Piperazinyl and dihydroxyethylamido derivative composition of Atropurpuran for 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: 2017-05-31
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 id

Method used

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  • Piperazinyl and dihydroxyethylamido derivative composition of Atropurpuran for anti-hepatic fibrosis
  • Piperazinyl and dihydroxyethylamido derivative composition of Atropurpuran for anti-hepatic fibrosis
  • Piperazinyl and dihydroxyethylamido derivative composition of Atropurpuran for anti-hepatic fibrosis

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Experimental program
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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] The synthesis of O-(piperazinyl) ethyl derivative (III) of embodiment 3 Atropurpuran

[0025] Compound II (209mg, 0.5mmol) was dissolved in 16mL of acetonitrile, anhydrous potassium carbonate (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and anhydrous piperazine (6892mg, 80mmol) were added thereto, and the mixture was heated to reflux 2h. After the reaction, the reaction solution was poured into ice water, extracted twice 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 (163 mg, 77%).

[0026] 1 H NM...

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Abstract

The invention relates to the field of organic synthesis and medicinal chemistry and discloses a composition composed of an O-(piperazinyl) ethyl derivative (III) and an O-(dihydroxyethylamido) ethyl derivative (IV) of Atropurpuran in a mass ratio of 70: 30 and a method of preparing the composition composed of the compounds in a mass ratio of 70: 30. A pharmacological experiment verifies that the composition provided by the invention can obviously inhibit NIH/3T3 proliferation and fibroblast proliferation induced by a transforming growth factor-beta1 when the concentration of the composition is 20[mu]g/ml, and has the action of anti-hepatic fibrosis. Therefore, the composition provided by the invention also provides use of the composition composed of the O-(piperazinyl) ethyl derivative (III) and the O-(dihydroxyethylamido) ethyl derivative (IV) of Atropurpuran in the mass ratio of 70: 30 in preparing drugs for anti-hepatic fibrosis. The formula is as 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): A61K31/495A61K31/133A61P1/16C07D295/088C07C217/12
CPCA61K31/495A61K31/133C07C217/12C07D295/088
Inventor 王卓婷
Owner NANJING FUHAIAOSAI PHARMA CO LTD
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