Application of benzimidazolyl and morpholinyl derivative composition of Atropurpuran to anti-hepatic 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: 2017-06-13
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 id

Method used

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  • Application of benzimidazolyl and morpholinyl derivative composition of Atropurpuran to anti-hepatic fibrosis
  • Application of benzimidazolyl and morpholinyl derivative composition of Atropurpuran to anti-hepatic fibrosis
  • Application of benzimidazolyl and morpholinyl derivative composition of Atropurpuran to anti-hepatic 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-(benzimidazolyl) ethyl derivative (III) of embodiment 3 Atropurpuran

[0025] Compound II (209mg, 0.5mmol) was dissolved in 12mL of acetonitrile, anhydrous potassium carbonate (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (4720mg, 40mmol) were added thereto, and the mixture was heated to reflux for 4h . 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 (162 mg, 71%).

[0026] 1 H...

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Abstract

The invention relates to the fields of organic synthesis and pharmaceutical chemistry. The invention discloses and provides a composition which is prepared from an O-(benzimidazolyl)ethyl derivative (III) and an O-(morpholinyl)ethyl derivative (IV) of Atropurpuran in a mass ratio of 65 to 35, and a method for preparing the composition by mixing the compounds in the mass ratio of 65 to 35. As proved by a pharmacology experiment, the composition provided by the invention can remarkably restrain NIH/3T3 multiplication and fibroblast proliferation induced by transforming growth factor-beta1, and has an anti-hepatic fibrosis effect. The invention further provides application of the composition prepared by mixing the O-(benzimidazolyl)ethyl derivative (III) and the O-(morpholinyl)ethyl derivative (IV) of the Atropurpuran in the mass ratio of 65 to 35 to preparation of an anti-hepatic fibrosis medicament. (The composition 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): A61K31/5375A61K31/4184C07D295/088C07D235/06A61P1/16
CPCA61K31/5375A61K31/4184C07D235/06C07D295/088
Inventor 王卓婷
Owner NANJING FUHAIAOSAI PHARMA CO LTD
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