Triptolide prodrug as well as preparation method and medical application thereof

A technology of triptolide and prodrugs, applied in the field of medicinal chemistry, can solve the problems of low content of alkaline phosphatase, unfavorable large-scale preparation, harsh reaction conditions, etc., and achieve good pharmacokinetic properties and good industrial performance. Optimize the foreground and synthesize simple effects

Pending Publication Date: 2022-05-13
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the structure of methylal is easy to be broken by hydrolysis, in the in vitro human plasma conversion experiment, we found that it still takes more than 24 hours for Minnelide to be completely converted into triptolide, which may be related to the low content of alkaline phosphatase in plasma
In addition, due to the high price of triptolide raw materials, the synthesis of Minnelide is difficult and the total yield is low (39%), making its development cost high; and due to the harsh reaction conditions, it is not conducive to large-scale preparation

Method used

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  • Triptolide prodrug as well as preparation method and medical application thereof
  • Triptolide prodrug as well as preparation method and medical application thereof
  • Triptolide prodrug as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Synthesis of compound TP-P1

[0046]

[0047] Synthesis of Intermediate II-1: Dissolve triptolide TP (1.8g, 5.0mmol) in 50mL of anhydrous dichloromethane, add DMAP (3.05g, 25.0mmol) at 0°C, and then add chlorine dropwise Acetyl chloride (4.0mL, 50.00mmol), after the dropwise addition, was reacted at 25°C for 12 hours; after the reaction was completed, the reaction solution was washed with 5% dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solution successively, and then Dry with anhydrous sodium sulfate; filter with suction, concentrate the filtrate, and purify by column chromatography (dichloromethane:methanol=200:1~100:1) to obtain 1.77g of white solid, with a yield of 88.8%. 1 H NMR(500MHz,MeOD)δ(ppm): 5.14(1H,s),4.78-4.85(2H,m),4.31(2H,d,J=1.0Hz),3.99(1H,d,J=3.2Hz ),3.67(1H,d,J=2.6Hz),3.53(1H,d,J=5.7Hz),2.79-2.81(1H,m),2.24-2.32(2H,m),2.07-2.12(1H, m),1.88-1.98(2H,m),1.50-1.54(1H,m),1.31-1.39(1H,m),1.05(3H,s),0.98(3H,d,J=7.0...

Embodiment 2

[0053] Synthesis of compound TP-P2

[0054]

[0055] Synthesis of Intermediate III-2: Compound II-1 (100mg, 0.23mmol) was dissolved in 10mL of anhydrous DMF, sodium iodide (86mg, 0.46mmol) and 4-methyl-1-piperazineacetic acid (73mg , 0.46mmol); after reacting at 25°C for 40 minutes, potassium carbonate (32mg, 0.23mmol) was added, and then heated to 50°C for 4 hours; after the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and organic layer, washed successively with aqueous sodium bicarbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate; filtered with suction, concentrated the filtrate, and purified by column chromatography (dichloromethane:methanol=100:1~40:1) to obtain a white solid 93mg, yield 72.3%; 1 H NMR (500MHz, MeOD-d 6 )δ(ppm):5.12(1H,s),4.81-4.85(2H,m), 4.77-4.80(2H,m),3.98(1H,d,J=3.1Hz),3.65(1H,d,J =2.8Hz),3.50(1H,d,J=5.7Hz), 3.47(2H,s),2.79-2.83(1H,m),2.66-2.78(8H,...

Embodiment 3

[0059] Synthesis of Compound TP-P3

[0060]

[0061] Synthesis of compound TP-P3: Compound II-1 (100 mg, 0.23 mmol) was dissolved in 10 mL of anhydrous DMF, and sodium iodide (86 mg, 0.46 mmol) and 2-piperidinylacetic acid (66 mg, 0.46 mmol) were added; After reacting at 25°C for 40 minutes, potassium carbonate (32mg, 0.23mmol) was added, and then heated to 50°C for 4 hours; Wash with aqueous sodium hydrogen solution and saturated sodium chloride solution, dry over anhydrous sodium sulfate; filter with suction, concentrate the filtrate, and purify by column chromatography (dichloromethane:methanol=100:1~40:1) to obtain 67 mg of white solid, yield 53.4 %; 1 H NMR (500MHz, CDCl 3 )δ (ppm): 5.11 (1H, s), 4.81-4.85 (2H, m), 4.65-4.73 (2H, m), 3.84 (1H, d, J = 3.1Hz), 3.64 (2H, d, J =4.2Hz), 3.56(1H,d,J=2.8Hz),3.48(1H,d,J=5.7Hz),2.87-2.98(4H,m),2.32-2.36(1H,m),2.16-2.26 (2H,m),1.89-1.95(2H,m),1.76-1.80 (4H,m),1.52-1.59(2H,m),1.32-1.38(2H,m),1.06(3H,s),0.97 (3H,d,J=7.0Hz),0....

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Abstract

The invention discloses a triptolide prodrug as well as a preparation method and medical application thereof. Belongs to the field of pharmaceutical chemistry. The preparation method comprises the following steps: 1, reacting triptolide with acyl chloride under the action of DMAP to generate an intermediate II; 2, reacting the intermediate II with a carboxylic acid compound under the action of sodium iodide and potassium carbonate to generate a compound III; and 3, salifying the compound III and acid to obtain the target compound I. The derivative has better water solubility and pharmacokinetic properties, and compared with Minnelide, the derivative has a faster conversion speed in an in-vivo blood environment and a more efficient synthesis method, and has a better treatment effect on malignant tumors, inflammatory diseases, autoimmune diseases and the like; in addition; due to good water solubility, the compound is effective in oral administration and can be prepared into an injection for use.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a class of triptolide water-soluble prodrugs or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds, their preparation methods and medical applications. Background technique [0002] Tripterygium wilfordii Hook.f. is a plant of the genus Tripterygium wilfordii Hook.f. in the family Celastraceae. It has the functions of expelling wind and dampness, promoting blood circulation and dredging collaterals, reducing swelling and pain, killing insects and detoxifying, etc. It is the first choice for clinical treatment of autoimmune diseases traditional Chinese medicine. At present, a variety of tripterygium extract drugs such as Tripterygium wilfordii polyglycoside tablets, Tripterygium wilfordii tablets (999), Tripterygium wilfordii double-layer tablets, Tripterygium terpene tablets, etc. have been listed for use in rheumatoid arthritis, aut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00A61K31/585A61P35/00A61P35/02A61P37/00A61P37/06A61P29/00A61P31/18A61P17/00A61P1/00A61P11/06A61P11/00A61P13/12A61P31/04A61P31/12
CPCC07J73/003A61P35/00A61P35/02A61P37/00A61P37/06A61P29/00A61P31/18A61P17/00A61P1/00A61P11/06A61P11/00A61P13/12A61P31/04A61P31/12
Inventor 胡立宏王均伟康迪朱学军潘祥宋祎刘琰
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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