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Inhibitor of hepatitis B virus surface antigen

A heteroatom, selected technology, applied in the field of hepatitis B virus surface antigen inhibitor, can solve problems such as poor water solubility of 7-membered carbocyclic rings

Active Publication Date: 2019-10-25
푸지엔에이키링크바이오테크놀로지컴퍼니리미티드
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally, the 7-membered carbon ring has poor water solubility and is prone to oxidative metabolism

Method used

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  • Inhibitor of hepatitis B virus surface antigen
  • Inhibitor of hepatitis B virus surface antigen
  • Inhibitor of hepatitis B virus surface antigen

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183]

[0184] Step A: 1-1 (200.00 g, 1.19 mol) was dissolved in N,N-dimethylformamide (1000.00 ml), potassium carbonate (164.39 g, 1.19 mol) was added, and then added dropwise at 90°C for one hour 1-Bromo-3-methoxy-propane (182.01 g, 1.19 mol). The mixture was stirred at 90°C for 15 hours. Add 3 liters of ethyl acetate (1 liter × 3) to the reaction solution, combine the organic phases, wash with 15.00 liters of water (3.00 liters × 5), and 3.00 liters of saturated brine (1.00 liters × 3), and dry over anhydrous sodium sulfate , and concentrated under reduced pressure to obtain a crude product. Then purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate=1 / 0) to obtain compound 1-2.

[0185] Step B: 1-2 (80.00 g, 332.98 mmol) was dissolved in acetonitrile (800.00 mL), then chlorosuccinimide (44.46 g, 332.98 mmol) was added and the mixture was stirred at 90°C for three hours. First spin off half the volume of acetonitrile, then add 200.00 ml o...

Embodiment 2

[0201]

[0202] ee value (enantiomeric excess): 100%.

[0203] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 microns. Mobile phase: methanol (0.05% diethylamine) from 5% to 40% in carbon dioxide. Flow rate: 3 ml per minute. Wavelength: 220 nm.

[0204] 1 H NMR (400MHz, deuterated chloroform) δ15.77(br s, 1H), 8.49(s, 1H), 7.52(s, 1H), 6.87(s, 1H), 6.68(s, 1H), 4.49-4.72 (m, 2H), 4.12-4.28(m, 2H), 3.92(br d, J=6.40Hz, 1H), 3.63(t, J=5.90Hz, 2H), 3.39(s, 3H), 2.06-2.24 (m, 3H), 1.10 (d, J=6.53Hz, 3H), 0.89 (d, J=6.53Hz, 3H).

Embodiment 3

[0206]

[0207] ee value (enantiomeric excess): 100%.

[0208] SFC (Supercritical Fluid Chromatography) Method: Column: Chiral pak AD-3 100 mm x 4.6 mm I.D., 3 microns. Mobile phase: methanol (0.05% diethylamine) from 5% to 40% in carbon dioxide. Flow rate: 3 ml per minute. Wavelength: 220 nm.

[0209] 1 H NMR (400MHz, deuterated chloroform) δ15.81(s, 1H), 8.88-9.18(m, 1H), 7.47(s, 1H), 6.78(s, 1H), 6.76(s, 1H), 4.48- 4.59(m, 2H), 4.19(dt, J=2.07, 6.12Hz, 2H), 3.59-3.67(m, 2H), 3.45-3.52(m, 1H), 3.39(s, 3H), 2.15(quin, J=6.05Hz, 2H), 1.14-1.31(m, 2H), 0.29-0.55(m, 2H), 0.09(s, 1H).

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Abstract

The invention discloses a novel derivative of 11-oxo-7,11-dihydro-6H-benzo [f] pyrido [1,2-d] [1,4] oxazepin-10-carboxylic acid as an inhibitor of a hepatitis B virus surface antigen, and particularlydiscloses a compound shown in a formula (V) (please see the description for the formula) or pharmaceutically acceptable salt thereof, and application of the compound shown in the formula (V) or the pharmaceutically acceptable salt and pharmaceutical composite thereof in the treatment of hepatitis B.

Description

[0001] Cross References to Related Applications [0002] This application claims the priority of Chinese patent application 201710365328.7 filed on May 22, 2017, the content of which is hereby incorporated into this application. This application is a divisional application of 201880001038.7. technical field [0003] The present invention relates to novel 11-oxo-7,11-dihydro-6H-benzo[f]pyrido[1,2-d][1,4]azepine- 10-carboxylic acid derivatives, specifically related to compounds shown in formula (V) or pharmaceutically acceptable salts thereof, and compounds shown in formula (V) or pharmaceutically acceptable salts and pharmaceutical compositions in the treatment of type B Application in viral hepatitis. Background technique [0004] Hepatitis B virus, referred to as hepatitis B, is a disease caused by hepatitis B virus (Hepatitis B Virus, HBV) infection after the body. Hepatitis B virus is a hepatotropic virus that mainly exists in liver cells and damages liver cells, causi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61P1/16A61P31/20A61K31/553
CPCC07D498/04A61P1/16A61P31/20A61K31/55C07D471/04A61K31/675A61K31/522A61K31/553A61K2300/00A61K31/683A61K31/708
Inventor 丁照中孙飞胡彦宾陈曙辉
Owner 푸지엔에이키링크바이오테크놀로지컴퍼니리미티드