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Delta<13(18)>-CDDO derivative, its preparation method and its use in pharmacy

A compound and generative technology, applied in antineoplastic drugs, drug combinations, pharmaceutical formulations, etc.

Inactive Publication Date: 2014-05-14
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] From a synthetic point of view, Barton et al. used 3β-hydroxy-12-oxooleanane-9(11)-ene-28,13β-lactone as raw material, tried to hydrolyze the lactone ring and then dehydrate to synthesize The important intermediate formula VIII in this patent, but failed (Journal of the Chemical Society, 1952, 3751-9)

Method used

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  • Delta&lt;13(18)&gt;-CDDO derivative, its preparation method and its use in pharmacy
  • Delta&lt;13(18)&gt;-CDDO derivative, its preparation method and its use in pharmacy
  • Delta&lt;13(18)&gt;-CDDO derivative, its preparation method and its use in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] 3β-Hydroxyoleanane-12-ene-28-carboxylic acid methyl ester

[0069] Oleanolic acid (20 g, 0.043 mol) and potassium carbonate (15.1 g, 0.107 mol) were suspended in 200 mL of DMF, methyl iodide (2.9 mL, 0.047 mol) was added at room temperature, and stirred overnight. The reaction solution was filtered, the filter cake was washed with DMF, the combined reaction solution and washing solution were added to ice water, a large amount of white solids were precipitated, left to stand until the particles became larger, filtered, the filter cake was fully washed with water, dried to obtain a white solid (20g , 96%). 1 H NMR (300MHz, CDCl 3 )δ5.30(1H, t, J=3.5Hz), 3.64(3H, s), 3.23(1H, m), 2.88(1H, dd, J=4.3, 11.8Hz), 0.75(3H, s), 0.80(3H,s), 0.92(3H,s), 0.93(3H,s), 0.95(3H,s), 1.01(3H,s), 1.15(3H,s)ppm.

Embodiment 2

[0071] 3β-Hydroxyoleanane-13(18)-ene-28-carboxylic acid methyl ester

[0072] Methyl oleanolic acid (20 g, 0.041 mol) was dissolved in 500 mL of dichloromethane, and 30 g of H-MontK was added 10 , stirring under reflux for 72 hours until the end of the reaction. The reaction liquid was filtered, and the filter cake was washed with dichloromethane. The reaction liquid and the washing liquid were combined and spin-dried to obtain a white solid (18.7 g, 93.5%). 1 H NMR (300MHz, CDCl 3 ): δ0.74(3H, s), 0.77(3H, s), 0.88(3H, s), 0.906(3H, s), 0.909(3H, s), 0.99(3H, s), 1.16(3H, s), 1.86-1.89(2H, m), 2.18(1H, d, J=7.5Hz), 2.43(1H, d, J=8.4Hz), 2.73-2.77(1H, m), 3.23(1H, m ), 3.66 (3H, s) ppm.

Embodiment 3

[0074] 3β-Acetoxyoleanane-13(18)-ene-28-carboxylic acid methyl ester

[0075] Dissolve δ-methyl oleanate (18 g, 0.037 mol) in 200 mL of dichloromethane, add acetyl chloride (3.9 mL, 0.055 mol) and a catalytic amount of triethylamine, and stir overnight at room temperature. The reaction solution was concentrated, and flash silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) gave a white solid (16.2 g, 85%). 1 HNMR (500MHz, CDCl 3 ): δ4.50(1H, m), 3.64(3H, s), 2.73(1H, m), 2.40(1H, d, J=14.05Hz), 2.16(1H, m), 2.03(3H, s) , 1.14(3H, s), 0.90(9H, s), 0.85(3H, s), 0.83(3H, s), 0.72(3H, s)ppm.

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PUM

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Abstract

The invention relates to the field of medicines, concretely relates to an oleanolic acid derivative represented by formula I and pharmaceutically acceptable salts, and a preparation method and a medicinal use thereof, and belongs to the field of biomedicines. The preparation method of the above compounds has the advantages of mild condition, simple operation, high yield and very strong practicality. Results of pharmacological experiments show that the compounds have excellent anti-inflammatory and antitumor activities, and can be clinically used as medicines for treating diseases and tumors caused by various inflammations.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to 2-cyano-3,12-dioxooleanane-1,9(11),13(18)-triene-28-carboxylic acid derivatives and a preparation method thereof and use in pharmaceuticals. Background technique [0002] Oleanic acid (OA) and its derivatives are an important class of pentacyclic triterpenoids, which are ubiquitous in nature and have various biological activities such as anti-tumor, anti-inflammation, and anti-virus. Important progress has been made in the research and development of new drugs with lead compounds. 2-Cyano-3,12-dioxooleanane-1,9(11)-diene-28-carboxylic acid (CDDO) compounds are known anti-inflammatory (Na molar level), anti-tumor (micromolar level) activity is the strongest. CDDO has a unique mechanism of action and is highly safe. The pharmacological activity of its methyl ester derivative (CDDO-Me) is comparable to that of CDDO (Nature Reviews 2007, 7, 357-69). Currently, CDDO-Me is in the clinical d...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/56A61P13/12A61P3/10A61P1/16A61P35/00A61P9/00
Inventor 孙宏斌孙炎
Owner CHINA PHARM UNIV
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