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Benzoic acid triazole anti-influenza-virus compounds as well as preparation method and application thereof

A compound and drug technology, which is applied in the field of benzoic acid triazole anti-influenza virus compounds, can solve the problems of cumbersome steps, reduced affinity, high price, etc., and achieve the effect of broad application prospects, high-efficiency inhibition effect, and simple synthesis steps

Inactive Publication Date: 2017-02-22
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with the increase of administration, oseltamivir-resistant strains appear frequently, and the affinity between the enzyme active site of NA and the inhibitor decreases, which greatly limits the therapeutic effect on drug-resistant influenza.
In addition, since oseltamivir and zanamivir both contain multiple chiral centers, the steps to synthesize their optical isomers are cumbersome and costly, making these drugs expensive

Method used

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  • Benzoic acid triazole anti-influenza-virus compounds as well as preparation method and application thereof
  • Benzoic acid triazole anti-influenza-virus compounds as well as preparation method and application thereof
  • Benzoic acid triazole anti-influenza-virus compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Synthesis of key intermediate parts

[0057] Preparation of Diethyl 2-[4-(ethoxycarbonyl)anilino]malonate (C)

[0058] Add 30g (181.82mmol) ethyl p-aminobenzoate (A) and 20g (84.03mmol) diethyl bromomalonate (B) into a 500mL eggplant-shaped bottle, react at 115°C for 24h, dissolve and filter with ether, and the filtrate Wash 3 times with 10% hydrochloric acid, 3 times with water, and dry over anhydrous sodium sulfate. Filter and stand to precipitate crystals. Suction filtration and washing with a small amount of ether gave 23 g of colorless crystal C with a yield of 85.0%. m.p.: 68-72°C.

[0059] MS[M+H] + :324.1;

[0060] 1 H NMR (500MHz, CDCL 3 ), δ: 7.9(d, 2H, J=8.8Hz, ArH); 6.6(d, 2H, J=8.8Hz, ArH); 5.2(d, 1H, J=7.2Hz, CH); 4.8(d, 1H,J=7.2Hz,NH); 4.33~4.37(m,2H,CH 2 ); 4.3(m,4H,2CH 2 ); 1.35~1.38(t,3H,J=7.2Hz,CH 3 ); 1.11~1.14(t,6H,J=7.2Hz,2CH 3 ).

[0061] Preparation of 1-[4-(ethoxycarbonyl)phenyl]-5,5-dicarboxylate-2-pyrrolidone (D)

[0062] Add 5.6...

Embodiment 2

[0089] Synthesis of Ⅳ series intermediates

[0090] Ethyl 4-[2,2-(dimethylol)-5-oxopyrrolidinonyl]-3-[3-(2-methylbenzoyl)thioureido]benzoate (Ⅳ-1)

[0091] Add 0.41g (5.39mmol) of ammonium thiocyanate (5.39mmol) and 8mL of anhydrous acetone into a 25mL three-necked flask, drop 0.68g (4.40mmol) of o-toluyl chloride into 15mL of acetone within 5min, reflux for 20min, and then slowly drop Add 0.73 g (2.37 mmol) of ethyl 3-amino-4-[2,2-(dimethylol)-5-oxopyrrolidinonyl]benzoate (II) and dissolve it in 15 mL of acetone. Continue to reflux for 12h. The lysozyme was distilled off under reduced pressure, and the residue was separated by column chromatography (CH 2 CL:CH 3 OH=50:1), 0.41 g of white solid was obtained, and the yield was 35.44%. m.p.141-143°C.

[0092] [M+K] + :524.1;

[0093] 1 H NMR (300MHz, DMSO) δ (ppm): 12.55 (s, 1H, NH); 11.76 (s, 1H, NH); 9.08 (s, 1H, ArH); 7.85~7.88 (m, 1H, ArH); 7.41~7.54(m, 3H, ArH); 7.29~7.32(m, 2H, ArH); 5.31(s, 1H, OH); 4.89(s, 1H, O...

Embodiment 3

[0112] 4-[2,2-(Dihydroxymethyl)-5-oxopyrrolidinyl]-3-[5-(2-methylphenyl)-4H-1,2,4-triazolyl- Preparation of 3-amino)benzoic acid (Ⅰ-1)

[0113] Compound (Ⅳ-1) 0.25g (0.51mmol), 1 drop of acetic anhydride and 0.1ml of hydrazine hydrate were mixed in 10ml of absolute ethanol, N 2 Under protection, reflux for 6 hours, evaporate lysozyme under reduced pressure, and the residue is separated by column chromatography (CH 2 CL:CH 3 OH=50:1), 0.15 g of light yellow oil was obtained, yield 62.7%. Dissolve the oil in 10ml of methanol, add 1ml of 2N NaOH solution, stir at room temperature, monitor by TLC until the raw material point disappears, spin off the methanol, add 10% HCl to adjust the pH to 2-3, a white solid precipitates out, filter and dry to obtain White solid 40 mg, yield 29.0%. m.p.224~226℃

[0114] [M+H] + :438.2;

[0115] 1 H NMR (300MHz, DMSO) δ (ppm): 13.23 (s, 1H, COOH); 9.03 (s, 1H, NH); 8.91 (s, 1H, NH); 7.65~7.68 (m, 1H, ArH); 7.40~7.45(m, 1H, ArH); 7.28~7.34...

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to benzoic acid triazole anti-influenza-virus compounds as well as a preparation method and a pharmaceutical application thereof. A pharmacological testing result shows that the compounds have an efficient inhibition effect on influenza viruses and oseltamivir drug-resistant mutants in vitro and vivo. Therefore, the compounds can be used for treating influenza.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of benzoic acid triazole anti-influenza virus compounds, their preparation method and their medical application. Background technique [0002] Influenza caused by pathogenic microorganism influenza virus is a respiratory infectious disease that seriously threatens human life and health. Influenza viruses can be divided into different subtypes, such as A / California / 7 / 2009(H1N1), A / Beijing / 32 / 92(H3N2), A / Vienam / 1203 / 2004(H5N1), Anhui / 1 / 2013(H7N9 )Wait. Influenza virus can cause very serious complications and death, and its prevention and control consume a lot of social resources. [0003] In view of the relative lag in vaccine development, the specific anti-influenza drugs currently used clinically are mainly M2 ion channel blockers (such as amantadine and rimantadine), neuraminidase (NA) inhibitors (such as osestatin Virus and zanamivir) and RNA polymerase inhibitors ...

Claims

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Application Information

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IPC IPC(8): C07D207/27C07D403/12A61K31/4015A61K31/4196A61P31/16
CPCC07D207/27C07D403/12
Inventor 周长林靳京张慧鑫窦洁王德传贾源宾
Owner CHINA PHARM UNIV
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