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Medicine for treating liver cirrhosis and synthesis method thereof

A compound and pharmaceutical technology, applied in the field of drugs for the treatment of liver cirrhosis and its synthesis, can solve the problems of failure to achieve the expected effect, complex formation mechanism of liver fibrosis, etc., achieve prevention and treatment of liver fibrosis and liver cirrhosis, and inhibit liver fibrosis Effects of chemicalization and liver damage

Inactive Publication Date: 2018-01-05
MUDANJIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The formation mechanism of liver fibrosis is very complicated. Many in vitro and animal experiments have proved effective treatment methods, but they have not achieved the expected effect after being used clinically.

Method used

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  • Medicine for treating liver cirrhosis and synthesis method thereof
  • Medicine for treating liver cirrhosis and synthesis method thereof
  • Medicine for treating liver cirrhosis and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058]Example 1: 8-(2-phenylacetyl)-7,8-dihydro-5H-pyridin[2,3-c]azepine-5,9(6H)-dione (AZE-1) Synthesis

[0059]

[0060] Step 1: In 150ml of anhydrous acetonitrile solution containing 8.9g 2,2,2-trichloro-1-(pyridin-2-yl)ethanone, add 7.38g β-alanine ethyl ester hydrochloride and 8ml tris Ethylamine, stirred at room temperature for about 8 hours, until the conversion of the raw materials was complete, the solvent was removed by rotary evaporation, and then 40mL of 2N NaOH solution was added, stirred at room temperature for 10 hours, the reaction solution was extracted with ethyl acetate, and the organic phase was extracted with water, 1N Wash with HCl solution and saturated brine respectively, and wash with anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure to obtain compound 3-(pyridinecarboxamide) propionic acid (6.9 g, yield 89%). ESI-MS: 195.07[M+H] +

[0061] Step 2: 9.80g P 2 o 5 Stir with 103.2g of PPA at 1...

Embodiment 2

[0067] Example 2: 8-(2-(4-methoxyphenyl)acetyl)-7,8-dihydro-5H-pyridin[2,3-c]azepine-5,9(6H)- Synthesis of diketone (AZE-2)

[0068]

[0069] According to the method of Example 1, except that phenylacetic acid was replaced by 4-methoxyphenylacetic acid, the title compound was obtained as a white solid, and the total yield of the three steps was 43%.

[0070] Elemental analysis: theoretical value / measured value, C(66.66 / 66.78), H(4.97 / 4.82), N(8.64 / 8.53), O(19.73 / 19.87)

[0071] ESI-MS: 325.11[M+H] +

[0072] 1 H NMR (400MHz, CDCl 3 )δ9.12(d,1H),8.74(d,1H),8.13(q,1H),7.13(s,2H),6.83(s,2H),3.93(s,2H),3.82(s,3H ), 3.72(t,2H), 2.63(t,2H).

[0073] According to a method similar to Example 1, the following compounds were synthesized by changing the raw materials used:

[0074]

[0075]

[0076] Next, the pharmacological effects of representative compounds are explained in detail through pharmacodynamic experiment examples.

experiment example 1

[0077] Drug efficacy experiment example 1: Evaluation of the target compound on inhibiting TGF-β production

[0078] In order to observe whether the compounds of the present invention can directly inhibit the production of TGF-β (which is overexpressed in macrophages) and evaluate the relevant molecular pharmacological mechanism, RAW264.7 macrophages were used for testing. When the compounds AZE-1 to AZE-6 of the present invention are directly added to RAW264.7 macrophages (which have increased the expression of TGF-β), taking AZE-1, AZE-3 and AZE-6 as examples, the test results are as follows :

[0079] Table 1: Inhibition of TGF-β expression in macrophages by target compounds

[0080]

[0081] The test results show that the compound of the present invention can inhibit the expression of TGF-β in a dose-dependent manner, indicating that the compound of the present invention can be used as an anti-fibrosis and anti-cirrhosis drug in hepatic macrophages of the liver by inhi...

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Abstract

The invention relates to a compound having a structure as shown in the chemical formula 1 or pharmacologically acceptable salt and a prodrug: as shown in the specification. The compound can inhibit TGF (Transforming Growth Factor)-beta expression in a dosage-dependent way, can be produced by inhibition of TGF-beta and is used as an anti-fibrosis and anti-liver cirrhosis medicine in kupffer cells of the liver; furthermore, by application of the compound disclosed by the invention, liver fibrosis and liver injury which are caused by DMN (dimethylnitrosamine) can be inhibited, and the compound has the treating effect better than that of simvastatin. Therefore, the compound can be used as a medicine for preventing and treating the liver fibrosis and the liver cirrhosis.

Description

technical field [0001] The invention relates to a drug with anti-hepatic fibrosis and anti-cirrhosis effects, and a synthesis method of the drug. Background technique [0002] The liver plays an important role in the metabolism of xenobiotics and endogenous substances. It is an important organ that coordinates enzyme reactions and energy metabolism. Among the many chronic diseases in Korea, hepatitis, cirrhosis, and liver cancer are the most prevalent and life-threatening diseases after cardiovascular disease. Since Korea has relatively more alcoholics compared to developed countries and the number of liver injuries caused by binge drinking is large, much attention has been paid to the treatment of liver diseases. Chronic liver damage from viral infections and alcohol abuse often leads to cirrhosis and liver cancer. Considering the physiological characteristics and significance of liver tissue, as well as the importance of treating and preventing liver diseases, it is urge...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/55A61P1/16
Inventor 卢丽岩刘秀玉郑秀英闫俊凤郭玲张春红于涛
Owner MUDANJIANG MEDICAL UNIV
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