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Thiourea and urea compounds and use thereof

A compound and hydrate technology, applied in the field of medicine, can solve problems such as lack of selectivity, poor curative effect, and difficult synthesis

Active Publication Date: 2018-07-31
SHANGHAI LONGWOOD PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, various problems are encountered in these direct HBV antiviral drugs, such as toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis, etc.

Method used

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  • Thiourea and urea compounds and use thereof
  • Thiourea and urea compounds and use thereof
  • Thiourea and urea compounds and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Embodiment 1: the synthesis of compound 10a

[0121]

[0122] step 1:

[0123]

[0124] Dissolve compound 1 (1.5g) and propylene bromide (1g) in acetonitrile (15mL), then add cesium carbonate (3.5g) into the reaction system, raise the temperature to 85°C for 2h, add 30(mL) to the reaction system, acetic acid Ethyl ester (3*20mL) was extracted, dried over anhydrous sodium sulfate, the organic phase was spin-dried, and the crude product was chromatographed to obtain compound 2 (1.0g). ESI-MS, (M+H=273.02)

[0125] Step 2:

[0126]

[0127] Compound (1.0 g), ethylene boron anhydride pyridine complex (1.1 g), tetrakistriphenylphosphine palladium (120 mg), potassium carbonate (2.5 g) were dissolved in ethylene glycol dimethyl ether (25 mL) and 4 mL of water, Raise the temperature of the system to 120 degrees under the protection of nitrogen and react for 10 hours, add water (40mL) to the reaction system, extract with ethyl acetate (3*40mL), dry over anhydrous sod...

Embodiment 2

[0140] Embodiment 2: the synthesis of compound 10b

[0141]

[0142] The preparation method of compound 6b refers to steps 1-5 of Example 1, except that in step 4, trifluoromethyl-substituted isopropylsulfonyl chloride is used instead of isopropylsulfonyl chloride.

[0143] According to step 6 of Example 1, only need to replace compound 6 with compound 6b, and keep other conditions unchanged, the target product 10b (12 mg) was obtained by column chromatography (n-heptane:ethyl acetate=1:1).

Embodiment 3

[0144] Embodiment 3: the synthesis of compound 10c

[0145]

[0146] The preparation method of compound 6c refers to steps 1-5 of Example 1, except that in step 4, tert-butylsulfonyl chloride is used instead of isopropylaminesulfonyl chloride.

[0147] According to step 6 of Example 1, only need to replace compound 6 with compound 6c, and keep other conditions unchanged, the target product 10c (22 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 1:1).

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Abstract

The present invention relates to thiourea and urea compounds and use thereof. Specifically, the present invention discloses a compound having a structure represented by formula (A), or a stereoisomer,a tautomer, a pharmaceutically acceptable salt, a hydrate and a solvate thereof which can be used as an inhibitor of HBV (hepatitis B virus) replication. The invention further relates to a pharmaceutical composition comprising the compound and the use thereof in the treatment of hepatitis B.

Description

technical field [0001] The invention belongs to the field of medicine, in particular, the invention relates to thioureas, urea compounds and applications thereof for treating hepatitis B. Background technique [0002] Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA), virus of the hepadnaviridae DNA family (Hepadnaviridae). Its genome contains 4 overlapping reading frames: prenuclear / nuclear gene, polymerase gene, UM and S genes (which encode three envelope proteins), and X gene. Before infection, the partially double-stranded DNA genome is converted in the host cell nucleus (open circular DNA, rcDNA) to covalently closed circular DNA (cccDNA) and the viral mRNA is transcribed. Once encapsidated, the pregenomic RNA (pgRNA), which also encodes core protein and Pol, serves as a template for reverse transcription, which regenerates the partial dsDNA genome (rcDNA) in the nucleocapsid. [0003] Transmission of HBV results from exposure to infectiou...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D487/04A61K31/437A61K31/55A61P31/20
CPCC07D471/04C07D487/04A61K31/437A61K31/55A61P31/20
Inventor 王喆范国钦王晓光
Owner SHANGHAI LONGWOOD PHARMA
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