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Preparation of 10-hydroxy epsiprantel and applications thereof

A technology of hydroxyiqualone and iqualone, applied in the field of drug discovery, can solve problems such as resistance, drug resistance, and sensitivity decline

Inactive Publication Date: 2014-06-25
QINGDAO VLAND BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, chemotherapy is still the main means of controlling schistosomiasis, but long-term and large-scale use of iqualone may lead to a decrease in the sensitivity of schistosomiasis to this drug, and even the emergence of anti-schistosomiasis. Medicinal properties
It is particularly worth noting that after the laboratory successfully induced praziquantel resistance in Schistosoma mansoni in the 1990s, geographical strains that were not sensitive to praziquantel, praziquantel, etc. Poor efficacy or ineffective treatment of quinone
Moreover, the reduced efficacy of praziquantel in the treatment of other trematodes has also been reported. Although there is not enough evidence to show that the geographical strains in these endemic areas are resistant to praziquantel, it has sounded the alarm to people, especially praziquantel It is also the only specific drug for the treatment of Schistosomiasis japonicum. In countries in Asia where schistosomiasis exists, excessive reliance on a single drug, praziquantel, in the treatment of Schistosomiasis japonicum obviously has the potential risk of developing resistance. It is necessary to find alternate or alternative drugs

Method used

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  • Preparation of 10-hydroxy epsiprantel and applications thereof
  • Preparation of 10-hydroxy epsiprantel and applications thereof
  • Preparation of 10-hydroxy epsiprantel and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018]

[0019]

[0020]

[0021] See existing literature reports (Bioorg.Med.Chem.Lett., 2007, 17, 4154-4157), the preparation of compounds with amino groups specifically includes:

[0022] Step a: Synthesis of Compound 1

[0023] Iquinone (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). The combined organic phases were dried with MgSO4, the organic solvent was removed under reduced pressure, and the product was purified with silica gel column (petroleum ether: ethyl acetate 5:1). The product was obtained as a yellow solid 1.34 g, with a yield of 39%. Compound 1 is analyzed, and the data are as follows: R F (EtOAc:Pet, 3:1) 0.23; m.p. 88...

Embodiment 2 Embodiment 1

[0027] Example 2 Insecticidal activity test of the gained 10-hydroxyl quinone in vitro of embodiment one

[0028] The portal vein infusion method was used to infect mice with Schistosoma japonicum C. japonicum, and the juvenile and adult worms were collected at the juvenile stage (16-18 days after infection) and adult stage (6 weeks after infection), and the synthesized compound 10- Hydroxyiqualone against schistosomiasis juvenile and adult worms.

[0029] (1) Observing the killing effect of the iqualone derivative 10-hydroxyiqualone on schistosome larvae: the compound 10-hydroxyiqualone at a concentration of 1-50 μM was used to kill schistosome larvae. At the same time, as a reference, set up a blank control group, an iqualone group, and an artesunate group, and then observe the death of schistosomiasis larvae under the light microscope. The action of 10-hydroxyiqualone caused spastic contraction and then died; the worms in the blank control group and the iqualone cont...

Embodiment 3 Embodiment 1

[0030] Example 3 Anti-schistosomiasis adult worm effect test in vivo of the compound 10-hydroxyl quinone obtained in embodiment 1

[0031] Three groups were set up for the experiment, one group was the iquinone positive control group, one group was the compound 10-hydroxy iquinone group, and the third group was the negative control group (no administration), with 10 mice in each group. Each mouse was infected with 60 tail butterflies, and on the 28th day after the infection, the mice were orally administered 10-hydroxyiquinone (amount of 200 mg / kg, that is, 200 mg per 1 kg according to the weight of the mice), for 5 consecutive days. Day; the mice in the iqualone control group were orally administered iqualone 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. As a result, it was found that the schistosomes in the normal contr...

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Abstract

The invention belongs to the field of medicine development, and relates to a preparation method of an epsiprantel derivative and applications thereof as antischistosomal medicine. The epsiprantel derivative is 10-hydroxy epsiprantel the structure of which is shown as follows. The epsiprantel derivative 10-hydroxy epsiprantel is obtained by hydroxylation derivatization on the 10 position of the aromatic ring based on the structure of epsiprantel. In-vitro tests and in-vivo tests show that: the 10-hydroxy epsiprantel can be used as an antischistosomal medicine and can kill schistosomula and adult worms of schistosome, while the epsiprantel is only effective to adult worms and is ineffective to schistosomula worms; and the 10-hydroxy epsiprantel is good in water solubility, and therefore the 10-hydroxy epsiprantel can overcome disadvantages of the epsiprantel with respect to druggability.

Description

technical field [0001] The invention belongs to the field of drug discovery, and relates to a preparation method of iquinone derivatives and the application of anti-schistosomiasis drugs. Background technique [0002] Schistosomiasis is a disease caused by humans or mammals infected with schistosomiasis, which seriously endangers human health. Schistosomiasis causes 200 million people to be infected with schistosomiasis every year, 779 million people are at risk of infection, 280,000 people die and the incidence rate exceeds 20 million. Despite the global efforts to control the occurrence of schistosomiasis, schistosomiasis continues to spread to new areas. According to statistics in the early days of the founding of the People's Republic of China, schistosomiasis in my country is distributed in 12 provinces (cities) including Jiangsu, Zhejiang, Shanghai, and Anhui, with a total area of ​​14.8 billion square meters of snails, a total of 11.6 million infected cases, and mo...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/55A61P33/12
CPCC07D487/04Y02A50/30
Inventor 孙伟之姚德勇侯青青
Owner QINGDAO VLAND BIOTECH INC
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