Application of composition of imidazolyl and dichloroethylamino derivatives of Atropurpuran to resistance of liver fibrosis

A liver fibrosis and composition technology, applied in the fields of organic synthesis and medicinal chemistry, can solve the problems of lack of clinical treatment methods

Inactive Publication Date: 2017-05-31
NANJING FUHAIAOSAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In recent years, some anti-hepatic fibrosis treatments have emerged, including chemical drugs, biological agents, traditional Chinese medicine and gene therapy, etc., but the ideal clinical treatment methods are still lacking (Liu Ping. Strengthen the research on the mechanism of anti-hepatic fibrosis. Chinese liver disease Magazine, 2005, 8(13): 561)

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  • Application of composition of imidazolyl and dichloroethylamino derivatives of Atropurpuran to resistance of liver fibrosis
  • Application of composition of imidazolyl and dichloroethylamino derivatives of Atropurpuran to resistance of liver fibrosis
  • Application of composition of imidazolyl and dichloroethylamino derivatives of Atropurpuran to resistance of liver fibrosis

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Embodiment 1

[0015] The preparation of embodiment 1 compound Atropurpuran

[0016] The preparation method of compound Atropurpuran (I) refers to the literature published by Pei Tang et al. (Pei Tang et al., 2009.Atropurpuran, a novel diterpene with an unprecedented pentacycliccage skeleton, from Aconitum hemsleyanum var.atropurpureum.Tetrahedron Letters50(2009)460-462 )Methods.

[0017]

Embodiment 2

[0018] The synthesis of the O-bromoethyl derivative (II) of embodiment 2 Atropurpuran

[0019] Compound I (312 mg, 1.00 mmol) was dissolved in 10 mL of benzene, tetrabutylammonium bromide (TBAB) (0.08 g), 1,2-dibromoethane (3.760 g, 20.00 mmol) and 6 mL of 50% sodium hydroxide solution. The mixture was stirred at 35 °C for 6 h. After 6h, the reaction solution was poured into ice water, extracted twice with dichloromethane immediately, and the organic phase solutions were combined. Then the organic phase solution was washed with water and saturated brine three times successively, then dried with anhydrous sodium sulfate, and finally concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether / acetone=100:1.0, v / v), the brown concentrated elution band was collected and the solvent was evaporated to obtain a yellow powder of Compound II (309mg, 74%) .

[0...

Embodiment 3

[0024] Synthesis of O-(imidazolyl) ethyl derivative (III) of embodiment 3 Atropurpuran

[0025] Compound II (209 mg, 0.5 mmol) was dissolved in 12 mL of acetonitrile, anhydrous potassium carbonate (345 mg, 2.5 mmol), potassium iodide (84 mg, 0.5 mmol) and imidazole (3480 mg, 40 mmol) were added thereto, and the mixture was heated to reflux for 4 h. After the reaction, the reaction solution was poured into ice water, extracted three times with an equal amount of dichloromethane, and the organic phases were combined. The combined organic phases were successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether / acetone=100:0.7, v / v), and the concentrated brown elution band was collected and concentrated to give compound III as a brown solid (156 mg, 77%).

[0026] 1 H...

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Abstract

The invention relates to the field of organic synthesis and pharmaceutical chemistry and discloses application of a composition of imidazolyl and dichloroethylamino derivatives of Atropurpuran to resistance of liver fibrosis, namely a composition composed of an O-(imidazolyl) ethyl derivative (III) and an O-(dichloroethylamino) ethyl derivative (IV) of the Atropurpuran at the mass ratio of 70 to 30 and a method for preparing the composition by mixing the compounds at the mass ratio of 70 to 30. A pharmacology experiment shows that the composition provided by the invention can be used for remarkably inhibiting NIH / 3T3 proliferation and transforming growth factor-beta1 induced fibroblast proliferation when the concentration is 20mug / ml; the composition has the liver fibrosis resisting effect, so that the invention also provides application of the Atropurpuran to preparation of a medicine for resisting the liver fibrosis. (The formula (III) is shown in the description and the formula (IV) is shown in the description.).

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a composition, a preparation method and an application thereof. Background technique [0002] Liver fibrosis is a dynamic process from chronic liver injury to liver cirrhosis, manifested in the synthesis and secretion of a large amount of extracellular matrix (ECM), while the degradation is absolutely or relatively insufficient, resulting in the diffuse deposition of ECM in the liver. It starts with necrosis of hepatocytes (HC), followed by inflammatory response, release of fibrogenesis mediators, activation of hepatic stellate cells (FSC), and finally, the synthesis and degradation of liver connective tissue components are obviously out of balance. Liver fibrosis is a common pathological process of many chronic liver diseases and an important factor affecting prognosis. [0003] In the past 20 years, the study of liver fibrosis has made great progress, ...

Claims

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Application Information

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IPC IPC(8): A61K31/4164A61K31/13C07D233/60C07C217/12A61P1/16
CPCA61K31/4164A61K31/13C07C217/12C07D233/60
Inventor 王卓婷
Owner NANJING FUHAIAOSAI PHARMA CO LTD
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