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Nitrogen heterocycle containing derivatives and application thereof in retinal diseases

A technology of derivatives and nitrogen heterocycles, applied in the field of nitrogen-containing heterocycle derivatives and their application in retinal diseases

Inactive Publication Date: 2018-11-30
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 been discovered. Under the complex regulatory network, the discovery of new and excellent retinal neovascularization has greater opportunities and challenges.

Method used

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  • Nitrogen heterocycle containing derivatives and application thereof in retinal diseases
  • Nitrogen heterocycle containing derivatives and application thereof in retinal diseases
  • Nitrogen heterocycle containing derivatives and application thereof in retinal diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: Synthesis of 5-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)benzo[d]thiazole 1, 2 Synthesis of -(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), 39.12 g. 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: 4-fluoro-5-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)benzo[d]thiazole synthesis

[0035]

[0036] Compound 5 (52.90g, 0.20mol), 4-fluoro-benzo[d]thiazol-5-amine (0.21mol) and N,N-dimethylformamide (DMF) (30mL) were added to the reaction flask together , then added 60% sodium hydride (5.2 g, 0.13 mol) 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 65.05 g of off-white solid 4-fluoro-5-(4-(2-( (Tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)benzo[d]thiazole in 89% yield. LC-MS (ESI, pos, ion) m / z: 366 [M+H].

Embodiment 3

[0037] Example 3: 2-fluoro-5-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)benzo[d]thiazole synthesis

[0038]

[0039] Compound 5 (52.90g, 0.20mol), 2-fluoro-benzo[d]thiazol-5-amine (0.21mol) and N,N-dimethylformamide (DMF) (30mL) were added to the reaction flask together , then added 60% sodium hydride (5.2 g, 0.13 mol) 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 62.13 g of off-white solid 2-fluoro-5-(4-(2-( (Tetrahydro-2H-pyran-2-yl)oxy)ethyl)piperazin-1-yl)benzo[d]thiazole in 85% yield. LC-MS (ESI, pos, ion) m / z: 366 [M+H].

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Abstract

The invention discloses nitrogen heterocycle containing derivatives and an application thereof in retinal diseases. The nitrogen heterocycle containing derivatives have a structural formula which is described in the specification. In the structural formula, R1, R2, R3 and R4 are independently selected from the group consisting of -H and -F. The nitrogen heterocycle containing derivatives providedby an embodiment 1, an embodiment 2, an embodiment 3 and an embodiment4 of the invention have an HRCEC proliferation inhibition rate superior to the HRCEC proliferation inhibition rate of a monoclonalantibody medicine namely Avastin at the same concentration of 5 [mu]g / mL. According to the invention, after intravitreal injection administration, a compound provided by the invention can reduce pathological neovascularization; thus, the nitrogen heterocycle containing derivatives with a formula I or salts thereof provided by the invention are proved to be able to be used for in-depth research and development for treatment of retinal neovascularization related diseases, such as retinal vein occlusion, proliferative diabetic retinopathy, subretinal neovascular membrane, neovascular glaucoma, retinopathy of prematurity, proliferative vitreoretinopathy, etc.

Description

technical field [0001] The invention belongs to the fields of medicinal chemistry, drug activity testing and the like, and relates to a nitrogen-containing heterocyclic derivative and its application in retinal 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 endothelial cells and vasc...

Claims

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Application Information

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IPC IPC(8): C07D417/12A61P27/02A61P27/06
CPCA61P27/02A61P27/06C07D417/12
Inventor 翟学旭
Owner 翟学旭
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