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Novel 2'-carbamyl biphenyl compounds and application thereof in anti-hepatic fibrosis medicines

A carbamoyl biphenyl, anti-liver fibrosis technology, applied in the directions of effective components of heterocyclic compounds, digestive system, organic chemistry, etc., to achieve the effects of simplifying the process, improving the yield, and facilitating large-scale industrial production

Inactive Publication Date: 2015-02-11
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The 2'-carbamoyl biphenyl compounds of the present invention and their application in anti-hepatic fibrosis have not been reported so far at home and abroad.

Method used

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  • Novel 2'-carbamyl biphenyl compounds and application thereof in anti-hepatic fibrosis medicines
  • Novel 2'-carbamyl biphenyl compounds and application thereof in anti-hepatic fibrosis medicines
  • Novel 2'-carbamyl biphenyl compounds and application thereof in anti-hepatic fibrosis medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] "Example 1" Synthesis of 4,4'-dimethoxy-5,6,5',6'-dimethoxy-2,2'-dicarboxylic acid biphenyl (III)

[0030] Add 4,4'-dimethoxy-5,6,5',6'-dimethoxy-2,2'-dicarboxylic acid methyl biphenyl (II) (500g, 1.20 mol), add acetone (5000 mL) and water (3000 mL), stir, the material cannot be completely dissolved, then add sodium hydroxide (250g, 6.25 mol), stir and heat to reflux, reflux for about 0.5h, the reaction system is light yellow and clear liquid, refluxed for 3-4 hours, the raw materials basically reacted completely (TLC detection), after the reaction was completed, the acetone was evaporated under reduced pressure, the temperature of the reaction bottle was lowered, and concentrated hydrochloric acid was added under ice bath to acidify to slightly acidic (pH=1-2), and a large amount of white Solid, stirred at room temperature for 0.5h, filtered with suction, washed with water 3-4 times close to neutral, and dried in vacuum at 40°C to obtain 441.4g of white solid product 4...

Embodiment 2

[0032] 《Example 2》Synthesis of acid anhydride derivatives (IV)

[0033] Add 4,4'-dimethoxy-5,6,5',6'-dimethoxy-2,2'-dicarboxylic acid biphenyl (III) (619g, 1.58mol) into a 10 L reaction flask , add acetic anhydride (4300 mL), reflux for 3 hours, distill off acetic anhydride under reduced pressure, add toluene (1000 mL) and petroleum ether (3000 mL) to the residue, stir and filter with suction to obtain a crude product, which is heated with toluene (1500 mL) Stir and wash, cool to room temperature and filter to obtain 516.2g off-white solid anhydride derivative (IV), melting point: 265-266°C, yield: 98.0%.

[0034] 1 H-NMR (400 MHz, CDCl 3 )δ: 7.05(s,2H), 6.06-6.17(m,4H), 3.96(s,6H).

Embodiment 3

[0035] "Example 3" Synthesis of 4,4'-dimethoxy-5,6,5',6'-dimethoxy-2-formic acid-2'-hydroxymethylbiphenyl (V)

[0036] Add an acid anhydride derivative (IV) (446.7g, 1.2mol) into a 10 L reaction flask, add tetrahydrofuran (THF 6000mL), add sodium borohydride (150.0g, 3.96 mol) in batches at room temperature, after the addition is complete, stir at room temperature for 8 h , slowly added 6 mol / L hydrochloric acid to the reaction solution until no bubbles were produced, evaporated THF, added 1000 mL of water to dissolve the residue, extracted with ethyl acetate, washed with water, dried, and concentrated to obtain 411.5 g of off-white solid product 4 , 4′-dimethoxy-5,6,5′,6′-dimethoxy-2-formic acid-2′-hydroxymethylbiphenyl (V), yield: 91.7%.

[0037] 1 H-NMR (400 MHz, CDCl 3)δ:7.40(s,1H),6.74(s,1H),6.02-6.05(m,2H),5.91-5.92(m,2H),4.35-4.44(m,2H),3.97(s, 3H), 3.94(s, 3H).

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Abstract

The invention relates to novel 2'-carbamyl biphenyl compounds and application thereof in anti-hepatic fibrosis medicines. Experimental research proves that the novel 2'-carbamyl biphenyl compounds are capable of obviously restraining generation of collagenous fiber, inhibiting TGFbeta / Smad signal channels, reversing loss of weight, improving liver function and inhibiting ductular proliferation. Therefore, the compounds or compositions comprising the compounds are expected to be developed into anti-hepatic fibrosis medicines with good potential.

Description

Technical field: [0001] The invention relates to biphenyl compounds and their application in anti-hepatic fibrosis. Background technique: [0002] Liver fibrosis is a pathological process of excessive deposition of diffuse extracellular matrix (ECM) in the liver, especially type I collagen α1 [Kisseleva T et al. Journal of gastroenterology and hepatology, 2007,22:S73-S78. ]. It is a repair response of the body to chronic liver damage, a common pathological process of chronic liver diseases caused by various etiologies, and the main link in the development of liver cirrhosis. The further development of liver fibrosis is also prone to be complicated by infectious and autoimmune hepatitis, primary and biliary cirrhosis, liver failure and portal hypertension, and eventually requires liver transplantation to prolong life [Fallowfield J et al Clinical Medicine, 2011 , 11:179-183.]. Studies have shown that liver fibrosis can be reversed [Zhang Jianrong et al., Hebei Medicine, 20...

Claims

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Application Information

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IPC IPC(8): C07D317/68C07D405/14A61K31/36A61K31/443A61P1/16
CPCC07D317/68C07D405/14
Inventor 邵荣光王菊仙何红伟王玉成赵双双白晓光任金凤杨志衡李子强
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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