3,4-di-oxygen-[3-substituted alkene propionyl]quinic acid compounds and medicine uses thereof

A compound, quinic acid technology, applied in the preparation of organic compounds, digestive system, organic chemistry, etc., can solve problems such as side effects

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

The clinical efficiency of interferon is only 30-50%, and it has the same side effects as nucleosides

Method used

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  • 3,4-di-oxygen-[3-substituted alkene propionyl]quinic acid compounds and medicine uses thereof
  • 3,4-di-oxygen-[3-substituted alkene propionyl]quinic acid compounds and medicine uses thereof
  • 3,4-di-oxygen-[3-substituted alkene propionyl]quinic acid compounds and medicine uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 : Compound 3, the preparation of 4-dihydroxyquinic acid lactone

[0044] Weigh quinic acid (900 mg, 4.7 mmol) into a thick-bottomed Erlenmeyer flask, heat it on an electric furnace to a molten state and keep it for several minutes, then quickly put it in a desiccator and place it to cool. Acetic acid was recrystallized to obtain 400 mg of white solid with a yield of 49.7%.

Embodiment 2

[0045] Example 2 : compound II-a is 3, the preparation of 4-di-oxo-[3-(4-methoxyphenyl)acryl]-quinic acid-1,5-lactone

[0046] Add p-methoxyphenylacrylate (103 mg, 0.58 mmol), carbonyldiimidazole (190 mg, 1.17 mmol) and 8 ml of THF in the reaction flask, heat to reflux for 2 hours, then add 3 , 4-Dihydroxyquinolactone (40 mg, 0.23 mmol), 1,8-diazabicyclo[5,4,0]11alk-7-ene (DBU, 90 mg, 0.58 mmol) , the whole solution was reacted under reflux for 8 hours. The solvent was distilled off under reduced pressure to obtain a light yellow viscous solid, which was separated by Sephadex LH-20 (100 ml, eluting with methanol) column chromatography to obtain 43 mg of a white solid with a yield of 38.6%.

[0047] White solid, melting point: 147~150°C (chloroform); R f (petroleum ether / ethyl acetate=3 / 1): 0.28; H NMR spectrum (400MHz, deuterated methanol): δ2.16~2.61 (4H, multiplet, H-2, 6), 3.82 (3H, single peak, OCH 3 ), 3.84 (3H, singlet, OCH 3 ), 4.95 (1H, double doublet, H-4), 5.1...

Embodiment 3

[0048] Example 3 : compound II-a is 3, the preparation of 4-di-oxo-[3-(4-methoxyphenyl)acryl]-quinic acid-1,5-lactone

[0049]

[0050] Add p-methoxyphenylacrylate (87 mg, 0.49 mmol), dicyclohexylcarbodiimide (100 mg, 0.49 mmol) and 8 ml of dichloromethane into the reaction flask, and stir at room temperature for 20 minutes , after white turbidity appeared, 3,4-dihydroxyquinic acid lactone (34 mg, 0.19 mmol), 4-dimethylaminopyridine (DMAP, 10 mg, 0.049 mmol) were added, and the whole solution was reacted at room temperature Overnight, the insolubles were removed by suction filtration, the solvent was evaporated, and the solvent was evaporated under reduced pressure to obtain a white solid, which was separated by Sephadex LH-20 (100 ml, eluting with methanol) column chromatography to obtain 37 mg of a white solid with a yield of 39.6%. .

[0051] Compound II-a, white solid, melting point, H NMR spectrum and other data are the same as those in Example 2.

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Abstract

The invention relates to 3,4-di-o-[3-substitued phenyl propionyl] quinic acid compounds having the formula of (I) and anti-hepatitis B virus activity and a pharmaceutical application thereof. The invention also relates to key intermediate compounds (II) for preparing the quinic acid compounds having the formula of (I), pharmaceutical application of the compounds having the formula of (I) and the compounds having the formula of (II), and drugs and pharmaceutical compositions containing the compounds (I) and (II). The compounds (I) and (II) inhibit hepatitis B virus DNA (HBVDNA) replication and reduces hepatits B virus surface antigen (HBsAg) expression. Thus, the compounds (I) and (II) and pharmaceutical application thereof have prospect pharmaceutical application in the preparation of a drug for 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 3,4-di-oxo-[3-substituted acryloyl]quinic acid compounds and their medical applications. The present invention also relates to A key intermediate compound of formula (II) related to the preparation of a compound of formula (I). Compounds of formula (I) and formula (II) have been found to inhibit the replication of hepatitis B virus DNA (HBVDNA) and reduce the expression of hepatitis B virus surface antigen (HBsAg). Medicinal use for viral infectious diseases. Background technique [0002] my country is an area with a high incidence of viral hepatitis, mainly infected with hepatitis B virus HBV. There are more than 120 million hepatitis B virus carriers, and about 30 million patients need treatment. About 300,000 people die from liver disease every year, causing at least 50 billion yuan in direct econom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/736C07C69/65C07C67/00C07D307/54A61K31/216A61K31/341A61P1/16A61P31/12
Inventor 黄可新胡利红韩方方熊伟白骅郝小江胡明辉赵昱巫秀美李校堃瞿佳
Owner WENZHOU MEDICAL UNIV
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