Quinone-, hydroquinone-and naphthoquinone-analogs of vatebenzoquinone for treatment of mitochondrial disorder diseases
A technology of stereoisomers and compounds, applied in the field of quinone-, hydroquinone- and naphthoquinone-analogues of vatibenone for the treatment of abnormal mitochondrial diseases, which can solve the problem of no drugs
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[0715] Accordingly, in some embodiments, the present application relates to a method for treating or preventing Friedrich's ataxia or a sign or symptom of reduced ataxia level or activity in a subject in need thereof, comprising administering to the subject A therapeutically effective amount of a compound of Formula E-F (as described above), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, hydrate and / or solvate thereof. Because they are considered an alternative therapeutic embodiment (i.e. they can cycle in the body between reduced and oxidized forms, respectively: ), so in some embodiments, the present application relates to a method for treating or preventing Friedrich's ataxia or a sign or symptom of reduced ataxia level or activity in a subject in need thereof, comprising administering to the subject A therapeutically effective amount of a compound of formula C-D (as described above), or a pharmaceutically acceptable salt, stereoi...
Embodiment 1
[0764] Example 1: Synthesis of 2-((R,6E,10E)-16-fluoro-15-(fluoromethyl)-3-hydroxy-3,7,11-trimethylhexadecane-6,10,14 -Trien-1-yl)-3,5,6-trimethylcyclohex-2,5-diene-1,4-dione (Compound A)
[0765]
[0766] plan 1:
[0767]
[0768] step a. Synthesis of (2E,6E)-1-bromo-3,7,11-trimethyldodecane-2,6,10-triene (2)
[0769] To (2E,6E)-3,7,11-trimethyldodecane-2,6,10-trien-1-ol (1.2 g, 8.99 mmol) in dry tetrahydrofuran (THF, 30 mL) The cooled (0°C) solution was added dropwise with phosphorus tribromide (PBr 3 , 1.02 mL, 10.8 mmol), and the reaction mixture was stirred at 0 °C for 1 hour (hr.). The reaction mixture was poured onto ice (50 g) and washed with diethyl ether (Et 2 0, 3x80mL) extraction. The combined organic phases were passed over anhydrous (anh.) Na 2 SO 4 Drying and concentration under reduced pressure gave 2 (2.5 g) in 98% yield.
[0770] step b. Synthesis of (((2E,6E)-3,7,11-trimethyldodecane-2,6,10-trien-1-yl)sulfonyl)benzene (3)
[0771] To a coo...
Embodiment 2
[0851] Example 2: Synthesis of 2-((R,6E,10E)-16-fluoro-3-hydroxy-3,7,11,15-tetramethylhexadecane-6,10,14-triene-1- base)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione (Compound B)
[0852]
[0853] Scenario 3:
[0854]
[0855] step a. Synthesis of tert-butyl (((R)-2-((3E,7E)-13-fluoro-4,8,12-trimethyltridecane-3,7,11-trien-1-yl)- 2,5,7,8-Tetramethylchroman-6-yl)oxy)dimethylsilane (28)
[0856] To a cooled (-78 °C) and stirred solution of 23 (0.750 g, 0.845 mmol, prepared according to the procedure described in Example 1 above) in dry THF (15 mL) under argon was added hexamethyldisilazide Alkyllithium (1M solution in THF, 0.89 mL, 0.887 mmol). After stirring at the same temperature for 30 minutes, a solution of fluoroacetone (27, 92 μL, 1.27 mmol) in dry THF (2.0 mL) was added dropwise. After continuous stirring at the same temperature for 1 hour, the reaction mixture was slowly (in about 4 hours) warmed to room temperature and stirred overnight. The reaction mixture...
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