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A kind of nitric oxide donor type netarsudil derivative and its preparation method and application

A compound and drug technology, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of retinal ganglion cell death, deformation of the connective tissue supporting the optic disc, blindness, etc., and achieve good application prospects and the effect of protecting retinal ganglion cells

Active Publication Date: 2022-02-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It eventually leads to the death of retinal ganglion cells (RGCs) and deformation of the connective tissue supporting the optic disc, resulting in complete blindness

Method used

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  • A kind of nitric oxide donor type netarsudil derivative and its preparation method and application
  • A kind of nitric oxide donor type netarsudil derivative and its preparation method and application
  • A kind of nitric oxide donor type netarsudil derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] 4-[3-Amino-1-(isoquinoline-6-amino)-1-oxypropan-2-yl]benzyl-4-(nitrooxy)butyrate and its hydrochloride (I 1 , I 1 2HCl)

[0082]

[0083] 4-(Nitroxy)butyric acid (77mg, 0.52mmol) was dissolved in 15mL of anhydrous DCM, EDCI (100mg, 0.52mmol), DMAP (6.4mg, 0.052mmol), compound IV (200mg, 0.47mmol) were added ), raised from 0°C to room temperature and stirred overnight. The reaction solution was extracted with EA and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain V 1 (157mg). Will Ⅴ 1 Dissolve in anhydrous DCM, add TFA (DCM:TFA=10:1), react at 0°C for 2h, NaHCO 3 The pH of the reaction solution was adjusted to 7. The reaction solution was extracted with EA, the organic layer was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain light yellow oily liquid I 1 (1...

Embodiment 2

[0087] 4-[3-Amino-1-(isoquinoline-6-amino)-1-oxopropan-2-yl]benzyl-5-(nitrooxy)pentanoate (I 2 )

[0088]

[0089] 5-(Nitroxy)valeric acid (85mg, 0.52mmol) was dissolved in 15mL of anhydrous DCM, EDCI (100mg, 0.52mmol), DMAP (6.4mg, 0.052mmol), compound IV (200mg, 0.47mmol) were added ), raised from 0°C to room temperature and stirred overnight. The reaction solution was extracted with EA and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain V 2 (161mg). Will Ⅴ 2 Dissolve in anhydrous DCM, add TFA (DCM:TFA=10:1), react at 0°C for 2h, NaHCO 3 The pH of the reaction solution was adjusted to 7. The reaction solution was extracted with EA, the organic layer was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain light yellow oily liquid I 2 (106mg). MS:[M+H] + =467.1. 1 ...

Embodiment 3

[0091] 4-[3-Amino-1-(isoquinoline-6-amino)-1-oxypropan-2-yl]benzyl-6-(nitrooxy)hexanoate (I 3 )

[0092]

[0093] 6-(Nitroxy)caproic acid (92mg, 0.52mmol) was dissolved in 15mL of anhydrous DCM, EDCI (100mg, 0.52mmol), DMAP (6.4mg, 0.052mmol), compound IV (200mg, 0.47mmol) were added ), raised from 0°C to room temperature and stirred overnight. The reaction solution was extracted with EA and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain V 3 (165 mg). Will Ⅴ 3 Dissolve in anhydrous DCM, add TFA (DCM:TFA=10:1), react at 0°C for 2h, NaHCO 3 The pH of the reaction solution was adjusted to 7. The reaction solution was extracted with EA, the organic layer was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain light yellow oily liquid I 3 (109mg). MS:[M+H] + =481.2. 1 ...

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PUM

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Abstract

The invention relates to the fields of medicinal chemistry and medicinal therapy, in particular to a nitric oxide (NO) donor-type Netarsudil derivative and a preparation method and application thereof. These derivatives retained strong ROCK inhibitory activity and released a certain amount of NO in human trabecular meshwork cells. The two synergistically reduced intraocular pressure in New Zealand white rabbits without the irritation of the conjunctiva. The present invention relates to such NO-donating Netarsudil derivatives, or pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these compounds and their medicinal uses, especially in the preparation of prevention and / or treatment of glaucoma , high intraocular pressure and other ophthalmic diseases.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, and relates to a nitric oxide (NO) donor-type Netarsudil derivative and its preparation method and application, and specifically relates to NO donor and Netarsudil synergistically relaxing trabecular meshwork and regulating cytoskeleton remodeling Combination drug strategy, synthesis and evaluation of anti-glaucoma activity. These compounds can be used for increased intraocular pressure caused by increased resistance to aqueous humor outflow. The invention also relates to pharmaceutical combinations containing these compounds and their use. Background technique [0002] Glaucoma (Glaucoma) is a kind of optic nerve disease caused by multiple factors, and its main features are persistent elevation of intraocular pressure (IOP), optic nerve damage and visual field defect. It eventually leads to the death of retinal ganglion cells (RGCs) and deformation of the co...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/02C07D493/04A61K33/00A61K31/472A61K31/4725A61P9/12A61P27/06A61P3/10A61P27/02
CPCC07D217/02C07D493/04A61K33/00A61P9/12A61P27/06A61P3/10A61P27/02
Inventor 黄张建张奕华毛宇婕吴建兵朱明超
Owner CHINA PHARM UNIV
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