morpholinophenyl) morpholine The title compound was obtained in the same manner as in Example 1-1-1 (yield 76%).
  • Example 1-3-2 Synthesis of 2,4-dimorpholinophenol dihydrochloride The title compound was obtained in the same manner as in Example 1-1-2 (yield 93%).
  • Example 1-36-2 Synthesis of 2- (4-methoxy-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride The title compound was synthesized in the same manner as in Example 1-4-2. Obtained (yield 91%).
  • Example 1-37 Synthesis of 2- (4-phenyl-1-piperidyl) -4- (1-piperidyl) phenol dihydrochloride (KT-437)
  • Example 1-37-1 Synthesis of 1- [2-benzyloxy-5- (1-piperidyl) phenyl] -4-phenylpiperidine The title compound was obtained in the same manner as in Example 1-18-2. (Yield 68%).
  • Example 1-41 Synthesis of 4- (1-piperidyl) -2- (4-pyrimidin-2-ylpiperazin-1-yl) phenol (KT-464)
  • Example 1-41-1 Synthesis of 2- [4- [2-methoxy-5- (1-piperidyl) phenyl] piperazin-1-yl] pyrimidine The title compound was the same as in Example 1-18-2 (Yield 68%).
  • Example 1-41-2 Synthesis of 4- (1-piperidyl) -2- (4-pyrimidin-2-ylpiperazin-1-yl) phenol The title compound was the same as in Example 1-40-2. Obtained by the method (yield 74%).
  • reaction solution was ice-cooled, and NaBH (OAc) 3 0.534 g was added, followed by stirring at room temperature for 16 hours.
  • the reaction solution was washed with sat. NaHCO 3 aq., Washed with water, dried over MgSO 4 and concentrated.
  • the obtained residue was purified by silica gel column chromatography purification (hexane-AcOEt system) to give the title compound (0.407 g, yield 78%).
  • Example 2-2 Synthesis of 2-amino-4- (isopentylamino) phenol dihydrochloride (KT-396)
  • Example 2-2-1 Synthesis of 4- (isopentylamino) -2-nitrophenol The title compound was obtained in the same manner as in Example 2-1-1 (yield 59%).
  • Example 2-6 Synthesis of 4-amino-2- (2-phenylethylamino) phenol dihydrochloride (KT-400)
  • Example 2-6-1 Synthesis of 4-nitro-2- (2-phenylethylamino) phenol The title compound was obtained in the same manner as in Example 2-1-1 (yield 16%) .
  • Example 2-6-2 Synthesis of 4-amino-2- (2-phenylethylamino) phenol dihydrochloride The title compound was obtained in the same manner as in Example 2-2-2 (yield 90%).
  • Example 2-7-2 Synthesis of 2,4-bis (1-piperidyl) phenol 1- [2-Benzyloxy-5- (1-piperidyl) phenyl] piperidine (1.5 g) in methanol (15 mL), THF (7.5 mL) And 20% Pd (OH) 2 —C 0.5 g was added. Hydrogen was added and catalytic reduction was performed at room temperature for 3 hours under atmospheric pressure. The catalyst was filtered off and the mother liquor was concentrated. The obtained residue was purified by silica gel column chromatography (hexane-AcOEt system) to give the title compound (1.05 g, yield 94%).
  • the effect of inhibiting tau aggregation at various concentrations of 2,4-diaminophenol derivatives and isoproterenol at a concentration of 1 ⁇ M was derived by the following formula 1 based on the Th-T fluorescence value during 72 hours incubation when each compound was added. .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Indole Compounds (AREA)

Abstract

Le problème décrit par la présente invention consiste à préparer un agent d'inhibition de l'agrégation de tau et/ou de l'amyloïde β. La solution selon la présente invention porte sur un composé représenté par la formule (I) ou son sel. Ce composé peut servir à la thérapie, au diagnostic, et au soulagement des symptômes et en prévention de la tauopathie et/ou de l'amyloïdose provoquée par l'agrégation d'Aβ.
PCT/JP2017/009189 2016-03-18 2017-03-08 DÉRIVÉ 2,4-DIAMINOPHÉNOL, ET AGENT D'INHIBITION DE L'AGRÉGATION DE TAU ET/OU DE L'AMYLOÏDE β WO2017159484A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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Publication number Priority date Publication date Assignee Title
DE1058514B (de) * 1955-05-13 1959-06-04 Ciba Geigy Verfahren zur Herstellung von AEthylenimino-hydrochinonen und deren Salzen
WO1998020864A2 (fr) * 1996-11-13 1998-05-22 Universita' Degli Studi Di Brescia - Dipartimento Di Scienze Biomediche Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives
JP2011518119A (ja) * 2008-03-13 2011-06-23 プロイェクト、デ、ビオメディシナ、シーマ、ソシエダッド、リミターダ ４−フェニル酪酸（４ｐｂａ）およびその医薬上許容し得る塩についての新規用途

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Publication number Priority date Publication date Assignee Title
DE1058514B (de) * 1955-05-13 1959-06-04 Ciba Geigy Verfahren zur Herstellung von AEthylenimino-hydrochinonen und deren Salzen
WO1998020864A2 (fr) * 1996-11-13 1998-05-22 Universita' Degli Studi Di Brescia - Dipartimento Di Scienze Biomediche Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives
JP2011518119A (ja) * 2008-03-13 2011-06-23 プロイェクト、デ、ビオメディシナ、シーマ、ソシエダッド、リミターダ ４−フェニル酪酸（４ｐｂａ）およびその医薬上許容し得る塩についての新規用途

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Title
DATABASE REGISTRY [O] 16 November 1984 (1984-11-16), retrieved from STN Database accession no. 53013-44-8 *
DATABASE REGISTRY [O] 23 January 1988 (1988-01-23), retrieved from STN Database accession no. 112441-21-1 *
HUIJBREGTS, M. A. J. ET AL.: "Human- Toxicological Effect and Damage Factors of Carcinogenic and Noncarcinogenic Chemicals for Life Cycle Impact Assessment", INTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT, vol. 1, no. 3, 2005, pages 181 - 244 *

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US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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