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2-substituted-4-site functionalized N (O, S)-quinazoline derivative and application thereof

A technology of functionalization and derivatives, which is applied in the field of 2-substituted-4-functionalized N-quinoline derivatives to achieve good druggability, good application prospects, and obvious effects of inhibiting activity

Active Publication Date: 2020-06-09
河北美信医药科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most influenza strains have developed resistance to amantadine and to some extent to oseltamivir and zanamivir

Method used

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  • 2-substituted-4-site functionalized N (O, S)-quinazoline derivative and application thereof
  • 2-substituted-4-site functionalized N (O, S)-quinazoline derivative and application thereof
  • 2-substituted-4-site functionalized N (O, S)-quinazoline derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] The preparation of 2-((2-(pyrrolidin-1-yl) quinazoline-4-yl) amino)-N-phenylacetamide, the structural formula is shown in the following formula:

[0075]

[0076] 1) Preparation of N-tert-butoxycarbonylglycine

[0077] Dissolve glycine (30.84g, 410mmol) in 200mL of methanol, add triethylamine (180mL, 1230mmol), add di-tert-butyl dicarbonate (179.11g, 820mmol) in batches, gradually raise the temperature to 70°C and stir for 6 hours, start Gas is produced. TLC monitored whether the reaction of the raw material was complete, concentrated under reduced pressure, added 200 mL of ethyl acetate, washed twice with water, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 36.41 g of a light yellow solid, which was directly obtained without further purification. for the next step. ESI-MS, m / z: 174.3 [M-H] - .

[0078] 2) Preparation of tert-butoxy (2-oxo-2-anilinoethyl) carbamate

[0079] N...

Embodiment 2

[0087] The preparation of 2-((2-pyrrolidinylquinazolin-4-yl)amino)-N-(β-naphthyl)acetamide, the structural formula is as follows:

[0088]

[0089] 1) Preparation of tert-butoxy (2-oxo-2-(β-naphthylamino) ethyl) carbamate

[0090] In Example 1, 2) aniline (2.43g, 26.1mmol) in the preparation of tert-butoxy (2-oxo-2-anilinoethyl) carbamate was replaced by β-naphthylamine (3.74g, 26.1 mmol) and other operations unchanged, tert-butoxy (2-oxo-2-(β-naphthylamino) ethyl) carbamate was obtained.

[0091] ESI-MS, m / z: 301.4 [M+H] + .

[0092] 2) Preparation of 2-amino-N-(β-naphthyl)acetamide hydrochloride

[0093] In Example 1, 3) tert-butoxy (2-oxo-2-anilinoethyl) carbamate (4.50 g, 18 mmol) was replaced by tert-butoxy (2-oxo-2-(β -Naphthylamino)ethyl)carbamate, and the other operations were unchanged to obtain 2-amino-N-(β-naphthyl)acetamide hydrochloride as a pale yellow solid. ESI-MS, m / z: 151.3 [M+H] + .

[0094] 3) Preparation of 2-((2-chloroquinazolin-4-yl)amino)-N-(β...

Embodiment 3

[0099] The preparation of 2-((2-(pyrrolidin-1-yl) quinazoline-4-yl) oxy)-N-phenylacetamide, the structural formula is shown in the following formula:

[0100]

[0101] 1) Preparation of 2-((2-chloroquinazolin-4-yl)oxy)ethyl acetate

[0102] Under ice-cooling, dissolve 60% sodium hydride (0.50 g, 12 mmol) in 15 mL of N,N-dimethylformamide, add ethyl glycolate (1.07 g, 10 mmol), stir at the same temperature for 10 minutes, then add 2, 4-Dichloroquinazoline (2.04 g, 10 mmol), stirred at the same temperature for 20 minutes and then at room temperature overnight. TLC detects that the raw materials have reacted completely, add 30 mL of water to the reaction solution, extract with ethyl acetate (20 mL×2), combine the organic phases, wash with deionized water and saturated sodium chloride solution successively, concentrate, silica gel column chromatography, petroleum ether / ethyl acetate 15:1 eluted to obtain 2.04 g of off-white solid. 1 H NMR (500MHz, DMSO-d 6 )δ8.26–8.15(m,1H)...

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Abstract

The invention relates to the technical field of medicine synthesis, and provides a 2-substituted-4-site functionalized N (O, S)-quinazoline derivative and an application thereof. The 2-substituted-4-site functionalized N (O, S)-quinazoline derivative provided by the invention has a clear anti-influenza virus effect, and has obvious inhibitory activity on replication of influenza viruses. Preliminary toxicity research shows that the derivative has good druggability, which shows that the derivative has a good application prospect as an antiviral drug and is expected to be developed into a clinically effective antiviral drug.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a 2-substituted-4-position functionalized N(O,S)-quin(oxazo)line derivative and its application. Background technique [0002] Influenza A virus (IAV) is a single-stranded negative-sense RNA virus belonging to the Orthomyxoviridae family. IAV infection is one of the leading causes of respiratory morbidity and mortality and has caused five world influenza pandemics. The flu is estimated to cause between 291,000 and 646,000 deaths and millions of severe cases each year. Influenza is airborne in most cases. And new or re-emerging IAV strains are prone to rapid and severe global epidemics, killing millions of people. Influenza B virus (IBV), which infects almost exclusively humans, is less common than IAV because it has less genetic diversity and tends to develop some degree of immunity to IBV in early life. [0003] Currently, only two main classes of antiviral ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/95C07D401/04C07D409/12A61K31/517A61K31/5377A61P31/16
CPCA61P31/16C07D239/95C07D401/04C07D409/12
Inventor 刘志锋
Owner 河北美信医药科技有限公司
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