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Niclosamide phosphate ester and pharmaceutically acceptable salt and application thereof

A technology of niclosamide phosphate and niclosamide phosphate, which is applied in the application field of preparing related drugs, can solve the problems of poor compound solubility and poor oral bioavailability, and achieve improved water solubility, improved effect, and improved Effect of Drug Concentration

Inactive Publication Date: 2010-07-14
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the poor oral bioavailability of niclosamide itself and the poor solubility of the compound in water and most organic solvents, this limits its further development and application.

Method used

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  • Niclosamide phosphate ester and pharmaceutically acceptable salt and application thereof
  • Niclosamide phosphate ester and pharmaceutically acceptable salt and application thereof
  • Niclosamide phosphate ester and pharmaceutically acceptable salt and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of Compound Niclosamide Phosphate Diethyl Ester 3

[0026] Under nitrogen protection, 8.32g of niclosamide was dissolved in 120mL of anhydrous acetonitrile, and 15.2g of carbon tetrachloride, 5.16g of diisopropylethylamine, and 240mg of N,N-methylaminopyridine were added at -10°C. Add 2.76g of diethyl phosphite dropwise, keep the internal temperature below 0°C, and react for 2 hours. After the reaction is complete, add 0.5M KH2PO4 Quenched, warmed to room temperature and stirred for 1 hour. Most of the organic solvent was evaporated under reduced pressure, extracted by adding 200 mL (X2) ethyl acetate, washed with water, washed with saturated brine, dried by adding anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain 11.5 g of light yellow solid quantitatively. 1 H-NMR (400MHz, CDCl 3 )1.33(t, 6H), 4.21(q, 4H), 7.52(m, 2H), 8.06(d, 1H), 8.22(m, 1H), 8.34(d, 1H), 8.23(d, 1H), 9.52(bs, 1H).m / z: 463(M+1)

Embodiment 2

[0028] Synthesis of Compound Niclosamide Monoethyl Phosphate 2a

[0029] Under nitrogen protection, 3.15g of compound 3 was dissolved in 60mL of anhydrous chloroform, 2.1g of trimethylchlorosilane was added dropwise, stirred at room temperature for 8 hours, after the reaction was complete, the solvent was evaporated under reduced pressure, 100mL of methanol was added, and stirred for 30 minutes before Evaporate the solvent under reduced pressure, add 50mL deionized water, adjust the pH to alkaline with ammonia water, add 50mL ethyl acetate to extract twice, separate the water phase, adjust the pH value to 3 with 10% hydrochloric acid, precipitate a large amount of solid, filter, and dry under pressure Finally, 1.3 g of compound 2a was obtained with a yield of 45%. m / z: 435(M+1)

Embodiment 3

[0031] Synthesis of Compound Niclosamide Phosphate 1

[0032] Under nitrogen protection, 3.15g of compound 3 was dissolved in 60mL of anhydrous chloroform, 5.2g of trimethylchlorosilane was added dropwise, stirred at room temperature for 8 hours, after the reaction was complete, the solvent was evaporated under reduced pressure, 100mL of methanol was added, and stirred for 30 minutes before The solvent was distilled off under reduced pressure to obtain 2.49 g of compound 1 as a white solid with a yield of 90%. 1 H-NMR (400MHz, DMSO) 7.54(d, 1H), 7.67(m, 1H), 7.82(d, 1H), 8.28(m, 1H), 8.40(d, 1H), 8.48(d, 1H). m / z: 407 (M+1).

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Abstract

The invention discloses niclosamide phosphate ester, a pharmaceutically acceptable salt thereof, and application of the niclosamide phosphate ester serving as a soluble pro-drug of niclosamide in preparing correlative medicaments. The niclosamide phosphate ester has a general formula of I or II. The niclosamide phosphate ester and the pharmaceutically acceptable salt thereof have good water solubility, and can be used for producing niclosamide parent drugs through metabolism. Thus, the niclosamide phosphate ester and the pharmaceutically acceptable salt can be used as water-soluble oncomelania-killing medicaments (for treating schistosomiasis), water-soluble human and livestock tapeworm expelling medicaments, and novel antineoplastic medicaments.

Description

technical field [0001] The invention relates to a compound niclosamide phosphate, a pharmaceutically acceptable salt thereof and the application of the compound as a soluble prodrug of niclosamide in the preparation of related medicines. technical background [0002] Niclosamide (Niclosamide), also known as Mietaolin and Yumosheng, was first successfully synthesized in 1959 by Schloafster et al. in Germany, and was industrially produced by Bayer AG in Germany. It was originally a snail-killing drug, which has excellent curative effect in the field of schistosomiasis treatment. Niclosamide can also be made into a coating agent to prevent acute schistosomiasis infection, kill snails, schistosomiasis cercariae and miracidia, and has good molluscicidal effect and toxic side effects. Small, low toxicity to humans and animals, etc., is a new force in the treatment of schistosomiasis. [0003] In addition, niclosamide is also a broad-spectrum, high-efficiency, and low-toxicity dru...

Claims

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Application Information

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IPC IPC(8): C07F9/12A61K31/661A61P35/00A61P33/10A61P33/12
Inventor 丁克裴端卿周净
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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