Oleandrin derivative and preparation method, pharmaceutical composition and use thereof

A technology of oleandrin and its derivatives, which is applied in the field of medicinal chemistry, can solve the problems of unsatisfactory physical and chemical properties, low water solubility of oleandrin, and poor drug-like properties, and achieve abundant synthetic raw materials, simple preparation methods, The effect of improving water solubility

Active Publication Date: 2022-07-15
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, oleandrin has low water solubility, unsatisfactory physical and chemical properties, and relatively poor drug-like properties. Therefore, it is of great significance to find new oleandrin derivatives with good drug-like properties.

Method used

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  • Oleandrin derivative and preparation method, pharmaceutical composition and use thereof
  • Oleandrin derivative and preparation method, pharmaceutical composition and use thereof
  • Oleandrin derivative and preparation method, pharmaceutical composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Synthesis of Compound A1

[0058]

[0059] Add oleandrin (0.3mmol, 172mg), N-acetylglycine (0.6mmol, 70mg, 2.0eq), DMAP (0.3mmol, 37mg, 1.0eq), HATU (0.6mmol, 228mg, 2.0eq) to the reaction flask eq) was dissolved in dichloromethane (5mL), triethylamine (0.9mmol, 125μL, 3.0eq) was added, then EDCI (0.9mmol, 172mg, 3.0eq) was slowly added, and the reaction was stirred at room temperature for 6h. After the reaction was completed, dichloromethane was added to dilute, and the reaction solution was diluted with saturated Na 2 CO 3 The solution was washed twice, the saturated sodium chloride solution was washed twice, the dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography (7:1~3:1, petroleum ether / acetone) to obtain the target product, Yield 56%.

[0060] 1 H NMR (500MHz, DMSO-d 6 )δ5.96(s,1H),5.37(s,1H),4.98–4.87(m,3H),4.47(s,1H),4.38(s,1H),3.82(s,1H),3.69(s ,1H),3.55(s,...

Embodiment 2

[0061] Example 2: Synthesis of Compound A2

[0062]

[0063] Add oleandrin (0.5mmol, 288mg, 1.0eq), N-Boc-L-valine (217mg, 1.0mmol, 2.0eq), DMAP (0.5mmol, 61mg, 1.0eq) to the reaction flask, HATU (1.0mmol, 380mg, 2.0eq, ) was dissolved in dichloromethane (5mL), triethylamine (1.5mmol, 207μL, 3.0eq) was added, and then EDCI (1.5mmol, 287mg, 3.0eq) was slowly added at room temperature The reaction was stirred for 2h. After the reaction was completed, dichloromethane was added to dilute, and the reaction solution was diluted with saturated Na 2 CO 3 The solution was washed twice, the saturated sodium chloride solution was washed twice, the dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate. The intermediate was dissolved in acetone (5 ml), trifluoroacetic acid (TFA) (2.6 mL) was added, and the mixture was stirred at room temperature for 48 h. After the reaction was completed, dichloromethane was...

Embodiment 3

[0065] Example 3: Synthesis of Compound A3

[0066]

[0067] The reaction was performed as in the preparation of A2, except that the starting material used N-Boc-L-alanine instead of N-Boc-L-valine. The target product A3 was obtained after column chromatography (100:1:0.5~100:2:0.5, dichloromethane / methanol / triethylamine) with a yield of 46%.

[0068] 1 H NMR (CDCl 3 ,400MHz)δ5.95(s,1H),5.46(t,J=9.2Hz,1H),5.01–4.82(m,3H),4.65(t,J=9.5Hz,1H),3.88(s,1H ), 3.83–3.76 (m, 1H), 3.66–3.60 (m, 1H), 3.58–3.3 (m, 1H), 3.31–3.06 (s, 3H), 3.18 (d, J=8.6Hz, 1H), 2.72(dd, J=15.4, 9.8Hz, 1H), 2.21(dd, J=12.6, 3.8Hz, 1H), 1.95(s, 3H), 1.89–1.59(m, 11H), 1.63–1.42(m, 6H), 1.37–1.23(m, 3H), 1.35(d, J=7.0Hz, 3H), 1.11(d, J=5.7Hz, 3H), 0.94(s, 3H), 0.92(s, 3H); ESI-MS(m / z)648[M+1] + .

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PUM

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Abstract

The present invention discloses a class of oleandrin derivatives represented by the following general formula I, and a preparation method, pharmaceutical composition and application thereof. The oleandrin derivatives have inhibitory activity on various human tumor cell lines, such as cervical cancer cell lines, leukemia cell lines, liver cancer cell lines and prostate cancer cell lines, and can be used as drugs for treating malignant tumors. In addition, the water solubility of the oleandrin derivative of the present invention is remarkably improved relative to that of oleandrin.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular, the present invention relates to a class of oleandrin derivatives, a preparation method thereof, a pharmaceutical composition and use thereof. Background technique [0002] Tumors are abnormal proliferations caused by the loss of normal regulation of cell growth due to genetic mutation of cells. At present, tumors have become one of the most important causes of human death. The International Agency for Research on Cancer pointed out in the Globocan 2018 report that it is estimated that there will be 18.1 million new cancer cases and 9.6 million deaths due to cancer in 2018, of which more than 50% of cancer patients occur in Asia, In my country, the number of cancer patients exceeds 15 million, and an average of 10,000 people are diagnosed with cancer every day. It can be seen that tumors have seriously threatened human health. [0003] Cardiac glycosides can selectively i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J41/00C07J43/00A61P35/00A61K31/706A61K31/7048
CPCC07J41/0088C07J41/0033C07J43/003A61P35/00
Inventor 吴婉莹雷敏侯晋军龙华丽张子佳周阳张延智
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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