1-oxygen-[3-aryl substituted-alkene propionyl]quinic acid compounds and uses

A technology of propylidene quinic acid and compounds, which is applied in the digestive system, organic chemistry, drug combination, etc., and can solve the problems of nucleoside drugs such as adverse effects, drug resistance, and high price

Inactive Publication Date: 2008-10-29
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the clinical treatment options for HBV patients can only achieve inhibition of HBV replication and secondary infection, and the most important drugs are still nucleoside drugs such as lamivudine (3-TC), entecavir, adefovir (ADV ), etc., although they can effectively control the disease, but one is expensive, and two, long-term use can lead to drug resistance, as well as different degrees of rebound, and the third is the relatively obvious well-known phenomenon of long-term use of nucleoside drugs. Adverse effects of

Method used

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  • 1-oxygen-[3-aryl substituted-alkene propionyl]quinic acid compounds and uses
  • 1-oxygen-[3-aryl substituted-alkene propionyl]quinic acid compounds and uses
  • 1-oxygen-[3-aryl substituted-alkene propionyl]quinic acid compounds and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 : Preparation of compound 3,4-oxo-isopropylidene quinic acid 1,5-lactone

[0036] In the reaction flask, add quinic acid (500 mg, 2.6 mmol), anhydrous sodium sulfate (2.5 g, 17.6 mmol), 15 ml of anhydrous acetone, stir for several minutes, then add 3 microliters of Concentrated sulfuric acid was heated to reflux for 5 hours. Cool to room temperature, add sodium bicarbonate to adjust the pH to about 7, remove insoluble matter by suction filtration, and concentrate the filtrate. The solid obtained by precipitation was dispersed in 3 ml of chloroform and 3 ml of distilled water, and the aqueous layer was extracted 3 times with chloroform (5 ml × 3), and all organic phases were combined, washed with water, washed several times with saturated brine, and dried over anhydrous sodium sulfate . The solvent was distilled off under reduced pressure to obtain a white solid, which was recrystallized in ethyl acetate to obtain 350 mg of white powder with a yield of 63.2%...

Embodiment 2

[0039] Example 2 : Compound II-a is the preparation of 1-oxo-[3-(2,6-dichlorophenyl)acryloyl]-3,4-oxo-isopropylidene quinic acid-1,5-lactone

[0040] Method 1: Add 2,6-dichlorobenzene-3-allylic acid (125 mg, 0.58 mmol), carbonyldiimidazole (190 mg, 1.17 mmol) and 10 ml of anhydrous tetrahydrofuran to the reaction flask, and heat to reflux Reacted for 2 hours, then added 3,4-oxo-isopropylidene quinic acid-1,5-lactone (83 mg, 0.47 mmol), 1,8-diazabicyclo[5,4,0 ] 11 alk-7-ene (DBU, 90 mg, 0.58 mmol), the whole solution was reacted under reflux for 8 hours. After distilling off the solvent under reduced pressure, a light yellow viscous solid was obtained, which was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1, crude product: silica gel = 1: 40) to obtain 73.6 mg of a yellow solid with a yield of 38 %.

[0041] Method two: add 2,6-dichlorobenzene-3-allylic acid (30.2 mg, 0.14 mmol) to the reaction flask, dicyclohexylcarbodiimide (29 mg, 0.14 mmol), ...

Embodiment 3

[0044] According to the same method as in Example 2, the compounds of Examples 3 to 5 shown in Table 1 were prepared:

[0045]

[0046] Table I

[0047]

[0048] List the physicochemical data of each compound in Table 1 below:

[0049] Compound II-b: pale yellow solid, melting point: 89-90°C, R f (petroleum ether / ethyl acetate: 3 / 1): 0.31; H NMR spectrum ( 1 HNMR, 400MHz, deuterated methanol): δ1.35 (3H, singlet, CH 3 ), 1.48 (3H, singlet, CH 3 ), 2.35~3.12 (4H, multiplet, H-2, 6), 4.36 (1H, double doublet, H-4), 4.59 (1H, multiplet, H-5), 4.85 (1H, double doublet , H-3), 6.57 (1H, doublet, J=16.0Hz, H-2′), 7.35 (1H, J=8.4Hz, H-8′), 7.52 (1H, singlet, H-6′ ), 7.78 (1H, doublet, J=8.4Hz, H-9'), 7.98 (1H, J=16.0Hz, H-3').

[0050] Compound II-c: yellow oil, melting point: 93~95°C (chloroform); R f (petroleum ether / ethyl acetate: 3 / 1): 0.40; H NMR 1 H NMR (400MHz, deuterated methanol): δ1.33 (3H, singlet, CH 3 ), 1.51 (3H, singlet, CH 3 ), 2.40~3.11 (4H, multiplet...

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Abstract

The invention relates to 1-o-[3-aryl substituted-acrylyl]quinic acid compounds having the formula of (I), and an application thereof. The invention also relates to a preparation method of the quinic acid compounds, and intermediate compounds (II) of the quinic acid compound, i.e. 1-o-[3-aryl substituted-acrylyl]-3,4-o-isopropylidene quinic acid-1.5-lactone. The invention relates to pharmaceutical application of the quinic acid compounds, and pharmaceutical compositions containing the same. The compounds having the formula (I) and the compounds having the formula of (II), and pharmaceutical salts thereof have the effects of inhibiting hepatitis B virus DNA replication and reducing hepatitis B virus surface antigen expression. Thus, the compounds having the formula of (I) and the compounds having the formula of (II) have pharmaceutical prospect application in the preparation of a drug for preventing and treating hepatitis B virus infectious disease.

Description

technical field [0001] The present invention relates to the fields of organic chemistry, medicinal chemistry and pharmacology, specifically, the present invention relates to a class of 1-oxo-[3-aryl substituted-acryloyl]quinic acid compounds of the structure shown in formula (I) And its intermediate formula (II) compound, namely 1-oxo-[3-aryl substituted-acryloyl]-3,4-oxo-isopropylidene quinic acid-1,5-lactone, and their possible Medicinal salts and their preparation and medicinal use. The compound is found to have the functions of reducing the expression of hepatitis B virus surface antigen (HBsAg) and inhibiting the replication of hepatitis B virus DNA (HBVDNA); it can be expected to be used for preparing medicines for treating related hepatitis B virus infectious diseases. Background technique [0002] Virus infection causes various diseases of humans and animals, seriously endangers health and life, and about 60% of infectious diseases are caused by viruses. So far, mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/65C07C69/738C07D307/54A61K31/216A61K31/341A61P1/16A61P31/12
Inventor 李校堃张丽娟李海波董建勇巫秀美黄可新赵昱瞿佳
Owner WENZHOU MEDICAL UNIV
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