Derivative containing nitrogen heterocyclic rings and application of derivative in retinal neovascularization diseases

A technology of new blood vessels and derivatives, applied in the field of medicinal chemistry and drug activity testing

Inactive Publication Date: 2018-11-09
翟学旭
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, in recent years, a deeper or new understanding of the formation of retinal neovascularization has been achieved, and some related factors have be

Method used

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  • Derivative containing nitrogen heterocyclic rings and application of derivative in retinal neovascularization diseases
  • Derivative containing nitrogen heterocyclic rings and application of derivative in retinal neovascularization diseases
  • Derivative containing nitrogen heterocyclic rings and application of derivative in retinal neovascularization diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: Synthesis of 1-(pyridin-2-yl)-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine

[0022] 1. Synthesis of 2-(2-chloroethoxy)tetrahydro-2H-pyran:

[0023]

[0024] 2-Chloro-1-ethanol (21.74 g, 0.27 mol), dichloromethane (50 mL) and Amberlyst H-15 (1 g) were added to the reaction flask together, followed by 3,4-dihydro -2H-pyran (25 mL, 0.27 mol), the reaction mixture was stirred at 25°C for 17 hours. After filtering off Amberlyst H-15, dichloromethane was evaporated in vacuo to give 2-(2-chloroethoxy)tetrahydro-2H-pyran (compound 3), 39.12g. The yield was 88%. It was directly used in the next step without purification. 1 H-NMR (400MHz, CDCl3) δ: 1.46-1.84 (m, 6H), 3.59-3.79 (m, 6H), 4.52 (t, 1H). 13 C-NMR (125MHz, CDCl3) δ: 19.74, 25.57, 30.21, 42.73, 65.40, 65.98, 99.57. LC-MS (ESI, pos, ion) m / z: 166[M+H].

[0025] 2. Synthesis of 2,2'-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)amino)bis(ethane-1-ol):

[0026]

[0027] Add diethanolamine (25.23g,...

Embodiment 2

[0034] Example 2: Synthesis of 1-(6-cyano-pyridin-2-yl)-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine

[0035]

[0036] Compound 5 (52.90g, 0.20mol), 6-cyano-pyridin-2-amine (0.21mol) and N,N-dimethylformamide (DMF) (30mL) were added to the reaction flask together, and then 60% sodium hydride (5.2 g, 0.13 mol) was added in portions. The reaction mixture was stirred at 50°C for 40 minutes, then warmed to 105°C and stirred for 4.5 hours. It was then cooled to 20°C and water (30 mL) was added. The product was extracted with ethyl acetate (50 mL), then washed with water (20 mL), the solvent was concentrated under reduced pressure, and flash column chromatography was used to obtain 54.42 g of off-white solid 1-(6-cyano-pyridin-2-yl )-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine in 86% yield. LC-MS (ESI, pos, ion) m / z: 317 [M+H].

Embodiment 3

[0037] Example Three: Synthesis of 1-(5-cyano-pyridin-2-yl)-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine

[0038]

[0039] Compound 5 (52.90g, 0.20mol), 5-cyano-pyridin-2-amine (0.21mol) and N,N-dimethylformamide (DMF) (30mL) were added to the reaction flask together, and then 60% sodium hydride (5.2 g, 0.13 mol) was added in portions. The reaction mixture was stirred at 50°C for 40 minutes, then warmed to 105°C and stirred for 4.5 hours. It was then cooled to 20°C and water (30 mL) was added. The product was extracted with ethyl acetate (50 mL), then washed with water (20 mL), the solvent was concentrated under reduced pressure, and flash column chromatography was used to obtain 51.89 g of off-white solid 1-(5-cyano-pyridin-2-yl )-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazine in 82% yield. LC-MS (ESI, pos, ion) m / z: 317 [M+H].

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PUM

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Abstract

The invention discloses a derivative containing nitrogen heterocyclic rings and application of the derivative in retinal neovascularization diseases. The derivative has the biological structural formula shown in the description, wherein R1, R2, R3 and R4 are respectively and independently selected from -H or -CN. Under the same concentration of 5microg/mL, the growth inhibition ratios of the embodiment II, the embodiment III and the embodiment IV to HRCEC are superior to a monoclonal antibody drug Avastin. By injecting the compound into a vitreous body, the formation of pathologic new vesselscan be reduced, so that the derivative of the formula I or the salt of the derivative can be used for deeply researching and developing retinal neovascularization relevant diseases such as retinal vein occlusion, proliferative diabetic retinopathy, subretinal neovascular membrane, neovascular glaucoma, retinopathy of prematurity and proliferative vitreoretinopathy.

Description

technical field [0001] The invention belongs to the fields of medicinal chemistry, drug activity testing and the like, and relates to nitrogen-containing heterocyclic derivatives and their application in retinal neovascularization diseases. Background technique [0002] Retinal neovascularization is a common pathological change in retinal vein occlusion, proliferative diabetic retinopathy, subretinal neovascular membrane, neovascular glaucoma, retinopathy of prematurity, and proliferative vitreoretinopathy. Pathological changes such as hemorrhage and hyperplasia damage the structure and function of the eye, which is an important cause of visual impairment. Neovascularization is an adaptive compensatory response of the body to chronic ischemia. Tissue ischemia, hypoxia, and changes in the shear stress of the blood vessel wall can trigger the accumulation of inflammatory cells around the vessel wall, causing the proliferation, differentiation, and migration of vascular endoth...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61K31/496A61P3/10A61P27/06
CPCA61P3/10A61P27/06C07D405/12
Inventor 翟学旭
Owner 翟学旭
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