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NO (nitric oxide) donor oleanolic acid derivative and preparation method and application thereof

A configuration and compound technology, applied in the combined drug strategy of NO donor vascular relaxation and CDDO-Me inhibition of vascular remodeling, anti-pulmonary hypertension activity evaluation, NO donor oleanolic acid derivatives, can solve a wide range of limitations application, methemoglobinemia and other problems, to achieve the effect of expanding pulmonary blood vessels, preventing oxidative stress, and good application prospects

Active Publication Date: 2017-09-01
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are some defects in inhaled NO, which limit its wide application.
For example, NO has a fast onset of action and a fast clearance rate, requiring multiple inhalations; excessive NO can react with hemoglobin after entering the blood, resulting in methemoglobinemia

Method used

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  • NO (nitric oxide) donor oleanolic acid derivative and preparation method and application thereof
  • NO (nitric oxide) donor oleanolic acid derivative and preparation method and application thereof
  • NO (nitric oxide) donor oleanolic acid derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Methyl 1-isosorbide-2-cyano-3-acetoxy-12-oxooleanane-2(3),9(11)-diene-28-carboxylate

[0064]

[0065] CDDO-Me (100mg, 0.2mmol) was dissolved in 2.5ml of anhydrous DMF, was added isosorbide mononitrate (57.3mg, 0.3mmol), K 2 CO 3 (41mg, 0.3mmol) was stirred overnight at room temperature, and the next morning, compound V (23.6mg, 0.3mmol) was added to continue stirring for 6h. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50mL), and saturated sodium bicarbonate solution and saturated saline were respectively Wash 3 times. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a white solid, which was obtained by flash silica gel column chromatography. 1 (35 mg, 35%).

[0066] mp: 247-248°C; 1H NMR (300MHz, CDCl3, 25°C, TMS): δ5.84(s, 1H), 4.69(s, 1H), 4.53(s, 1H), 4.21(d, J=10.2 Hz,2H),4.05(q,2H),3.86(d,J=4.8Hz,2H),3.61(s,3H),2.97(d,J=13.5Hz,1H),2.85(s,1H), 2.25(s,3H),...

Embodiment 2

[0068] 1-isosorbide-2-cyano-3-acetoxy-12-oxooleanane-2(3),9(11)-diene-28-carboxylic acid

[0069]

[0070] CDDO (100mg, 0.2mmol) was dissolved in the anhydrous DMF of 2.5ml, added isosorbide mononitrate (57.3mg, 0.3mmol), K 2 CO 3 (41mg, 0.3mmol) was stirred overnight at room temperature, and the next morning, compound V (23.6mg, 0.3mmol) was added to continue stirring for 6h. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50mL), and saturated sodium bicarbonate solution and saturated saline were respectively Wash 3 times. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a white solid, which was obtained by flash silica gel column chromatography. 2 (35 mg, 35%).

Embodiment 3

[0072] 1-isosorbide-2-cyano-3-propionyloxy-12-oxooleanane-2(3),9(11)-diene-28-carboxylic acid

[0073]

[0074] CDDO (100mg, 0.2mmol) was dissolved in the anhydrous DMF of 2.5ml, added isosorbide mononitrate (57.3mg, 0.3mmol), K 2 CO 3 (41mg, 0.3mmol) was stirred overnight at room temperature, and the next morning, compound V (27.8mg, 0.3mmol) was added to continue stirring for 6h. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50mL), and saturated sodium bicarbonate solution and saturated saline were respectively Wash 3 times. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a white solid, which was obtained by flash silica gel column chromatography. 3 (35 mg, 35%).

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Abstract

The invention relates to the fields of medicine chemistry and medicine therapy, in particular to a NO (nitric oxide) donor oleanolic acid derivative. A NO donor can effectively relax blood vessels; a CDDO compound can inhibit the reconstruction of pulmonary arterial vascular. The invention particularly relates to a joint medicine utilization strategy of NO donor on relaxing blood vessels and CDOO and derivative thereof on inhibiting reconstruction of blood vessels, synthesis, and evaluation on pulmonary arterial hypertension-resistant activity. The compound can be used for treating the increasing of pulmonary arterial pressure due to increase of pulmonary vessel resistance. The invention also relates to a preparation method of the compound and a medicine composition containing the compound.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and relates to a NO donor type oleanolic acid derivative, in particular to a combined drug strategy, synthesis and anti-pulmonary artery vasodilatation of NO donors and CDDO-Me to inhibit vascular remodeling. High pressure activity evaluation. Such compounds can be used for the increase of pulmonary artery pressure caused by the increase of pulmonary vascular resistance. The invention also relates to processes for the preparation of these compounds and pharmaceutical combinations containing them. Background technique [0002] Pulmonary arterial hypertension (PAH) is a kind of malignant progressive disease with increased pulmonary vascular resistance and pulmonary artery pressure, eventually leading to right heart failure and even death. In recent years, with the in-depth research on the pathogenesis of PAH and the marketing of corresponding therapeutic drugs, ...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/58A61P9/12
CPCC07J63/008
Inventor 黄张建张奕华巩岩孔辉钱帅程玉生解卫平王虹
Owner CHINA PHARM UNIV
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