Nitrile thiophene-amidotoluene double-target inhibitor and application thereof
An acid chloride and compound technology, applied in the field of nitrile thiophene amide toluene SGLT2/SGLT1 dual-target inhibitors, can solve the problem of weak SGLT1 inhibition and other problems
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Embodiment 1
[0018] The synthesis of embodiment 1 compound I
[0019]
[0020] A. Synthesis of Compound V
[0021] 3.04g (20mmol) of compound II was dissolved in 10mL of dry dichloromethane, stirred at room temperature, and 3.81g (30mmol) of freshly distilled oxalyl chloride was slowly added dropwise, followed by 2 drops of DMF, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness on a rotary evaporator, then dried on a vacuum oil pump for 5 minutes, then dissolved in 10 mL of dichloromethane, stirred under ice-water bath cooling, and then slowly added dropwise 2.70 g (20 mmol) IV and 6.07 g (60 mmol) Triethylamine, after the dropwise addition, the reaction mixture was stirred overnight at room temperature, and the reaction was checked by TLC for completion. After the reaction is complete, pour the reaction mixture into 100mL ice water, stir, and use 50mL×3 CH 2 Cl 2 After extraction, the extract phases were combined, was...
Embodiment 2
[0024] The preparation of embodiment 2 reference compound D-1
[0025] In order to further illustrate the outstanding pharmacological effect of the compound of the present invention, the application records the preparation of a new compound D-1 (not yet disclosed) in the research process of the present invention, its structure is as follows:
[0026]
[0027] Its preparation method is as follows:
[0028]
[0029] A. Synthesis of Compound V-1
[0030] 2.84g (20mmol) of compound II-1 was dissolved in 10mL of dry dichloromethane, stirred at room temperature, slowly added dropwise 3.81g (30mmol) of freshly distilled oxalyl chloride, and then 2 drops of DMF, and then the reaction mixture was heated at room temperature Stir overnight. The reaction mixture was evaporated to dryness on a rotary evaporator, then dried on a vacuum oil pump for 5 minutes, then dissolved with 10mL of dichloromethane, stirred under ice-water bath cooling, then slowly added dropwise 2.42g (20mmol) ...
Embodiment 3
[0033] Inhibition of the compound of Example 3 on human SGLT2 and human SGLT1 in vitro
[0034] Preparation of human SGLT2 expression vector
[0035] The full-length cDNA clone expressing human SGLT2 (purchased from GenScript Company) (with Hind III and Not I sites placed at both ends of the cDNA) was subcloned into the pEAK15 expression vector (Theracos, USA) between the Hind III and Not I sites between. Clones containing the target gene were identified by restriction endonuclease digestion.
[0036] Preparation of human SGLT2 stable transfection cell line
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