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Phosphoryl methyl salinomycin ether derivative and preparation method thereof

A technology of phosphoryl methyl salinomycin ether and methyl salinomycin ether, which is applied in the field of phosphoryl methyl salinomycin ether derivatives and its preparation, can solve the problem of poor water solubility of salinomycin and local pain and other problems, to achieve the effect of effectively killing cancer cells, preventing cancer metastasis, and high bioavailability

Active Publication Date: 2010-03-17
HANGZHOU ADAMERCK PHARMLABS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Salinomycin has poor water solubility and needs to be made into emulsion or surfactant before it can be administered for injection, which can easily cause local pain

Method used

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  • Phosphoryl methyl salinomycin ether derivative and preparation method thereof
  • Phosphoryl methyl salinomycin ether derivative and preparation method thereof
  • Phosphoryl methyl salinomycin ether derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Synthesis of 9-Methylthiomethyl Salinomycin Ether

[0039]

[0040] Add salinomycin (10.74g, 14.3mmol) and dimethyl sulfoxide (250ml) into the reaction flask and stir to dissolve, then add acetic anhydride (125ml) and acetic acid (35ml) therein. The mixture was stirred vigorously at room temperature for 24 hours and followed by spot plate until the reaction was complete. Pour onto ice (800ml), stir for a further 30 minutes and extract with dichloromethane (4 x 100ml). The combined dichloromethane extracts were washed with water (2 x 100ml) and dried over magnesium sulfate. Dichloromethane was removed under reduced pressure and purified to give 9-methylthiomethyl salinomycin ether.

[0041] 1 H-NMR (D6-DMSO-D2O): δ0.96 (3CH3, t, 9H), 1.06 (4CH3, d, 12H), 1.16 (CH3, d, 3H), 1.21 (CH3, d, 3H), 1.31 (CH3, s, 3H), 1.44 (CH2, m, 2H), 1.56 (CH2, m, 2H), 1.57 (CH2, m, 2H), 1.64, 1.39 (CH2, m, 2H), 1.68, 1.43 ( CH2, m, 2H), 1.76 (CH, m, H), 1.84, 1.59 (CH2, m, 2H), 1.89,...

Embodiment 2

[0043] Synthesis of 9-phosphoryloxymethyl salinomycin ether dibenzyl ester

[0044]

[0045]Add N-iodosuccinimide (2.00 mL) to a well-stirred suspension of methylthiomethyl salinomycin ether (1.98 g, 2.44 mmol), powdered activated 4A molecular sieves (5 g) in tetrahydrofuran (20 mL) g, 95%, 8.44mmol) and a suspension of dibenzyl phosphate (2.20g, 7.83mmol) in dichloromethane (12ml). The mixture was stirred vigorously at room temperature for 30 minutes and followed by spot plate until the reaction was complete. Filter and dilute with ethyl acetate (300ml). The solution was washed with aqueous sodium thiosulfate (10%, 2 x 15ml), water (2 x 20ml), brine (50ml) and dried over magnesium sulfate. The mixture was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain 9-phosphoryloxymethyl salinomycin ether dibenzyl ester.

[0046] 1 H-NMR (D6-DMSO-D2O): δ0.96 (3CH3, t, 9H), 1.06 (4CH3, d...

Embodiment 3

[0048] Synthesis of 9-phosphoryloxymethyl salinomycin ether

[0049]

[0050] To a solution of 9-phosphoryloxymethyl salinomycin ether dibenzyl ester (0.81 g, 0.78 mmol) in tetrahydrofuran (100 mL) and water (5 mL) was added palladium on carbon (10%, 500 mg). The mixture was stirred under hydrogen (1 atm) for 35 minutes and followed by spot plate until the reaction was complete. The catalyst was removed by filtration through celite. Celite was then washed with tetrahydrofuran (300ml) and the combined filtrates were evaporated under reduced pressure. The solid formed was washed with diethyl ether (2 x 20ml), hexane (50ml), dried in vacuo and dissolved in hot methanol (60ml). The solution was filtered and concentrated under reduced pressure to a volume of about 10 ml. After standing at room temperature for 1 hour, the solution was placed in the refrigerator overnight. The crystalline precipitate formed overnight was filtered off and dried in vacuo to yield the product. T...

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Abstract

The invention provides a phosphoryl methyl salinomycin ether derivative, which can be prepared by the following steps: conversing a hydroxyl and a halogeno methyl alkyl sulfur compound of site 9 and site 20 in a salinomycin compound into alkyl sulfide methyl ether so as to generate an alkyl sulfide methyl salinomycin ether compound; reacting with SO2Cl2 to generate halogeno methyl salinomycin ether; then reacting with phosphoryl-protecting group to generate a phosphoryl methyl salinomycin ether with the protecting group; and then conducting catalytic hydrogenation, adding alkali or amine, thus preparing the phosphoryl methyl salinomycin ether derivative. The phosphoryl methyl salinomycin ether derivative has good water-solubility and can be converted into salinomycin in blood and effectively kill cancer stem cells, thus achieving the treatment purposes of effectively killing cancer cells, preventing cancer reoccurrence and cancer metastasis. A preparation method of the invention has moderate reaction conditions, high yield, easy operation and capability of industrialized production. The structural general formula of the phosphoryl methyl salinomycin ether derivative is shown general formula (I).

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and relates to a phosphorylmethyl salinomycin ether derivative and a preparation method thereof. The compound has greater water solubility and bioavailability, and is transformed into salinomycin in blood, thereby effectively killing cancer stem cells. technical background [0002] Salinomycin (salinomycin) is white or light yellow crystalline powder with a slight specific odor and a melting point of 140-142°C. Soluble in acetone, chloroform, benzene, ethyl acetate, ether, etc., almost insoluble in water. It is a polyether monocarboxylic acid antibiotic with a special ring structure and is a typical ionophore antibiotic. It has a particularly strong affinity for cations in cells, especially K+, Na+, and Rb+, which enhances the permeability of cations necessary for biology through the lipid barrier on the membrane, thereby making Gram-positive bacteria, fungi, pathogens and malaria ...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61P35/00
CPCY02P20/55
Inventor 漆又毛揭清张冯敏
Owner HANGZHOU ADAMERCK PHARMLABS INC
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