Synergistic prodrug derivatives of ubenimex derivatives and compounds with antitumor activity, preparation methods and applications thereof
A technology with anti-tumor activity and ubenimex, which is applied in the preparation of organic compounds, urea derivatives, sugar derivatives, etc., can solve the problems of poor fat solubility, low bioavailability, and large toxic and side effects, and achieve Effects of prolonging residence time, increasing bioavailability, and improving pharmacokinetic properties
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preparation example Construction
[0054] In a specific embodiment, the preparation method of the synergistic prodrug derivative of the ubenimex derivative and the compound with anti-tumor activity comprises: putting 5 mmol of the compound with anti-tumor activity into a reaction bottle, adding 20 ml Pyridine was dissolved completely, and then 0.65 g of activated carbon was added, and 0.5 g of triphosgene was slowly added in an ice bath, and the reaction was continued for 1 hour under an ice bath, the phosgene was drawn out, and then poured into N 2 , carried out three times; under ice bath, slowly added 5 mmol of the ubenimex derivative, and then reacted at room temperature for 12 hours; filtered activated carbon, extracted with ethyl acetate, washed 3 times with 6mol / L hydrochloric acid solution, and then washed with saturated brine 3 times, dried over anhydrous sodium sulfate, distilled off the ethyl acetate until solid precipitation stopped, put it in the refrigerator for crystallization, and filtered to obt...
preparation example 1
[0065] Put 5mmol pentafluorouracil (0.65g) in a reaction flask, add 20ml of pyridine to dissolve it completely, then add 0.65g of activated carbon, slowly add 0.5g of triphosgene under ice bath, continue to react under ice bath for 1 hour, draw out Phosgene, rushed into N 2 , for three times. Under ice-cooling, 5 mmol of ubenimex (1.7 g) was slowly added, followed by reaction at room temperature for 12 hours. Activated carbon was filtered, extracted with ethyl acetate, washed three times with 6 mol / L hydrochloric acid solution, washed three times with saturated brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off until the precipitation of solids ceased, put into the refrigerator for crystallization, and filtered to obtain a white product, which was compound 5FU-Bestatin, a white solid, yield: 36.7%, melting point=165-167°C. MS-ESI: [M-1]=463.6; [M-1+Na]=485.8. Its proton nuclear magnetic resonance spectrum data are as follows:
[0066] 300MHz 1...
preparation example 2-13
[0068] Synergistic prodrug derivatives were prepared according to a method similar to that of Preparation Example 1, the difference being that the compounds with antitumor activity and ubenimex derivatives used were listed in the following table 1 respectively to obtain synergistic prodrug derivatives I -1 to I-12, their structural formulas are shown in Table 1 below.
[0069] Table 1
[0070]
[0071]
PUM
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