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Preparation method and use of (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives

An epoxy and drug technology, used in medical preparations, drug combinations, and pharmaceutical formulations containing active ingredients, which can solve problems such as threats to human health, reduced sensitivity, and drug resistance.

Inactive Publication Date: 2016-10-05
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] The emergence of antibiotics and chemotherapeutic drugs has made great contributions to human health, but with the application of these drugs, pathogens and tumor cells are less sensitive to chemotherapeutic drugs, resulting in drug resistance, and the emergence of drug resistance has become serious threat to human health

Method used

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  • Preparation method and use of (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives
  • Preparation method and use of (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives
  • Preparation method and use of (20S, 24R/S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] (20S, 24S)-epoxydammarane-12β, 25-diol-3β-amine (OSA)

[0052] Dissolve 20(S)-protopanaxadiol (500mg, 1.08mmol) in anhydrous pyridine (3mL), add DMAP (20mg, 0.16mmol), stir well and slowly add acetic anhydride (0.42mL, 4.43mmol) dropwise , stirred at room temperature for 12h. Dilute with ethyl acetate (20 mL), wash with 10% hydrochloric acid until acidic, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and column chromatography (petroleum ether: ethyl acetate = 10:1) to give white Solid 1 (508 mg, 85%).

[0053]The above-obtained 1 (208 mg, 0.38 mmol) was dissolved in anhydrous dichloromethane (6 mL), and the dichloromethane of m-chloroperoxybenzoic acid (185 mg, 75%, 0.16 mmol) was slowly added dropwise under ice-salt bath precooling. Methane (5 mL) solution, half an hour after the dropwise addition was completed, the mixture was raised to room temperature and stirred for 2 h. Add isopropanol (0.1mL), continue to s...

Embodiment 2

[0061] (20S, 24R)-epoxydammarane-12β, 25-diol-3β-amine (ORA)

[0062] Referring to the synthesis method of (20S, 24S)-epoxydammarane-12β, 25-diol-3-amine (OSA), a white solid ORA (120 mg, 73%) was obtained from compound 4 through compounds 6 and 8. 1 H NMR (CDCl 3 , 300MHz) δ3.84(dd, J=13.7Hz, 7.0Hz, 1H), 3.50(td, J=10.4Hz, 4.6Hz, 1H), 2.35(dd, J=11.5Hz, 4.4Hz, 1H), 2.18(td, J=10.9Hz, 3.5Hz, 1H), 1.28(s, 3H), 1.26(s, 3H), 1.09(s, 3H), 0.98(s, 3H), 0.94(s, 3H), 0.90(s, 3H), 0.83(s, 6H), 0.74(s, 3H). 13 C NMR (CDCl 3 , 75MHz) δ86.5, 85.4, 80.0, 70.1, 59.7, 56.6, 52.0, 50.6, 49.4, 47.9, 39.6, 39.5, 38.1, 37.3, 34.8, 32.6, 31.2, 28.6, 28.3, 27.9, 27.6, 26.1, 25.0 , 18.6, 18.1, 16.2, 15.5, 15.4; ESI-MS m / z 476.4 [M+H] + ; HR-MS (ESI) m / z: calculated for C 30 h 54 NO 3 [M+H] + : 476.4098, found: 476.4091.

Embodiment 3

[0064] (20S, 24S)-epoxy-3β-methylaminodammarane-12β, 25-diol

[0065] (20S,24S)-epoxydammarane-12β,25-diol-3-amine (OSA, 200 mg, 0.42 mmol) and anhydrous potassium carbonate (60 mg, 0.42 mmol) were added to anhydrous THF (8 mL) , then iodomethane (60 mg, 0.42 mmol) was added. N 2 React at room temperature for 5 hours under protection. Diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatographed to give a pale yellow product (155 mg, 75%). 1 H NMR (CDCl 3 , 300MHz) δ3.86(dd, J=10.2Hz, 5.0Hz, 1H), 3.51(td, J=9.8Hz, 4.0Hz, 1H), 3.16(s, 3H), 2.54(m, 1H), 2.22 (td, J=9.8Hz, 5.8Hz, 1H), 1.26(s, 3H), 1.21(s, 3H), 1.10(s, 3H), 1.02(s, 3H), 1.00(s, 3H), 0.89 (s,6H), 0.88(s,3H), 0.85(s,3H); ESI-MS m / z 490.4[M+H] + .

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Abstract

The invention relates to the field of organic synthesis and pharmaceutical chemistry and concretely relates to dammarane derivatives with novel structures shown in the formulas (I) and (II). The invention also discloses a preparation method of the (20S, 24R / S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives, a pharmaceutical composition containing the (20S, 24R / S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives and a use of the (20S, 24R / S)-epoxy-12 beta, 25-hydroxy-dammarane-3 beta-amine derivatives in preparation of drugs for reversion of tumor resistance to multiple drugs.

Description

technical field [0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, in particular to (20S, 24R / S)-epoxy-12β, 25-hydroxyl-dammarane-3β-amine derivatives, and the present invention also discloses these dammarane derivatives The preparation method of the compound, the pharmaceutical composition containing the compound and the application of the compound in the preparation of drugs for reversing tumor multidrug resistance. technical background [0002] The emergence of antibiotics and chemotherapeutic drugs has made great contributions to human health, but with the application of these drugs, pathogens and tumor cells are less sensitive to chemotherapeutic drugs, resulting in drug resistance, and the emergence of drug resistance has become serious threaten human health. It has been found that although the mechanisms of drug resistance are diverse, the common main reason is that some active transporters pump a series of molecules with...

Claims

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Application Information

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IPC IPC(8): C07J41/00A61K31/58A61P35/00
Inventor 徐进宜陈哲生张恒源张运闿周志文魏国湘
Owner CHINA PHARM UNIV
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