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Phosphoryl carboxylic acid salinomycin ester derivative and preparing method thereof

A technology of risamycin ester and phosphoryl carboxylic acid, which is applied in the field of phosphoryl methyl salinomycin ether derivatives and its preparation, can solve the problems of easy local pain, poor water solubility, and influence on practical application, and increase the Good compliance, good stability, fast onset effect

Active Publication Date: 2010-03-10
HANGZHOU ADAMERCK PHARMLABS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Both salinomycin and its sodium salt have poor water solubility and need to be made into emulsions or surfactants to make injections, which can easily cause local pain and affect practical application.

Method used

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  • Phosphoryl carboxylic acid salinomycin ester derivative and preparing method thereof
  • Phosphoryl carboxylic acid salinomycin ester derivative and preparing method thereof
  • Phosphoryl carboxylic acid salinomycin ester derivative and preparing method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Synthesis of Salinomycin 9-Chloroacetate

[0051]

[0052] Dissolve salinomycin (20mg, 0.027mmol) in pyridine (1ml), add chloroacetic anhydride (9.1mg, 0.053mmol) dropwise in an ice bath under magnetic stirring, protect with nitrogen, keep anhydrous environment, and dropwise add Finally, the ice bath was removed, the reaction solution was gradually raised to room temperature, and stirred for 3 hours under the protection of argon. After the spot reaction was complete, ethyl acetate and water were added, extracted with ethyl acetate, the organic phases were combined, and washed 2-3 times with water. , the organic phase was dried, filtered, and concentrated to obtain salinomycin 9-chloroacetate.

[0053] 1H-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, 2...

Embodiment 2

[0055] Synthesis of 9-(phosphorylthio)acetate salinomycin ester disodium

[0056]

[0057] In a three-necked flask, add sodium thiophosphate (7.2mg, 0.02mmol), 9-chloroacetic acid salinomycin ester (18.21mg, 0.022mmol) and 0.4ml of distilled water at one time, stir, and under ice water cooling, in the flask The temperature naturally drops to about 15°C, while adding 0.12ml of dimethyl sulfoxide (DMSO) dropwise, the reaction temperature rises gradually, and does not exceed 20°C. After the addition is completed, continue to stir until the reaction is complete to obtain a product solution. Add acetone (the amount of acetone is 5 times the volume of the mother liquor), stir, add anhydrous sodium sulfate to it and dry for 2 hours, filter, pull the mother liquor to dry at room temperature to remove acetone, add ether to the residue to precipitate the product, wash with ether, and dry After that, 9-(phosphorylthio) acetate disodium salinomycin was obtained.

[0058] 1 H-NMR (D6-...

Embodiment 3

[0060] Synthesis of Disodium 9-(Phosphoryloxy) Salinomycin Ester Acetate

[0061]

[0062] In a three-necked flask, add sodium phosphate (7.6mg, 0.02mmol), 9-chloroacetic acid salinomycin ester (18.21mg, 0.022mmol) and 0.4ml of distilled water at one time, stir, and under ice water cooling, the temperature in the flask is natural Decrease to about 15°C, dropwise add 0.12ml of dimethyl sulfoxide (DMSO), the reaction temperature rises gradually, not exceeding 20°C, after the addition is complete, continue to stir until the reaction is complete to obtain a product solution, filter the reaction solution, add acetone to the mother liquor (the amount of acetone is 5 times the volume of the mother liquor), stir, add anhydrous sodium sulfate to it and dry for 2 hours, filter, pull the mother liquor at room temperature to remove acetone, add ether to the residue to precipitate the product, wash with ether, and dry to obtain 9-(phosphoryloxy) salinomycin disodium acetate, 1 molecule ...

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Abstract

The invention provides a phosphoryl carboxylic acid salinomycin ester derivative having a structure as stated in the lower right general formula (I): ensuring that salinomycin compound reacts with (a) at the existence of alkali to obtain corresponding ester; reacting with (b) to obtain a target product (I); or ensuring that salinomycin (a) reacts with (c) at the existence of alkali to obtain corresponding ester (c); and performing catalytic hydrogenation to obtain a target product. The derivative of the invention has favourable water solubility and can be prepared into injection, and the derivative is converted into salinomycin in blood, the prepared preparation has the characteristics of high bioavailability, fast adsorption, favourable stability and the like, and can effectively kill cancer stem cells. The preparing method of the invention has high yield, simple operation and industrial production foreground. The general formula (I) structure of the invention is disclosed.

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 high 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 par...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/665A61P35/00
Inventor 漆又毛揭清张冯敏
Owner HANGZHOU ADAMERCK PHARMLABS INC
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