Novel pharmaceutical compositions comprising agonists of the thyroid receptor
A technology of solvates and compounds, applied in the field of new pharmaceutical compositions containing thyroid receptor agonists
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[0862] The following compounds are exemplified compounds of the invention or, where appropriate, used to illustrate compounds used in the invention.
[0863] Description 1
[0864] Methyl 3-(4-hydroxy-3,5-dibromophenyl)propionate
[0865] To a solution of methyl 3-(4-hydroxyphenyl)propionate (10 g, 55.5 mmol) in acetic acid (150 mL) was slowly added bromine (19.5 g, 121.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 5 hours, then evaporated and co-evaporated with ethyl acetate (2 x 200 mL). The residue was purified on a silica gel column to obtain 17.0 g of the title compound (yield 90.6%).
[0866] Description 2:
[0867] Methyl 3-(4-hydroxy-3,5-dichlorophenyl)propionate
[0868] Methyl-3-(4-hydroxyphenyl)propionate (35.6 g, 0.198 mol) was dissolved in dichloromethane (200 mL). The reaction mixture was cooled to 4°C, and sulfuryl chloride (120 mL, 1.42 mol) dissolved in diethyl ether (200 mL) was added dropwise to the reaction mixture over a p...
Embodiment 61
[0925] {3,5-Dibromo-4-[(E)-2-(3-methanesulfonamide-phenyl)-vinyl]-benzyloxy}-acetic acid
[0926]
[0927] To {4-[(E)-2-(3-amino-phenyl)-vinyl]-3,5-dibromo-benzyloxy}-acetic acid tert-butyl ester in dichloromethane (0.6 mL) (Description 10, 0.015 g, 0.03 mmol) were added methanesulfonyl chloride (9 μL, 0.11 mmol) and pyridine (6 μL, 0.07 mmol), and the mixture was stirred at reflux for 2 hours. The water and the more dichloromethane added were separated. The organic phase was dried and evaporated.
[0928] To the above crude product was added 1 mL of a mixture of dichloromethane / TFA (4:1), and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by semi-preparative HPLC to give {3,5-dibromo-4-[(E)-2-(3-methanesulfonamide-phenyl)-vinyl]-benzyloxy}-acetic acid (4.3 mg, 27% yield over two steps).
Embodiment 62
[0930] {3,5-Dibromo-4-[2-(3-methanesulfonamide-phenyl)-ethyl]-benzyloxy}-acetic acid
[0931]
[0932] To {4-[(E)-2-(3-amino-phenyl)-vinyl]-3,5-dibromo-benzyloxy}-acetic acid tert-butyl ester in a round bottom flask (Instruction 10 ) was added a catalytic amount of Wilkinson catalyst (10 mol%). A nitrogen atmosphere was applied and degassed THF was added. The atmosphere was changed to hydrogen and the reaction was stirred overnight. The reaction mixture was filtered through silica gel and the solvent was evaporated. The crude reaction was dissolved in dichloromethane containing 20 vol% trifluoroacetic acid and stirred overnight. Analysis by LCMS showed the reaction mixture to be the title compound {3,5-dibromo-4-[(E)-2-(3-methanesulfonamide-phenyl)-ethyl]-benzyloxy}-acetic acid.
[0933] abbreviation:
[0934] NBS: N-Bromosuccinimide
[0935] ACN: Acetonitrile
[0936] DMPU: 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
[0937] PBr 3 : Phosphorus tribromide ...
PUM
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