Hydroxyl diamantane amide derivative, preparation method and use thereof
A kind of technology of aspect and compound, applied in the field of drugs for the treatment of diabetes, can solve problems such as undiscovered weight gain
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Embodiment 1
[0022] The preparation of embodiment 1 compound I
[0023]
[0024] Add 2.10g (10mmol) compound II, 3.21g (10mmol) compound III, 2.06g (10mmol) N,N'-dicyclohexylcarbodiimide (DCC) and 1.22g (10mmol) in a 100mL round bottom flask ) 4-dimethylaminopyridine (DMAP), dissolved in 20 mL of dry THF, stirred overnight at room temperature, and TLC showed that the reaction was substantially complete. The reaction mixture was suction filtered to remove the solid, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by column chromatography to obtain compound IV as a white solid, ESI-MS, m / z=531 ([M+NH 4 ] + ).
[0025] 3.08g (6mmol) compound IV was dissolved in 30mL THF, 0.10g 10% Pd / C was added, catalytic hydrogenolysis was carried out at room temperature, and the reaction was completed within 12 hours. The reaction mixture was suction filtered to remove the catalyst, and the filtrate was concentrated on a rotary evaporator, poured into 200 m...
Embodiment 2
[0028] The preparation of embodiment 2 reference compound D1
[0029] In order to fully illustrate the beneficial effects of the compounds of the present invention, the applicant recorded the following compound D1 (unpublished) found during the experiment as a pharmacodynamic reference compound.
[0030]
[0031] Its preparation method is as follows:
[0032]
[0033] In a 100mL round bottom flask, add 1.94g (10mmol) compound II-1, 3.21g (10mmol) compound III, 2.06g (10mmol) N, N'-dicyclohexylcarbodiimide (DCC) and 1.22g (10mmol) 4-dimethylaminopyridine (DMAP), dissolved in 20mL of dry THF, stirred at room temperature overnight, TLC showed that the reaction was almost complete. The reaction mixture was suction filtered to remove the solid, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by column chromatography to obtain compound IV-1, a white solid, ESI-MS, m / z=515 ([M+NH 4 ] + ).
[0034] 2.99g (6mmol) of compound IV-1 wa...
Embodiment 3
[0037]Embodiment 3 compound measures the inhibition of DPP-IV enzyme
[0038] Using the fluorescent DPP4 activity detection kit of BPS Bioscience Company, the inhibitory activity of the compound of the present invention on DPP-IV enzyme was determined.
[0039] Dilute the samples sequentially according to the concentration of 5, 10, 30, 100 and 200ng / kg, respectively, and add the samples in the following table in the fluorescence reaction 96-well plate:
[0040]
[0041]
[0042] Place in a water bath at 22°C for 10 minutes, use a Spectra Max M5 fluorescence detector with an excitation light of 350nm, and measure the absorbance with 450nm fluorescence. Calculation of IC from the concentration-fluorescence intensity curve 50 values, see the table below.
[0043] IC of compounds for inhibition of DPP-IV enzymes 50 value
[0044]
[0045] It can be seen from the above table that the compound of the present invention has a strong inhibitory effect on DPP-IV enzyme.
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