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N-substituted fluorinated phenyl-14 beta-(aminomethyl) triptodiolide derivative and preparation method and application thereof

A technology of Tripterygium wilfordii and its derivatives, applied in the field of medicine, can solve the problems of narrow treatment window, no fundamental change of the main structure, large toxic and side effects, etc.

Inactive Publication Date: 2012-05-09
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

In addition to extensive research on anti-tumor effects, triptolide has also entered clinical trials for the treatment of leukemia. However, triptolide's relatively large toxic and side effects and too narrow therapeutic window limit its clinical application.
In the past, most of the structural modification of triptolide was limited to the introduction of water-soluble groups, and there was no fundamental change in the main structure

Method used

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  • N-substituted fluorinated phenyl-14 beta-(aminomethyl) triptodiolide derivative and preparation method and application thereof
  • N-substituted fluorinated phenyl-14 beta-(aminomethyl) triptodiolide derivative and preparation method and application thereof
  • N-substituted fluorinated phenyl-14 beta-(aminomethyl) triptodiolide derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0056] Preparation Example 1 compound (3)

[0057]

[0058] Under argon protection, 50 mL of anhydrous tetrahydrofuran was added into a reaction flask containing magnesium chips (900 mg, 37.5 mmol), and chloromethyldimethylisopropoxysilane (6 mL) was added dropwise to the reaction flask via a constant pressure dropping funnel. in the reaction system. After the addition, the dark gray reaction system was stirred at 50° C. for 30 min, and the Grignard reagent was prepared. The prepared Grignard reagent was added dropwise to triptolide ketone (LLDT-1) (3 g, 8.4 mmol) dissolved in 100 mL of dry THF. After reacting for 1.5 h at room temperature, the reaction was stopped. The reaction system was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude compound (2). Without further purification, compound (2) was dissolved in 50 mL ...

preparation Embodiment 2

[0060] Preparation Example 2 Compound (4)

[0061]

[0062] Compound 3 (420mg, 1.08mmol) was dissolved in 15mL of dichloromethane solvent, trichloroisocyanuric acid (376mg, 1.62mmol) was added at 0°C, followed by TEMPO (16mg, 0.108mmol) and quickly detected by TLC, the reaction Completely add sodium carbonate solution to quench the reaction and adjust the pH value to neutral, extract with dichloromethane, wash the organic phase with water and saturated brine respectively, dry over anhydrous sodium sulfate and concentrate, separate and purify by column chromatography to obtain compound 4 as a white solid (340 mg, 0.87 mmol, yield: 81%).

[0063] Compound 4: 1 H NMR (CDCl 3 , 300MHz) δ10.03(s, 1H), 4.76-4.59(m, 2H), 3.97(d, J=3.0Hz, 1H), 3.91(s, 1H), 3.75(d, J=5.9Hz, 1H ), 3.60(d, J=3.0Hz, 1H), 2.79-2.67(m, 1H), 2.38-2.26(m, 1H), 1.87(dd, J=14.7, 13.6Hz, 1H), 1.58(dd, J=12.6, 4.0Hz, 1H), 1.03(s, 3H), 0.83(d, J=6.9Hz, 3H), 0.79(d, J=6.9Hz, 3H); 13 C NMR (CDCl 3 , 100MHz)...

preparation Embodiment 3

[0064] Preparation Example 3 (14S)-14β-N-(2′-fluorophenyl)-aminomethyl epitriptolide (LLDT-215)

[0065]

[0066] Compound 4 (39 mg, 0.1 mmol) was dissolved in 4 mL of acetonitrile solvent, 2-fluoroaniline (11.1 mg, 0.1 mmol) was added, stirred at room temperature for 0.5 h, and then sodium triacetoxyborohydride (42 mg, 0.2 mmol) was added, After reacting at room temperature for 4 hours, the reaction was stopped, most of the solvent was evaporated under reduced pressure, the residue was diluted with water and extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography Separation and purification gave white solid compound (14S)-14β-N-(2′-fluorophenyl)-aminomethyl epitriptolide (LLDT-215) (29 mg, yield: 60%).

[0067] LLDT-215: 1 H NMR (CDCl 3 , 300MHz) δ7.06-6.96(m, 2H), 6.85(t, J=8.1Hz, 1H), 6.77-6.69(m, 1H), 4.67(s, 2H), 4.54(brs, 1H), 3.92 -3.80(m, 3H), 3.63(s, 1...

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Abstract

The invention provides a tripterygium diterpenoid lactone derivative shown in Formula II-3 or a pharmaceutically acceptable salt thereof, a preparation method thereof, a drug combination thereof and an application thereof in preparation of drugs for treatment of tumors, in particular to ovarian cancer or prostate cancer.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a class of tripterygium wilfordii diterpenoid lactone derivatives and pharmaceutically acceptable salts thereof, their preparation methods and their use in the preparation of drugs for treating tumors, especially reproductive system tumors in the application. Background technique [0002] Tripterygium wilfordii, commonly known as Broken Heart Grass, is a woody vine of the genus Tripterygium genus Celastraceae, and is a plant with relatively abundant resources in my country. There are four kinds of Tripterygium plants, namely Tripterygium wilfordii Hook f., Tripterygium hypoglaucum Levl. Hutch, Tripterygium regelii Sprague et Takeda and Tripterygium regelii Sprague et Takeda. Rattan (Tripterygium forretii Dicls) is distributed in my country. Tripterygium wilfordii was first recorded in "Shenlong Materia Medica", and its main chemical components include diterpenes, triterpenes, sesquiterpe...

Claims

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Application Information

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IPC IPC(8): C07J73/00A61K31/585A61P35/00A61P35/02
Inventor 李援朝楼丽广周兵王蕾杨亚玺全海天冯慧瑾谢成英李征
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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