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Triazinetrione derivatives and their use as modulators of neurotrophin receptor and receptor tyrosine kinases

A technology of uses, compounds, in the field of triazinetrione derivatives and their use as modulators of neurotrophin receptors and receptor tyrosine kinases, capable of addressing unselected potential candidates for Alzheimer's disease compounds, lack of inhibitory activity, etc.

Inactive Publication Date: 2019-08-23
ALZECURE PHARMA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the cellular prion protein (PrP C ) lacked similar inhibitory activity and was therefore not selected for further study as a potential candidate compound for the treatment of Alzheimer's disease

Method used

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  • Triazinetrione derivatives and their use as modulators of neurotrophin receptor and receptor tyrosine kinases
  • Triazinetrione derivatives and their use as modulators of neurotrophin receptor and receptor tyrosine kinases
  • Triazinetrione derivatives and their use as modulators of neurotrophin receptor and receptor tyrosine kinases

Examples

Experimental program
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example

[0331] General method:

[0332] All solvents were of analytical grade, and commercially available anhydrous solvents were typically used for reactions. Starting materials used can be purchased from commercial sources or prepared according to literature procedures, room temperature means 20°C-25°C. Solvent mixture compositions are given in volume percent or volume ratio.

[0333] MW heating was performed in a standard MW reactor producing continuous irradiation at 2450 MHz. It is understood that MW can be used to heat the reaction mixture.

[0334] On Merck TLC-plate (silica gel 60F 254 ) and spot UV visible. TLC is usually used to monitor the progress of the reaction and the solvents used are eg: 1-10% MeOH in ethyl acetate or acetonitrile or DCM, 0-95% hexane in ethyl acetate. Direct phase flash column chromatography ("flash" / "column chromatography") performed on Merck silica gel 60 (0.040-0.063mm) or basic or neutral alumina, or automatically using ISCO Companion T...

Synthetic example 1

[0359] Synthesis example 1 (compound 4)

[0360] 1-[3-Methyl-4-(4-trifluoromethanesulfinylphenoxy)phenyl]-3-phenyl-1,3,5-triazinane-2,4,6-trione

[0361]

[0362] In a 30 ml sealed tube pre-equipped with a magnetic stirrer, ethoxycarbonyl isocyanate (0.291 g, 0.0025 mol) was added to 1-(3-methyl-4-{4-[(trifluoromethyl yl)sulfinyl]phenoxy}phenyl)-3-phenylurea (Intermediate 69, 0.570 g, 0.0012 mol) in toluene (5.70 mL). The resulting reaction mixture was heated at 110 °C for 16 hours. The solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified by preparative HPLC using 0.1% ammonia as modifier and water: acetonitrile (0-100% gradient system) as mobile phase to give 0.045 g (8% yield) of the title compound. 1 H NMR(400MHz,DMSO-d6)δppm 2.18(s,3H)7.15-7.26(m,3H)7.29-7.36(m,1H)7.37-7.55(m,6H)7.90-7.98(m,2H)12.05( s,1H); MS(ES-)m / z 502[M-H] -

Synthetic example 2

[0363] Synthesis example 2 (compound 5)

[0364] 1-(3-Methyl-4-{4-[(trifluoromethyl)sulfanyl]phenoxy}phenyl)-3-phenyl-1,3,5-triazinane-2,4 ,6-trione

[0365]

[0366] In a 30 ml sealed tube pre-equipped with a magnetic stirrer, 1-(3-methyl-4-{4-[(trifluoromethyl)sulfanyl]phenoxy}phenyl)-3-phenylurea (Intermediate 68, 0.60 g, 0.0014 mol) was dissolved in toluene (6.00 mL) and cooled to 0 °C. Ethoxycarbonyl isocyanate (0.247 g, 0.0021 mol) was added to the reaction mixture. The reaction mixture was stirred at 110 °C for 16 hours. The solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified by combined flash chromatography using ethyl acetate as mobile phase and 60-120 silica as stationary phase. The obtained product was further purified by preparative HPLC purification using 5 mM ammonium bicarbonate + 0.05% ammonia as modifier and water: acetonitrile (0-100% gradient system) as mobile phase to give 0.020 g (2.9% yield ) of t...

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Abstract

The present invention relates to a new use of 4-phenoxy-phenyl-1,3,5-triazine derivatives or pharmaceutically acceptable salts thereof, according to formula I, wherein R1, R2 and U have meanings as provided in the description, as medicaments for the treatment and / or prevention of diseases characterized by impaired signalling of neurotrophins and / or other trophic factors. In particular, the invention relates to the treatment of such diseases in patients with the Val66Met mutation in the brain-derived neurotrophic factor gene.

Description

technical field [0001] The present invention relates to 4-phenoxy-phenyl-1,3,5-triazine derivatives and pharmaceutically acceptable salts thereof as medicaments for the treatment and / or prophylaxis characterized by neurotrophic and / or other nutritional Novel use for diseases in which the signaling of factors is impaired. The present invention also relates to novel compounds, pharmaceutical compositions and their use in the treatment and / or prevention of diseases characterized by impaired signaling of neurotrophic factors and / or other trophic factors. Background technique [0002] Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) and neurotrophin-4 / 5 all belong to the neurotrophin protein family. These hormones act through a class of receptor tyrosine kinases called tropomyosin receptor kinases (Trks). Ligand binding to Trk triggers receptor dimerization and autophosphorylation of the kinase domain, which activates the kinase act...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/53C07D251/30A61P25/28
CPCA61K31/53C07D251/30A61P25/28A61P25/00A61P3/10A61P25/16A61K45/06
Inventor G·诺得瓦尔P·福塞尔J·桑丁
Owner ALZECURE PHARMA AB
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