ABCG2 inhibitor
An anticancer agent, acrylonitrile technology, applied in medical preparations containing active ingredients, organic active ingredients, organic chemistry, etc., can solve problems such as insufficient effects, improve bioavailability, and overcome resistance to anticancer agents , Excellent solubility effect
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Embodiment 1
[0081] Example 1: Production of acrylonitrile derivatives with heterocycles
[0082] (Production process 1) Production process of 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carbaldehyde (step of introducing 4-hydroxypiperidine into 5-bromothiophene-2-carbaldehyde)
[0083] Add 5-bromothiophene-2-carbaldehyde to the reaction vessel and add water. Add 3 equivalents of 4-hydroxypiperidine, and stir under reflux for tens of minutes to overnight. Immediately after the reaction was completed, filter with filter paper, and cool the filtrate with running water for several tens of minutes, and then with ice for several hours. The precipitated crystals were suction-filtered, washed with cold water, and dissolved in chloroform after removing water. The chloroform solution was dried with anhydrous sodium sulfate, filtered through a silica gel plug, and washed with chloroform until the color of the filtrate became lighter. The filtrate was concentrated under reduced pressure, and the conce...
Embodiment 2
[0166] Example 2: Anticancer drug resistance overcoming effect in In vivo (oral administration)
[0167] BCRP gene was subcutaneously transplanted into the neck of 6-week-old BALB / c male congenital athymic mice (5 mice / group) into human colorectal cancer HCT116 cells (HCT116 / BCRP cells) (from the Human Cancer Research Society Yoshiichi Sugimoto Chemotherapy Center) (2 x 10 6 cells / 0.1ml / mouse), from 1 / 2ab 2 (a is the long diameter of the tumor, b is the short diameter) The calculated estimated tumor volume is about 100-150mm 3 From 2006 to 2006, the compounds of the present invention shown in Table 1 to Table 4 and the compound disclosed in Patent Document 3 (International Publication No. 2006 / 106778 ) as a positive control compound were administered once a day for 9 days (9 times in total). 14((Z)-2-(3,4-dimethoxy-phenyl)-3-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiophene-2 CPT-11 (45 mg / kg / day) was intravenously administered once a day (3 times in total) on days 1, 5, an...
Embodiment 3
[0185] Example 3: Solubility
[0186] The compound of the present invention shown in Table 5 or Compound 14 of the prior application (10 mg) was weighed in a sealed container, and water or 5% glucose solution was added so that the final concentration was 100 mg / mL. After stirring at room temperature for about 30 minutes, the concentration of the compound in the supernatant obtained by centrifugation was quantified by high-speed liquid chromatography. The results are shown in Table 5. In addition, regarding the compounds of the present invention (compounds 5, 12, 14, 20) and compound 14 of the prior application, the solubility in saline was also confirmed (except for adding saline as a solvent, the same operation as above was performed, and the supernatant was quantified. concentration of the compound in the solution).
[0187] Compounds of the present invention (compounds 5, 8, 10, 12, 14, 16, 18, 20, 22) show extremely high solubility when using water or 5% glucose solution...
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