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CDDO-Me derivative, preparation method and medical application

A derivative, cddo-me technology, applied in the field of preparation of CDDO-Me derivatives, can solve the problems of high toxicity and side effects, and achieve the effects of low toxicity, low proliferation inhibition, and mild conditions

Active Publication Date: 2018-08-24
泰州学院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CDDO-Me has strong anti-inflammatory activity, it also has the problem of large toxic and side effects

Method used

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  • CDDO-Me derivative, preparation method and medical application
  • CDDO-Me derivative, preparation method and medical application
  • CDDO-Me derivative, preparation method and medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Dissolve CDDO-Me (298mg, 0.59mmol) in 10ml of DMF, add pure water (106mg, 5.9mmol), K 2 CO 3 (162.8mg, 1.18mmol), stir overnight at room temperature, add bromomethyl phenylboronic acid pinacol (349.3mg, 1.18mmol) and continue stirring for 0.5h, add 1N dilute hydrochloric acid 5ml to terminate the reaction. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50 mL), and washed with saturated sodium bicarbonate solution and saturated brine each 3 times. The organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a pale yellow solid, which was subjected to flash silica gel column chromatography to obtain a white solid I 1 (305mg, 53%).

[0022] 1 H NMR (300M Hz, CDCl3, 303K, TMS): δ 7.83 (d, 2H, J = 7.65 Hz), 7.38 (d, 2H, J = 7.62 Hz), 5.87 (s, 1H), 5.52 (q, 2H), 4.53 (s, 1H), 3.69 (s, 3H), 3.05 (d, 1H, J = 13.32 Hz), 2.95 (s, 1H), 2.02 (d, 1H), 1.90, 1.86 (s, each 1H), 1.73 (s, 1H), 1.67,...

Embodiment 2

[0026] Dissolve CDDO-Me (298mg, 0.59mmol) in 10ml of DMF, add anhydrous methanol (188mg, 5.9mmol), K 2 CO 3 (162.8 mg, 1.18 mmol) was stirred overnight at room temperature, bromomethyl phenylboronic acid pinacol (349.3 mg, 1.18 mmol) was added and stirring continued for 0.5 h, and 5 ml of 1N dilute hydrochloric acid was added to terminate the reaction. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50 mL), and washed with saturated sodium bicarbonate solution and saturated brine each 3 times. The organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a pale yellow solid, which was subjected to flash silica gel column chromatography to obtain a white solid I 2 (297mg, 67%).

[0027] 1 H NMR (300M Hz, CDCl3, 303K, TMS): δ 7.80 (d, 2H, J = 7.60 Hz), 7.29 (d, 2H, J = 7.58 Hz), 5.84 (s, 1H), 5.51 (q, 2H), 4.49 (s, 1H), 3.69 (s, 3H), 3.49 (s, 3H) 3.05 (d, 1H, J = 13.32 Hz), 2.95 (s, 1H), 2.17 (...

Embodiment 3

[0031] Dissolve CDDO-Me (298mg, 0.59mmol) in 10ml of DMF, add absolute ethanol (271mg, 5.9mmol), K 2 CO 3 (162.8 mg, 1.18 mmol) was stirred overnight at room temperature, bromomethyl phenylboronic acid pinacol (349.3 mg, 1.18 mmol) was added and stirring continued for 0.5 h, and 5 ml of 1N dilute hydrochloric acid was added to terminate the reaction. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50 mL), and washed with saturated sodium bicarbonate solution and saturated brine each 3 times. The organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a pale yellow solid, which was subjected to flash silica gel column chromatography to obtain a white solid I 3 (221mg, 49%).

[0032] 1 H NMR (300M Hz, CDCl3, 303K, TMS): δ 7.83 (d, 2H, J = 7.65 Hz), 7.38 (d, 2H, J = 7.62 Hz), 5.87 (s, 1H), 5.52 (q, 2H), 4.53 (s, 1H), 3.92 (m, 1H), 3.65 (s, 3H), 3.51 (m, 1H), 3.03 (s, 1H), 3.05 (d, 1H, J = 13.3...

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Abstract

The invention discloses a CDDO-Me derivative, a preparation method and medical application. In view of the shortcoming that CDDO-Me has strong toxic and side effects, the invention provides the CDDO-Me derivative. An anti-inflammatory activity test shows that compared with the CDDO-Me, the CDDO-Me derivative provided by the invention has the anti-inflammatory action at the similar activity intensity; and a cytotoxic activity test shows that compared with the CDDO-Me, the CDDO-Me derivative provided by the invention is lower in proliferation inhibition effect on RAW 264.7 macrophage, lower in toxicity and higher in safety. Therefore, the CDDO-Me derivative provided by the invention can be used for preparing an anti-inflammatory drug with higher safety to prevent and treat inflammation-related diseases, such as acute lung injury, pulmonary arterial hypertension and diabetic nephropathy. The invention further provides the preparation method of the CDDO-Me derivative. The conditions are mild, the number of steps is small, and the practicability is high.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a CDDO-Me derivative, a preparation method and medical use. Background technique [0002] Oleanolic acid is an important class of pentacyclic triterpene compounds, which has a wide range of anti-inflammatory, anti-tumor, anti-viral and other biological activities. Among them, 2-cyano-3,12-dioxo oleanorane-1, 9(11)-Diene-28-carboxylic acid (CDDO) compounds are known to have the strongest anti-inflammatory (nanomolar) activity among the known oleanane derivatives. The structure and anti-inflammatory of CDDO and its derivatives IC 50 The values ​​are shown below. [0003] [0004] However, in the Phase III clinical trials for the treatment of chronic kidney disease caused by type 2 diabetes, CDDO-Me was forced to stop due to its abnormally high fatality rate, but the specific details were not disclosed. Although CDDO-Me has strong anti-inflammatory activity, it also has the problem of gr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61P29/00A61P11/00A61P9/12A61P3/10A61P13/12
CPCA61P3/10A61P9/12A61P11/00A61P13/12A61P29/00C07J63/008
Inventor 牟伊
Owner 泰州学院
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