Novel thyroid receptor ligands
A compound, selected technology, applied in the field of antagonists, can solve the problems of unknown potency and tolerability
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Embodiment 1
[0078] {4,6-Dibromo-5-[3-isopropyl-4-(naphthyl-2-methoxy)phenoxy]indanyl-1}acetic acid
[0079] (a) Add sodium acetate (7.0 g, 83 mmol) to a mixture of 5-hydroxy-1-indanone (5.6 g, 38 mmol), acetic acid (260 ml) and 4-5 drops of water, then add dropwise Bromine (13.3 g, 83 mmol) in acetic acid (60 mL). The reaction mixture was stirred at room temperature for 18 hours, and the precipitate was filtered and dried. 8.4 g (72%) of 4,6-dibromo-5-hydroxy-1-indanone were obtained as a solid, which was used directly in the next experiment without further purification.
[0080] (b) In a mixture containing bis-(3-isopropyl-4-methoxyphenyl)iodonium tetrafluoroborate (6.25 g, 12.2 mmol), bronze (1.02 g) and dichloromethane (25 mL ) in a stirred suspension system containing 4,6-dibromo-5-hydroxyl-1-indanone (2.50 g, 8.17 mmol) and triethylamine (1.00 g, 8.99 mmol) in nitrogen at room temperature Dichloromethane solution (25 mL). The reaction mixture was stirred for 48 hours in the dark ...
Embodiment 2
[0086] {4,6-Dibromo-5-[4-(4-fluorobenzyloxy)-3-isopropylphenoxy]indanyl-1}acetic acid
[0087] 4-Fluorobenzyl bromide (15 mg, 0.080 mmol) and ethyl[4,6-dibromo-5-(3-isopropyl-4-hydroxyphenoxy)indanyl-1]acetate (20 mg, 0.039 mmol) was coupled and then worked up according to the procedure described in Example 1. Obtained 5.3 mg (23%) of {4,6-dibromo-5-[4-(4-fluorobenzyloxy)-3-isopropylphenoxy]indanyl-1}acetic acid. LC-MS (ES) m / z 591 (M-1).
Embodiment 3
[0089] {4,6-Dibromo-5-[3-isopropyl-4-(5-methylisoxazolyl-3-methoxy)phenoxy]indanyl-1}acetic acid ethyl[4 , 6-dibromo-5-(3-isopropyl-4-hydroxyphenoxy)indanyl-1] acetate (20 mg, 0.039 mmol), potassium carbonate (11 mg, 0.080 mmol) The mixture with acetonitrile (0.75 mL) was stirred at room temperature for 30 minutes. 3-Chloromethyl-5-methylisoxazole (10.5 mg, 0.080 mmol) and a catalytic amount of potassium iodide in acetonitrile (0.25 mL) were added, and the reaction mixture was stirred at 80°C. After 16 hours, the reaction mixture was purified on a short column (SPE-silica, 1 g / 6 mL, n-heptane / ethyl acetate 65:35), the resulting filtrate was concentrated, the residue and THF (0.50 mL) and Lithium hydroxide (0.5 mL, 1N) was stirred at room temperature for 16 hours. The reaction mixture was filtered through an SCX-column (strong cation exchanger: silane benzenesulfonate, 1 g / 3 ml, eluting with methanol), and the filtrate was concentrated. The filter residue was dissolved with ...
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