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Preparation and application of novel pyridone human immunodeficiency virus-1 (HIV-1) reverse transcriptase inhibitor

A technology of pyridone and CH20H, which is applied in antiviral agents, medical preparations containing active ingredients, organic chemistry, etc.

Inactive Publication Date: 2011-04-06
PEKING UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of drug is prone to drug resistance, only one nucleotide mutation is needed to produce drug resistance, and it can produce cross-resistance with other NNRTIs

Method used

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  • Preparation and application of novel pyridone human immunodeficiency virus-1 (HIV-1) reverse transcriptase inhibitor
  • Preparation and application of novel pyridone human immunodeficiency virus-1 (HIV-1) reverse transcriptase inhibitor
  • Preparation and application of novel pyridone human immunodeficiency virus-1 (HIV-1) reverse transcriptase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1: the preparation of isopropylidene malonate (compound 1)

[0016] Dissolve 52g (0.5mol) of malonic acid in 60ml (0.6mol) of acetic anhydride, add 1.5ml of concentrated sulfuric acid under ice water cooling and stirring, add dropwise 40ml (0.55mol) of acetone after 10min, stir at room temperature for 20min, and dissolve the mixture Place in the refrigerator overnight, filter under reduced pressure to obtain a white solid, recrystallize in acetone-ice water, and the yield is 72.2%. mp: 95-96°C (literature value 94-95°C).

Embodiment 2

[0017] Example 2: Preparation of 3-oxo-4-phenyl-butyric acid ethyl ester (compound 2a)

[0018] Add 5.45g (37.81mmol) isopropylidene malonate, 70ml dichloromethane, 6.2ml pyridine to a 100ml round-bottomed flask, add 7ml (52.93) phenylacetyl chloride dropwise after cooling in ice water for 15min, and continue cooling for 1h. Stir overnight. The reaction solution was washed with 10% HCl aqueous solution (50ml*2), washed with water (50ml), anhydrous Na 2 SO 4 dry. Filter and evaporate to dryness under reduced pressure to obtain a red-black solid, add 100ml of absolute ethanol to the solid, heat to reflux for 4h, spin to dry the solvent, petroleum ether: ethyl acetate = 50:1 and purify to obtain the target product 2a, light yellow oil, yield: 56.75%.

[0019] 1 H NMR (300MHz, CDCl 3 )δ: 7.20-7.37 (m, 5H, Ar-H), 4.16 (q, 2H, OC H 2 CH 3 ), 3.83(s, 2H, CH 2 -Ph), 3.51(s, 2H, CH 2 ), 1.26(t, 3H, OCH 2 CH 3 ).

[0020] Preparation of 3-oxo-4-(4'-fluorophenyl)-butyric ...

Embodiment 3

[0037] Example 3: Preparation of ethyl 4-hydroxy-6-benzyl-2(1H)-pyridone-3-carboxylate (compound 3a)

[0038] Add 61ml (60.68mmol) of 2M ammonia methanol solution to 5g (24.27mmol) of 3-oxo-4-phenyl-butyric acid ethyl ester, seal the upper end of the reflux tube with a balloon, heat to reflux for 6h, and spin dry the solvent for later use.

[0039] In 40ml of absolute ethanol, add 1.2g of sodium metal, cool down after the reaction is complete, add dropwise 7.4ml (48.8mmol) diethyl malonate, the solution becomes cloudy, heat to reflux for 2h, after cooling, dropwise add 3-oxo- The ethanol solution after ammonolysis of 4-phenyl-butyric acid ethyl ester was heated to reflux for 3 days, and a large amount of white precipitate appeared. After the solution was cooled, a large amount of solid appeared when poured into 1N HCl, filtered through a Buchner funnel, and washed with ethyl acetate to obtain the target product. It is a white solid, and the raw material is recycled. Yield: 25...

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Abstract

The invention relates to a novel molecule with a relative structure, which is designed according to the bioisosteric principle and the theories of hydrogen bonding interaction and the like by using a non nucleoside human immunodeficiency virus-1 (HIV-1) reverse transcriptase inhibitor 4-(cyclohexyl methoxyl)-6-phenethyl-2(1H)-pyridone-3-carboxylic acid ethyl ester as a primer. In a general formula I, the definitions of groups are described in claims. Meanwhile, the invention relates to reverse transcriptase activity evaluation of a compound and application of the compound as the HIV-1 reverse transcriptase inhibitor. The conformation of the synthesized novel compound is more easily combined with HIV-1 reverse transcriptase, so that the novel compound is more favorable for inhibiting the activity of the reverse transcriptase and becomes the novel high-activity low-toxicity HIV-1 reverse transcriptase inhibitor.

Description

1. Technical field [0001] The application relates to non-nucleoside HIV-1 reverse transcriptase inhibitor 4-(cyclohexylmethyloxy)-6-phenethyl-2(1H)-pyridone-3-carboxylic acid ethyl ester as a lead substance, according to Based on the theory of biological isosteres and hydrogen bonding, a class of new molecules with related structures has been designed. By changing the 3, 4, and 6 substituents, the conformation of the synthesized new compound is more conducive to the combination with HIV-1 reverse transcriptase, which is more conducive to its inhibition of reverse transcriptase activity, and to find a new class of high activity, Low toxicity HIV-1 reverse transcriptase inhibitor. Among them, the 4-position 2-methylcyclohexyl group of the compound has better flexibility, can better adapt to the binding pocket of RT enzyme, and also has a certain effect on mutant strains, so that the force with reverse transcriptase is enhanced; increase 5 The volume of the substituent is more ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/80C07D213/803C07D213/69C07D409/06A61K31/4412A61K31/4436A61P31/18
Inventor 李阿敏王孝伟马丽英邵一鸣刘俊义
Owner PEKING UNIV
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