A compound containing fxr agonist and its preparation method and application
A compound and agonist technology, applied in the field of medicine, can solve problems such as toxicity and short plasma half-life
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preparation example Construction
[0104] Second, the preparation method of the compound containing FXR agonist
[0105] The above-mentioned compounds of the present invention can be synthesized by the methods described in the following schemes and / or other techniques known to those of ordinary skill in the art, but are not limited to the following methods.
[0106] Reaction equation:
[0107]
[0108] Reaction steps:
[0109] Step 1: Dissolve the raw material 1 in an ether solvent, add lithium tetrahydroaluminum under cooling, react at room temperature until the raw material disappears, quench the reaction, and separate the intermediate 1 through a silica gel column; or use an alcohol solvent, and the reducing agent is hydroboration Sodium, room temperature to heating reaction;
[0110] Step 2: Dissolve intermediate 1 in an inert solvent, add excess chlorination reagent, stir at room temperature until the raw materials disappear, and concentrate the system to obtain intermediate 2;
[0111] Step 3: Disso...
experiment example 1
[0144] Experimental Example 1 In vitro pharmacological activity of the compounds of the present invention
[0145] Test sample: some compounds of the present invention, prepared according to the methods of Examples.
[0146] Experimental method: cellular assay, which was entrusted to Shanghai Ruizhi Chemical Research Co., Ltd.
[0147] Cell-based transient co-transfection reporter assay
[0148] Using HEK293 cell line, after culturing for 24 hours, the cell concentration was adjusted to 500,000 cells / mL, and the prepared cell transfection reagents (pBIND 50ng / well, pG5Luc 50ng / well, FuGENE HD 0.3ul / well, No FBSmedia 3.7 μL / well were added). ) into a 96-well plate at 100 μL / well, 37°C, 5% CO 2 Incubate for 24h at the concentration. Compounds were dissolved in DMSO and diluted to 21-fold final concentration. After 3-fold dilution, they were transferred to 5 μL / well of 96-well plates containing transfected cells, 37°C, 5% CO. 2, incubated for 18h. After removing the cell cul...
experiment example 2
[0156] Experimental Example 2 In vivo pharmacological activity of the compounds of the present invention
[0157] Experimental animals:
[0158] Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. SPF grade C57BL / 6 male mice 31 weeks old, aged 8-10 weeks
[0159] Experimental Drugs and Materials
[0160] Reagent 1: ConA, source: Sigma; Reagent 2: DPBS, source: Invitrogen.
[0161] experimental method
[0162] Reagent preparation:
[0163] 1) 20mg / mL ConA preparation
[0164] 1 bottle of 100 mg of ConA, add 5 mL of DPBS to the bottle with a pipette, let it dissolve, mix gently up and down, and dispense into 0.7 mL centrifuge tubes, with 420 μL and 320 μL, and protect from light. , -80 ℃ preservation.
[0165] 2) 1.5mg / mL ConA preparation
[0166] During the test, when preparing 1.5 mg / mL ConA, take 320 μL of ConA dispensed from 1 bottle and wait for it to dissolve. First add 3.7mL of DPBS to a 5mL centrifuge tube, take 300μL of dissolved 20mg / mL ConA into a 5mL...
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