1-oxygen-substituted benzene formyl quinic acid pharmaceutical use of inhibiting hepatitis b virus

A technology of benzoylquinic acid and quinic acid, which can be used in antiviral agents, drug combinations, pharmaceutical formulations, etc., can solve the problems of drug resistance, high price, and adverse effects of nucleoside drugs.

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

AI Technical Summary

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-substituted benzene formyl quinic acid pharmaceutical use of inhibiting hepatitis b virus
  • 1-oxygen-substituted benzene formyl quinic acid pharmaceutical use of inhibiting hepatitis b virus
  • 1-oxygen-substituted benzene formyl quinic acid pharmaceutical use of inhibiting hepatitis b virus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 : compound 3, the preparation of 4-acetonylidene quinic acid lactone

[0039] 3,4-Acetonylidene quinic acid lactone

[0040] In the reaction flask, add quinic acid (500 mg, 2.6 mmol), anhydrous sodium sulfate (2.5 g, 17.6 mmol), 15 milliliters 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...

Embodiment 2

[0042] Example 2 : Preparation of Compound II-a[1-oxo-(4-methoxybenzoyl)-3,4-acetonylidene quinic acid lactone]

[0043]

[0044] Add p-methoxybenzoic acid (90 mg, 0.58 mmol) to the reaction flask, carbonyldiimidazole (190 mg, 1.17 mmol), 8 ml of anhydrous tetrahydrofuran, reflux for 2 hours, then add 3,4- Acetonide (100 mg, 0.47 mmol), 1,8-diazabicyclo[5,4,0]11alk-7-ene (DBU) (90 mg, 0.58 mmol), whole The solution was refluxed for 8 hours. Precipitation gave a pale yellow viscous solid, which was separated by HPLC to obtain 50 mg of a white solid with a yield of 31.8%.

[0045] Melting point: 63~64℃; R f (chloroform / methanol / formic acid: 50 / 2 / 1): 0.75; H NMR spectrum ( 1 H NMR, 400MHz, deuterated methanol): δ1.33 (3H, singlet), 1.43 (3H, singlet), 2.46~2.76 (4H, multiplet), 3.91 (3H, singlet), 4.09 (1H, Double doublet), 4.51 (1H, multiplet), 4.74 (1H, double doublet), 7.07 (2H, singlet), 8.03 (2H, singlet).

[0046] According to the same method of embodiment 1 and 2...

Embodiment 7

[0056] Example 7 : Preparation of Compound I-a[1-oxo-(4-methoxybenzoyl)-quinic acid]

[0057]

[0058] Add compound 1-oxygen-(4-methoxybenzoyl)-3,4-acetonylidene quinic acid lactone II-a (50 mg, 0.144 mmol) in a two-necked flask, add 5 ml of tetrahydrofuran, Add 5 ml of 1N hydrochloric acid dropwise, react at room temperature for 72 hours, add saturated salt to the reaction system, extract with chloroform, wash the combined chloroform layer with a large amount of water, wash with saturated brine, and dry over anhydrous sodium sulfate. After separation by HPLC, 29 mg of white solid was obtained with a yield of 62.5%.

[0059] Melting point: 84~87℃, R f (chloroform / methanol / formic acid: 50 / 2 / 1): 0.25; H NMR spectrum ( 1 H NMR, 400MHz, deuterated methanol): δ2.46~2.76 (4H, multiplet), 3.91 (3H, singlet), 4.09 (1H, double doublet), 4.51 (1H, multiplet), 4.74 (1H , double doublet), 7.07 (2H, singlet), 8.03 (2H, singlet).

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Abstract

The invention relates to 1-o-substituted benzoyl quinic acid compounds having the formula of (I) and anti-hepatitis B virus activity and pharmaceutical salts thereof. The invention also relates to a preparation method of the quinic acid compounds and intermediate compounds of the quinic acid compounds. The invention also relates to a pharmaceutical application of the quinic acid compounds, and pharmaceutical compositions containing the same. The compounds (I) and intermediate compounds thereof, and pharmaceutical salts thereof inhibit hepatitis B virus DNA (HBVDNA) replication and reduces hepatits B virus surface antigen (HBsAg) expression. Thus, the 1-o-substituted benzoyl quinic acid compounds and intermediate compounds thereof have prospect pharmaceutical application in the preparation of a drug for treating correlated hepatitis B virus infectious disease.

Description

technical field [0001] The invention relates to the fields of organic chemistry, medicinal chemistry and pharmacology, in particular, the invention relates to 1-oxo-substituted benzoylquinic acid compounds and key intermediates thereof, their preparation methods and medical applications. The compound is found to inhibit the replication of hepatitis B virus DNA (HBVDNA) and reduce the expression of hepatitis B virus surface antigen (HBsAg), so it can be expected to be used for preparing and 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, more than 3,000 kinds of viruses have been discovered in the world, and new viruses are constantly being discovered. AIDS caused by the human immunodeficiency virus (HIV) discovered by medical scientists in the 1980s is a very harmful infe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/92C07C69/76A61K31/216A61P1/16A61P31/12
Inventor 李校堃胡利红冯治国李海波黄可新巫秀美赵昱瞿佳
Owner WENZHOU MEDICAL UNIV
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