Preparation method of 10-hydroxyl praziquantel and application thereof as anti-schistosomiasis medicine
A technology of hydroxypraziquantel and praziquantel, applied in the field of drug discovery, can solve the problems of poor biological activity and no anti-schistosome activity
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Embodiment 1
[0029]
[0030] See existing literature reports (Bioorg. Med. Chem. Lett., 2007, 17, 4154-4157), Compound 2 is prepared, specifically comprising:
[0031] Step a: Synthesis of Compound 1
[0032] Praziquantel (3.00 g, 9.60 mmol) was dissolved in sulfuric acid (9.42 g, 5.14 mL, 96 mmol, 10 eq) cooled to 0 °C. Concentrated nitric acid (3.03 g, 2.12 mL, 48 mmol, 5 eq ) was then carefully added. The reaction mixture was stirred at room temperature for 24 hours, cooled with ice, and neutralized with sodium carbonate to pH 8. The reaction mixture was extracted 3 times with EtOAc (150 mL). Combined organic phases with MgSO 4 ), the organic solvent was removed under reduced pressure, and the product was purified by silica gel column (petroleum ether: ethyl acetate 5:1). get the product 1 As a yellow solid 1.34 g, yield 39%. pair compound 1 For analysis, the data is as follows: R F (EtOAc:Pet, 3:1) 0.23; m.p. 88 – 90 ℃; 1 H NMR (200 MHz, CDCl 3 ): 1.44 (m, 10H), 2.47 (...
Embodiment 2
[0037] Embodiment two: In vitro insecticidal activity test of the 10-hydroxypraziquantel obtained in embodiment one
[0038] The mice were infected with the cercariae of Schistosoma japonicum by portal vein infusion, and the juvenile stage (16-18 days after infection) and the adult stage (6 weeks after infection) were collected to collect juvenile and adult worms, and observe the synthesized compound 10-OH by in vitro culture. -PZQ anti-schistosomimesis, adult worms.
[0039] (1) Observe the killing effect of praziquantel derivative 10-OH-PZQ on schistosome larvae: the compound 10-OH-PZQ with a concentration of 1~50 μM has the effect on schistosome larvae. At the same time, as a reference, set the blank control group, praziquantel group, and artesunate group, and then observe the death of schistosome larvae after the action under a light microscope. The results can be found in figure 1 , 2 , 3 and Table 1.
[0040] Figure 1~3 Display: observed under a light microscope, i...
Embodiment 3
[0049] Embodiment 3: The compound 10-OH-PZQ obtained in embodiment 1 in vivo anti-schistosomiasis adult worm test
[0050] Three groups were set up for the experiment, one group was the positive control group for praziquantel, the other group was the compound 10-OH-PZQ group, and the third group was the negative control group (no administration), with 10 mice in each group. Each mouse was infected with 60 cercariae, and on the 28th day after infection, the mice were orally administered with 10-OH-PZQ (200 mg / kg, that is, 200 mg per 1 kg of mouse weight), for 5 consecutive days; The mice in the praziquantel control group were orally administered praziquantel 100 mg / kg for 5 consecutive days; the mice in the three groups were dissected on the 21st day after the administration, the hepatic portal vein was perfused aseptically, and the worms were counted. It was found that the schistosomes in the normal control group did not die (see Figure 5 ), while schistosome death was found...
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