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Urea derivative and application thereof to prevention and treatment of inflammation

A technology of derivatives and ureas, applied in the field of urea derivatives and their application in the prevention and treatment of inflammation

Inactive Publication Date: 2018-11-09
王若锴
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

mPGES-1 was discovered in 1999. It is located at the end of the prostaglandin inflammatory mediator production pathway, and its expression is only up-regulated under the induction of inflammation. mPGES-1 is considered to be an inflammatory drug target that can avoid toxic side effects. mPGES-1 inhibitors enter clinical trials

Method used

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  • Urea derivative and application thereof to prevention and treatment of inflammation
  • Urea derivative and application thereof to prevention and treatment of inflammation
  • Urea derivative and application thereof to prevention and treatment of inflammation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Synthesis of 1-hydroxyl-1-(2-(pyrrol-2-yl)-2,3-dihydro-1H-inden-1-yl)urea

[0028] Synthesis of 1-1,2-bromo-2,3-dihydro-1H-inden-1-ylmethanesulfonic acid:

[0029]

[0030] To a solution of 2-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g, 46.93 mmol), triethylamine (10.8 g, 106.73 mmol) in DCM (50 mL) at 0 °C was added dropwise Methanesulfonyl chloride MsCl (9.9 g, 86.43 mmol) was added dropwise over 30 minutes. The mixture was stirred for an additional 2 hours, then allowed to warm to room temperature. Water (50 mL) was added, the DCM layer was separated and the aqueous phase was extracted twice more with DCM (2 x 30 mL). The combined organic phases were washed with brine (50 mL), then washed with Na 2 SO 4 dry. The solvent was removed under vacuum to give 2-bromo-2,3-dihydro-1H-inden-1-ylmethanesulfonic acid as a light oil, yield 13.53 g, 99% yield, which was directly obtained without further purification for the next step. 1 H-NMR (400MHz, CDCl3) δ: 3....

Embodiment 2

[0040] Example 2: Synthesis of 1-hydroxyl-1-(2-(5-fluoro-pyrrol-2-yl)-2,3-dihydro-1H-inden-1-yl)urea:

[0041]

[0042] 1-(2-Bromo-2,3-dihydro-1H-inden-1-yl)-1-hydroxyurea (10.77 g, 39.73 mmol) was dissolved in 96 mL of H 2 O:EtOH (1:1) mixture and placed in a three-necked flask (250mL). 5-Fluoro-pyrrole-2-boronic acid (55.47 mmol) and potassium carbonate (8.29 g, 59.99 mmol) were added to the mixture. Then PdNPs catalyst (0.4 mmol% Pd) was added, and the mixture was vigorously stirred at 60 °C for 10 min under nitrogen atmosphere. The reaction mixture was added to 0.2 mol / L sodium hydroxide solution (55 mL) and extracted with ethyl acetate (40 mL). The organic layers were combined and crystallized by volatilization in air to obtain the solid product 1-hydroxyl-1-(2-(5-fluoro-pyrrol-2-yl)-2,3-dihydro-1H-inden-1-yl) Urea, 9.32 g, 85% yield. LC-MS (ESI, pos, ion) m / z: 277 [M+H].

Embodiment 3

[0043] Example 3: Synthesis of 1-hydroxyl-1-(2-(5-methyl-pyrrol-2-yl)-2,3-dihydro-1H-inden-1-yl)urea:

[0044]

[0045] 1-(2-Bromo-2,3-dihydro-1H-inden-1-yl)-1-hydroxyurea (10.77 g, 39.73 mmol) was dissolved in 96 mL of H 2 O:EtOH (1:1) mixture and placed in a three-necked flask (250mL). 5-Methyl-pyrrole-2-boronic acid (55.47 mmol) and potassium carbonate (8.29 g, 59.99 mmol) were added to the mixture. Then PdNPs catalyst (0.4 mmol% Pd) was added, and the mixture was vigorously stirred at 60 °C for 10 min under nitrogen atmosphere. The reaction mixture was added to 0.2 mol / L sodium hydroxide solution (55 mL) and extracted with ethyl acetate (40 mL). The organic layers were combined and evaporated and crystallized in the air to obtain the solid product 1-hydroxyl-1-(2-(5-methyl-pyrrol-2-yl)-2,3-dihydro-1H-inden-1-yl ) urea, 8.75g, the yield was 81%. LC-MS (ESI, pos, ion) m / z: 273 [M+H].

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Abstract

The invention discloses a urea derivative and application thereof to prevention and treatment of inflammation. The formula I is shown in the description, wherein R1, R2 and R3 are independently selected from H, F or CH3 respectively. An in-vitro activity determination result shows that a compound provided by the invention has 5-lipoxygenase inhibition activity and prostaglandin E synthetase inhibition activity, and can be used as a medicine for treating the inflammation for deeper and wider researches; the inflammation can be gynecological inflammation, hepatitis, myocarditis, encephalitis, nephritis, pneumonia, trachitis, pharyngitis, periodontitis, gastritis, enteritis and the like.

Description

technical field [0001] The invention belongs to the field of chemical medicine and relates to a urea derivative and its application in preventing and treating inflammation. Background technique [0002] Inflammation refers to the defense response of living tissue with vascular system to injury factors. Vascular responses are central to the inflammatory process. Inflammation, which is commonly referred to as "inflammation", is a defense response of the body to stimuli, manifested as redness, swelling, heat, pain and dysfunction. Inflammation can be infectious inflammation caused by infection, or non-infectious inflammation not caused by infection. Normally, inflammation is beneficial and is the body's automatic defense response, but sometimes it is also harmful, such as attacks on the body's own tissues, inflammation in transparent tissues, and so on. In the inflammatory process, on the one hand, the damage factors directly or indirectly cause tissue and cell destruction, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/52C07D307/56A61P29/00A61P15/00A61P1/16A61P1/00A61P13/12A61P11/00A61P11/04A61P1/02A61P9/00A61P43/00
CPCC07D307/52A61P1/00A61P1/02A61P1/16A61P9/00A61P11/00A61P11/04A61P13/12A61P15/00A61P29/00A61P43/00C07D307/56
Inventor 王若锴
Owner 王若锴
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