Halogenated triazole sulfuryl malonic acid compound, as well as preparation method and application thereof
A technology of dimethyl bromomalonate and compounds, applied in the field of uric acid transporter 1 inhibitors, can solve problems such as allopurinol liver and bone marrow toxicity, fulminant hepatitis, and allergic reactions
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Embodiment 1
[0020] The synthesis of embodiment 1 compound I-1
[0021]
[0022] A. Synthesis of Compound IV-1
[0023] 5.52g (20mmol) of compound II-1 and 4.22g (20mmol) of compound III were dissolved in 100mL of dry DMF, stirred at room temperature, and 8.29g (60mmol) of solid K was added 2 CO 3 , and then the reaction mixture was stirred at room temperature until TLC tracking found that the reaction was complete (generally within 12 h). The reaction mixture was poured into 400 mL of ice water, stirred, using 100 mL × 3 CH 2 Cl 2 After extraction, the extract phases were combined, washed with 100 mL of 5% brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the obtained residue was purified by column chromatography to obtain compound IV-1, a yellow-white solid, ESI-MS, m / z=429 ([M+Na] + ).
[0024] B. Synthesis of Compound V-1
[0025] 4.87g (12mmol) of compound IV-1 ...
Embodiment 2-4
[0031] Referring to the operation steps of Example 1, the compounds listed in the following table were synthesized.
[0032]
Embodiment 5
[0034] The IC50 values of the compounds of the present invention and related compounds on URAT1 inhibition were determined according to similar methods described in the literature (Example 12 in US2014 / 0005136).
[0035] Construction of a cell line stably expressing the humanized URAT1 transporter: The humanized URAT1 gene (SLC22A112) was subcloned from the plasmid pCMV6-XL-5 (Origene) into the eukaryotic expression plasmid pCMV6 / neo (Origene). Gene sequencing confirmed that the humanized URAT1 was consistent with the information recorded in the gene bank (NM_144585.2). HEK293 human embryonic kidney cells (ATCC#CRL-1573) were cultured in EMEM tissue culture medium under 5% CO 2 And cultured in 95% air atmosphere. pCMV6 / Neo / URAT1 was transfected onto HEK293 cells using L2000 type transfection reagent (Invitrogene). After 24 hours, the transfected cells were divided into tissue culture dishes with a diameter of 10 cm, continued to grow for one day, and then the medium was re...
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