Nitrobenzene-containing oxadiazole sulfoxide compound as well as preparation method and application thereof
A compound and drug technology, applied in the field of drugs related to thrombotic diseases, can solve problems such as high bleeding risk
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Embodiment 1
[0024]
[0025] A. Synthesis of IV-1
[0026] 2.23 g (10 mmol) of compound II-1, 3.70 g (10 mmol) of compound III and 4.15 g (30 mmol) of solid potassium carbonate were stirred overnight in 20 mL of ethanol. The reaction mixture was poured into 200 mL of ice water, stirred, adjusted to pH=4 with concentrated hydrochloric acid, extracted with 50 mL×3 dichloromethane, combined organic phases, washed with brine, dried over anhydrous sodium sulfate, and evaporated the solvent on a rotary evaporator. The obtained residue was purified by column chromatography to obtain pure product IV-1, white solid, MS, m / z=535 ([M+Na] + ).
[0027] B. Synthesis of I-1
[0028] 2.56g (5mmol) of compound IV-1 was dissolved in 25mL of dichloromethane, stirred at -10°C, and 3.13g (20mmol) of m-chloroperoxybenzoic acid (mCPBA) was slowly added. After the reaction mixture was stirred at this temperature for 1 hour, stirring was continued overnight at room temperature. The reaction mixture was pou...
Embodiment 2-3
[0030] According to the method of Example 1, the following compounds with general formula I were synthesized.
[0031]
[0032] Among them, Example 4 is a comparative compound (still a brand new structure discovered by the applicant), to fully illustrate the pharmacological effect.
Embodiment 5
[0033] Example 5 In vitro platelet aggregation inhibition test
[0034] Pharmacological tests of substances were performed in TRAP (thrombin receptor activating peptide)-induced platelet aggregation in 96-well plates. 3.13% sodium citrate solution was added to the syringe in advance, and then 20 mL of blood from healthy volunteers was drawn in, centrifuged at 1500 g for 20 minutes, platelet-rich plasma (PRP) was separated and mixed with 1 μL of PGE1 solution (500 μg / mL ethanol solution) / mL PRP for treatment. After incubation at room temperature for 5 minutes, they were centrifuged at 1200 g for 20 minutes to remove leukocytes. Transfer the leukocyte-free PRP to 15 mL PP tubes in batches at 5 mL / portion, and centrifuge at 3600 g to pellet the platelets. Then, decant the upper plasma layer and resuspend the platelet pellet from 5 mL of PRP in 1 mL of Tyrode (120 mM NaCl, 2.6 mM KCl, 12 mM NaHCO3, 0.39 mM NaH2PO4, 10 mM HEPES, 0.35% BSA, 5.5 mM glucose, pH=7.4 ), and adjusted ...
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