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
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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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