Amino acid tanshinone phenolic ester derivatives and preparation method thereof

A technology of tanshinol ester and tanshinone diphenol, which is applied in the field of amino acid tanshinol ester derivatives and its preparation, can solve the problems of increasing water solubility and not meeting the requirements of clinical medication, and achieve the effect of good water solubility and high application value

Active Publication Date: 2014-08-13
南京虹桥医药技术研究所有限公司
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  • Abstract
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  • Claims
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AI Technical Summary

Problems solved by technology

The first two types of structural modification are mainly aimed at improving their anti-tumor activity. Although the anti-tumor activity of the structurally modified compound has improved compared with the original compound in vitro and in vivo, no matter in vitro or in vivo animal anti-tumor tests, because the solubility problem has not been solved, All need to be administered after dissolving in DMSO, which obviously does not meet the requirements of clinical medication; and although the purpose of the third type of structural modification has significantly increased its water solubility, because sodium sulfonate is an ionic compound, it is difficult to pass through lipids and proteins. Component-based biofilm structure system, which may be one of the reasons why its efficacy is lower than that of tanshinone IIA (Shi Yuan, Li Xiuying, Wang Tianyi, Chang Di, Zheng Li, Wang Siling

Method used

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  • Amino acid tanshinone phenolic ester derivatives and preparation method thereof
  • Amino acid tanshinone phenolic ester derivatives and preparation method thereof
  • Amino acid tanshinone phenolic ester derivatives and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] a: Reduction reaction: Weigh 2.94g of tanshinone IIA raw material into a 100ml three-necked bottle, add about 160mg of 10% palladium carbon (Pd / C), dissolve it in about 30ml of anhydrous THF, stir at room temperature under the protection of hydrogen until the color of the solution fades .

[0035] b: Preparation of amino acid intermediate: in a 500ml reaction flask, add 1.8g sodium bicarbonate, 180ml water, add 1.7g glycine under stirring in an ice bath, dissolve 3.8g benzyl chloroformate in 40ml ether, then add dropwise to In the amino acid reaction bottle, after the addition, slowly rise to room temperature and stir for 4 hours, pour into ice water, adjust pH=1.5 with hydrochloric acid, stir at room temperature for 15 minutes, add 200ml ether for extraction three times, the ether layer is washed three times with saturated saline, and the organic layer Dry over anhydrous sodium sulfate, filter, and column chromatography to obtain N-benzyloxycarbonylglycine (Cbzglycine)...

Embodiment 2

[0044] a: Reduction reaction: Weigh 2.94g of tanshinone IIA raw material into a 100ml three-necked bottle, add about 160mg of 10% palladium carbon (Pd / C), dissolve it in about 30ml of anhydrous THF, stir at room temperature under the protection of hydrogen until the color of the solution fades .

[0045] b: Preparation of amino acid intermediates: Add 1.7g of glycine, 0.4g of sodium hydroxide, 10ml of water and 10ml of dioxane into a single-port bottle, cool to an ice bath, slowly add 1.1 equivalents of Boc anhydride dropwise, and slowly rise to React at room temperature for more than 6hrs. The excess anhydride was removed by extraction with ethyl acetate, the pH of the aqueous layer was adjusted to 3-4 with 2N HCl, extracted with EA, dried, and evaporated to dryness to obtain Boc amino acid for use.

[0046] c: Add an appropriate amount of THF and 1.1 equivalents of N-methylmorpholine to b, add 1.05 equivalents of pivaloyl chloride at -10°C, insert a drying tube and stir at ...

Embodiment 3

[0054] a: Reduction reaction: Weigh 2.94g of tanshinone IIA raw material into a 100ml three-neck flask, add about 300mg of 5% Pd / C, dissolve in about 50ml of anhydrous ethyl acetate, stir at room temperature under the protection of hydrogen until the color of the solution fades.

[0055] b: Preparation of amino acid intermediates: Weigh 2.2g of L-alanine and dissolve it in 30ml of 10% Na 2 C0 3 In the solution, stir in an ice bath; weigh 5.7g of fluorenylmethoxycarbonyl chloride (Fmoc-Cl) and dissolve it in 20ml of acetone, add it dropwise to the alanine solution system, after the addition is complete, stir in an ice bath for 30min, then stir at room temperature for 2.0 h. After the reaction is complete, pour it into 400ml of water, extract it twice with diethyl ether, cool it and adjust the pH to about 2 with concentrated hydrochloric acid, a large amount of white solid precipitates, extract it three times with 50ml ethyl acetate, dry it with anhydrous magnesium sulfate, rem...

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Abstract

The invention relates to amino acid tanshinone phenolic ester derivatives and a preparation method thereof. The derivatives are obtained by reducing tanshinone compounds and performing esterified modification on the reduced tanshinone compounds and an amino acid into prodrugs, wherein the tanshinone compounds are phenanthrenequinone compounds which exist in salvia miltiorrhiza and have an o-quinone structure; the esterified amino acid is alpha-amino acid. The amino acid tanshinone phenolic ester derivatives are compounds having a structure of a general formula (I) or medicinal salts thereof, wherein R1 and R2 represent H or acyl alpha-amino acid and a salt thereof, and R1 and R2 are not H at the same time. The amino acid tanshinone phenolic ester derivatives have the beneficial effects that firstly, the new tanshinone derivatives are provided and the new substances have potential treatment effect on some serious diseases such as tumors, and secondly, amino acid tanshinone phenolic ester derivatives have excellent water solubility and thus can be prepared into injections conveniently in addition to various oral preparations, and therefore, the amino acid tanshinone phenolic ester derivatives are capable of quickly taking effect in disease treatment. As important prodrugs, the amino acid tanshinone phenolic ester derivatives have important application value.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an amino acid tanshinol ester derivative, a preparation method and application thereof. Background technique [0002] Danshen is a commonly used traditional Chinese medicinal material. The main active ingredient of Danshen is tanshinone, which is a group of fat-soluble phenanthrene quinones. According to their different chemical structures, they are divided into tanshinone I, dihydrotanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, tanshinone and other components, collectively called tanshinone. This series of compounds has various activities such as anti-inflammatory, antibacterial, anti-tissue fibrosis, anti-tumor, anti-oxidation, anti-mutation and anti-platelet aggregation (Xihong Wang, Susan L. Morris-Natschke, Kuo-Hsiung Lee. New Developments in the Chemistry and Biology of the Bioactive Constituents of Tanshen. Medicinal Research Reviews. 2007, 27(1): 133-1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00C07C227/20C07C229/08A61K31/58A61K31/223A61P35/00
Inventor 周长新甘礼社曾林伟朱志彬
Owner 南京虹桥医药技术研究所有限公司
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