Condensed ring based ketone derivatives, preparation method thereof and application of derivatives in medicine

A technology of heterocyclyl and cycloalkyl, which can be used in the field of TLR7 agonists to solve problems such as side effects

Active Publication Date: 2018-11-13
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Interferon α is one of the main drugs for the treatment of chronic hepatitis B or C, while TNF-α is a pro-inflammatory cytokine, excessive secretion may lead to serious side effects

Method used

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  • Condensed ring based ketone derivatives, preparation method thereof and application of derivatives in medicine
  • Condensed ring based ketone derivatives, preparation method thereof and application of derivatives in medicine
  • Condensed ring based ketone derivatives, preparation method thereof and application of derivatives in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0260] 5-Amino-7-butoxy-1-(4-(pyrrolidin-1-ylmethyl)benzyl)pyrimido[4,5-d]pyrimidin-2(1H)-one

[0261]

[0262]

[0263] first step

[0264] 2-Butoxy-4,6-dichloropyrimidine-5-carbaldehyde 1b

[0265] Dissolve phosphorus oxychloride (6.24g, 0.0407mol) in 75mL tetrahydrofuran, cool to 0°C, add N,N-dimethylformamide (2.98g, 0.0407mol), stir for 1 hour, then add 2- Butoxypyrimidine-4,6-diol 1a (5 g, 0.0271 mol, prepared by the method disclosed in the patent application "US20160075707") was stirred for 30 minutes, then raised to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, 50 mL of phosphorus oxychloride was added, cooled to 0°C, N,N-diisopropylethylamine (6.99 g, 0.0542 mol) was added, the temperature was raised to 60°C and the reaction was stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 50 mL of water was added to the resulting residue, extracted wi...

Embodiment 2

[0285] 4-Amino-2-butoxy-8-(4-(pyrrolidin-1-ylmethyl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0286]

[0287]

[0288] first step

[0289] 4-(bis(4-methoxybenzyl)amino)-2-butoxy-6-((4-(pyrrolidin-1-ylmethyl)benzyl)amino)pyrimidine-5-carbaldehyde 2b

[0290] Compound 1c (200mg, 0.425mmol) was dissolved in 10mL N,N-dimethylformamide, and (4-(pyrrolidin-1-ylmethyl)phenyl)methanamine 2a (121.5mg, 0.638mmol, Prepared by the known method "Journal of Medicinal Chemistry, 2012, 55(23), 10387-10404") and potassium carbonate (118mg, 0.85mmol), heated to 40°C and stirred for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified with eluent system A by a CombiFlash rapid preparation apparatus , to obtain the title compound 2b (230 mg, yield: ...

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PUM

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Abstract

The invention relates to condensed ring based ketone derivatives, a preparation method thereof and an application of the derivatives in medicine, in particular to the new condensed ring based ketone derivatives shown as the general formula (I) in the description, the preparation method of the derivatives, pharmaceutical composition containing the derivatives and the application of the derivative as a therapeutic agent, especially a TLR7 (toll-like receptor 7) agonist. Substituent groups in the general formula (I) are defined as the description.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a new fused ring-based ketone derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a TLR7 agonist use of the agent. Background technique [0002] Toll-like receptors (toll-like receptors; TLRs) are an important class of protein molecules involved in innate immunity. TLRs are monomeric transmembrane non-catalytic receptors, usually expressed in sentinel cells such as macrophages and dendritic cells, which can recognize structurally conserved molecules produced by microorganisms. Once these microorganisms break through physical barriers such as skin or intestinal mucosa, they are recognized by TLRs, which in turn activate immune cell responses (Mahla, R S. et al., Front Immunol. 4:248 (2013)). The ability of the immune system to widely recognize pathogenic microorganism...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04A61P31/18A61P31/12A61P31/14A61P35/00A61P31/16A61P11/06A61P11/02A61P1/16A61P1/04
CPCA61P1/04A61P1/16A61P11/02A61P11/06A61P31/12A61P31/14A61P31/16A61P31/18A61P35/00C07D471/04C07D487/04Y02P20/55
Inventor 张国宝陈友喜黄智明贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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