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Novel capsid protein assembly inhibitor

An alkyl group selected technology, applied in the field of medicinal chemistry, can solve the problems of affecting virus replication, blocking the assembly process of capsid protein, accelerating the degradation of capsid protein, etc.

Pending Publication Date: 2021-09-24
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current drugs for the treatment of viral hepatitis B are difficult to completely clear the viral infection, and there is still a lack of effective cure methods in clinical practice. Currently, only control therapy can be used for incurable hepatitis B, and the therapeutic drugs are limited to interferon and nucleoside analogs / viruses Two types of polymerase inhibitors
Clinical studies have shown that less than 50% of patients are sensitive to interferon therapy, and existing nucleoside analogue drugs induce drug-resistant mutations in transcriptases, which are not effective against drug-resistant strains. Such drugs are usually difficult to completely eliminate HBV Infections that cannot be cured even with long-term medication
Therefore, blocking the capsid protein assembly, or accelerating the capsid protein degradation, will block the capsid protein assembly process, thereby affecting viral replication
In addition, the N-terminal 149 amino acid residues (Cp149) that constitute the core protein dimerization motif and assembly domain have no human protein homologous sequence

Method used

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Experimental program
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Effect test

specific Embodiment approach

[0249] The purpose of the following specific examples is to enable those skilled in the art to understand and implement the present invention more clearly. They should not be considered as limiting the scope of the invention, but only illustrative and typical of the invention. It will be appreciated by those skilled in the art that there are other synthetic routes to the compounds of the present invention and the following non-limiting examples are provided.

[0250] All starting materials were commercially available unless otherwise stated and were used without further purification.

[0251] Nuclear magnetic resonance chromatogram (NMR) of the present invention uses BRUKER-300 and BRUKER-500 nuclear magnetic resonance instrument to measure, and chemical shift is internal standard with tetramethylsilane (TMS=δ0.00), and the format of proton nuclear magnetic resonance spectrum data record is: proton Number, peak type (s, singlet; d, doublet; t, triplet; q, quartet; m, multiple...

Embodiment 1

[0252] Example 1 1-(3-chloro-4-fluorophenyl)-3-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)urea

[0253]

[0254] Reaction flow:

[0255]

[0256] Step A: Add 3,4,5-trichloropyridine (736mg) and ethylenediamine (960mg) into a 100mL single-necked bottle, and react at 70°C for 1h. Add dichloromethane (40mL) after reaction finishes, wash three times with water (3*10mL), dry, concentrate, obtain N 1 -(3,5-Dichloropyridin-4-yl)ethane-1,2-diamine (643 mg) crude product was directly used in the next reaction.

[0257] 1 H-NMR (500MHz, DMSO-d6): δ8.16(s, 2H), 3.60(t, 2H), 2.76(t, 2H); 13 C-NMR (125MHz, DMSO-d6): δ 148.32, 147.03, 117.38, 47.20, 42.06. HRMS(ESI+,[M+H] + ) m / z: 206.0248.

[0258] Step B: Add N to a 100 mL one-necked bottle 1 -(3,5-Dichloropyridin-4-yl)ethane-1,2-diamine (540mg), dichloromethane (30mL), add dropwise 3-chloro-4-fluorophenylisocyanate (674mg), room temperature Reaction 1h. Filter after the reaction, wash the filter cake with a small amount of ...

Embodiment 2

[0260] Example 2 1-(3-chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)propyl)urea

[0261]

[0262] Step A: According to Example 1, ethylenediamine was replaced with 1,3-propanediamine in step A to prepare N 1 -(3,5-Dichloropyridin-4-yl)propane-1,3-diamine.

[0263] 1 H-NMR (500MHz, DMSO-d6): δ8.15(s, 2H), 3.70(t, 2H), 2.61(t, 2H), 1.60(t, 2H); 13 C-NMR (125MHz, DMSO-d6): δ 148.37, 146.92, 117.28, 49.05, 43.65, 33.97. MS(ESI+,[M+H] + ) m / z: 220.0.

[0264] Step B: According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino) was obtained by the method used in Step B ) Propyl) urea.

[0265] 1 H-NMR (500MHz, DMSO-d6): δ8.70(s, 1H), 8.15(s, 2H), 7.76(m, 1H), 7.23-7.24(m, 2H), 6.30(t, 1H), 6.24(t, 1H), 3.65(t, 2H), 3.16(t, 2H), 1.70(m, 2H); 13 C-NMR (125MHz, DMSO-d6): δ155.86, 153.30, 151.39, 148.37, 146.79, 138.27, 119.50, 118.29, 117.13, 116.96, 42.38, 36.75, 31.98. HRMS(ESI+,[M+H] + ) m / z: 391.0239.

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a novel capsid protein assembly inhibitor, in particular to a compound as shown in a formula I, a stereoisomer or pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition and medical application, including application to treatment of diseases benefited from capsid protein assembly inhibition, especially diseases caused by hepatitis B virus infection, wherein the definitions of A, M, L and D in the general formula I are the same as those in the specification. and the general formula I: A-M-L-D I is shown in the description.

Description

[0001] This application is a divisional application of the following application: filing date: September 18, 2017; application number: 201780055155.7; invention name: "Novel Capsid Protein Assembly Inhibitor". [0002] Cross References to Related Applications [0003] This application claims the rights and interests of the Chinese invention patent application No. 201610829370.5 submitted to the State Intellectual Property Office of the People's Republic of China on September 18, 2016, the entire content of which is hereby incorporated herein by reference. technical field [0004] The application belongs to the field of medicinal chemistry, and specifically relates to a compound shown in formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, and also relates to its preparation method, pharmaceutical composition and medical use, especially as a method for treating and preventing B Application of drugs for hepatitis virus infection. Background technique [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/74C07D401/04C07D405/12C07D401/12A61K31/4545A61K31/453A61K31/44A61P31/20A61P1/16
CPCC07D213/74C07D401/04C07D405/12C07D401/12A61K31/44A61K31/453A61K31/4545A61P1/16A61P31/20
Inventor 张寅生敖汪伟李元沈杭州柳英帅李东旭刘保民王辉陆鹏
Owner CHIA TAI TIANQING PHARMA GRP CO LTD