Butene lactone compound containing sulfonyl lactones as well as synthesis method and application thereof

A technology containing sulfonyl lactone and butenolide, which is applied in the directions of effective components of heterocyclic compounds, digestive system, organic chemistry, etc., can solve problems such as incompatibility, achieve good inhibitory effect, feasible synthesis route and high yield Effect

Active Publication Date: 2014-04-02
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although the combination therapy of interferon and ribavirin has made great progress in the clinical treatment of HCV, there are still many patients who are not suitable for this therapy, especially those with immune compromise and HIV / HCV co-infection. Targeted antiviral drugs are imperative

Method used

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  • Butene lactone compound containing sulfonyl lactones as well as synthesis method and application thereof
  • Butene lactone compound containing sulfonyl lactones as well as synthesis method and application thereof
  • Butene lactone compound containing sulfonyl lactones as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: Preparation of compound Ia containing cyclic γ-lactone-δ-sultone structure

[0037]Step 1: Dissolve 10 g (58 mmol) 3,4-difluorophenylacetic acid in 100 mL tetrahydrofuran, add 15.78 g (87 mmol) ethyl α-bromopropionate, 8.79 g (87 mmol) triethyl The amine was heated to 60-70°C and reacted for 7-8 h, followed by TLC monitoring. After the reaction was completed, it was filtered with suction and concentrated to obtain a yellow oily compound 3a crude product.

[0038] Step 2: Dissolve the crude compound 3a in 60 mL DMF, add potassium tert-butoxide 9.74 g (87 mmol) in 6 times in an ice bath, after the addition is complete, continue to stir in the ice bath for 0.5 h, and then leave to stir at room temperature After 12 h of reaction, TLC monitored the completion of the reaction. To deal with the reaction, first dilute the system with 20 mL of water, then adjust the pH value of the system to 3-4 with dilute hydrochloric acid, and then add about 200 mL of water to ...

Embodiment 2

[0043] Embodiment 2: table 1 adopts the method described in embodiment 1 to prepare following compound

[0044] Compounds R Ia m,p -diF Ib o -F IC m -F ID p -F Ie H If o -Br Ig p -Br Ih p -CH 3 o II p -CF 3 Ij p -CH 3 Ik p -Cl

[0045] Ia

[0046] 1 H NMR (400 MHz, CDCl 3， TMS) δ 7.31 (d, J = 8.3 Hz, 3H), 4.69 (d, J = 13.8 Hz, 1H), 4.60 (d, J = 10.7 Hz, 1H), 4.42 (d, J = 10.7 Hz, 1H), 4.22 (d, J = 13.8 Hz, 1H). 13C NMR (101 MHz, CDCl 3 , TMS) δ 168.73, 151.73, 125.50, 125.46, 118.52, 118.42, 118.34, 118.24, 78.76, 77.23, 76.87, 49.42, 20.79. IR 1764.28 C=O , 1173.69 SO2 (s), 1369.27 SO2 (as).

[0047] Ib

[0048] 1 H NMR (400 MHz, CDCl 3， TMS) δ 7.63 (d, J = 1.6 Hz, 1H), 7.51 (ddd, J = 15.5, 5.4, 1.7 Hz, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 4.59 (d, J = 10.8 Hz, 1H), 4.47 (s, 1H), 4.45 (d, J = 2.6 Hz, 1H), 4.26 (d, J = 14.2 Hz,...

Embodiment 3

[0067]Embodiment 3: In vitro HCV activity screening experiment of the compound of the present invention

[0068] 1 Material:

[0069] Bovine kidney cells (MDBK) cultured in RMPI-1640 medium containing 10% fetal bovine serum (FBS); bovine viral diarrhea prepared by three times of plaque purification in prepared bulk monolayer bovine kidney cells (MDBK) Pathogenic strain AV-69 of virus (BVDV).

[0070] 2 methods:

[0071] a Anti-HCV activity assay

[0072] Bovine kidney cells (MDBK) were seeded in 96-well plates after counting, 2×10 per well 4 Cells were cultured in a 37°C, 5% carbon dioxide incubator for 24 hours, and the supernatant was discarded, and 100 uL of bovine viral diarrhea virus (100TCID50) was added to each well. Two hours later, the culture medium was removed, and each well was washed twice with 100 uL of phosphate-buffered saline (PBS), and the drug solution prepared with the culture medium at a concentration of 0.01 μM-1 μM was immediately added. The culture...

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PUM

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Abstract

The invention discloses a butene lactone compound containing sulfonyl lactones as well as a synthesis method and an application thereof, and belongs to the chemical field of medicines. The butene lactone compound has the following general structure formula I, wherein in the formula I, R represents hydrogen, mono-substituted or poly-substituted methoxy groups, methyl groups, fluorine, chlorine, bromine, trifluoromethyl and the like; the poly-substituted groups are same. The butene lactone compound has a good function of inhibiting HCV (Hepatitis C Virus) and cannot generate the significant cytotoxicity. Thus, the butene lactone compound can be used for preparing HCV-resisting medicines, and has the potential for developing the HCV-resisting medicines with novel functional actions.

Description

technical field [0001] The invention relates to a class of compounds containing a cyclic gamma-lactone-delta-sultone structure and its synthesis method and application, belonging to the field of medicinal chemistry. Background technique [0002] Hepatitis C (hepatitis C) was initially defined as non-A non-B hepatitis after blood transfusion. In 1989, its pathogen was isolated and confirmed as hepatitis C virus (HCV, hepatitis C virus). There are 170 million people worldwide with HCV serum Positive, its infection accounts for about 3% of the global population, and there are 6 main genotypes of HCV, and its genome difference reaches 30%. In my country, HCV infection is mainly type II, and there are many mixed infections of II / III. HCV infection is closely related to liver lesions. It is estimated that about 75% of seropositive individuals will develop chronic infection and turn into liver cirrhosis. Some cases may also develop into liver cancer, which is the main cause of chr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D497/04A61K31/39A61P31/14A61P1/16
CPCC07D497/04
Inventor 徐海伟赵玲洁刘宏民戴桂馥刘文省谢晓平刘欢飞赵丹罗姣
Owner ZHENGZHOU UNIV
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