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Nitric oxide donor type rivasdil derivative as well as preparation method and application thereof

A compound and configuration technology, applied in the field of medicinal chemistry and pharmacotherapeutics, has good application prospects and the effect of protecting retinal ganglion cells

Pending Publication Date: 2020-08-11
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A significant increase in aqueous humor outflow was observed after 0.4% K-115 instillation; however, K-115 instillation was not found to have a significant effect on the uveoscleral outflow pathway or aqueous humor flow rate (CurrEye Res, 2014, 39(8):813-22; J Ocul Pharmacol Ther,2016,32(7):405-14)

Method used

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  • Nitric oxide donor type rivasdil derivative as well as preparation method and application thereof
  • Nitric oxide donor type rivasdil derivative as well as preparation method and application thereof
  • Nitric oxide donor type rivasdil derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] (S)-4-(Nitrooxy)butan-4-((4-fluoroisoquinolin-5yl)sulfonyl)-3-methyl-1,4-azepane-1-carboxylic acid Esters (I 1 ) and its hydrochloride (I 1 ·HCl)

[0073]

[0074] Dissolve 4-hydroxybutyl nitrate (53mg, 0.39mmol) in 5ml of anhydrous THF, add bis(pentafluorophenyl)carbonate (200mg, 0.51mmol), tetrabutylammonium fluoride (117μl, 0.117mmol ) and stirred at room temperature for 2 h, added TEA (113 μl, 0.78 mmol) to the free compound V ripasudil (154.1 mg, 0.39 mmol) and stirred overnight at room temperature. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50 mL), and washed three times with saturated sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain I 1 . 1 H NMR (300MHz, CD 3 OD)δ9.25(s,1H),8.69–8.58(m,1H),8.55(d,J=5.1Hz,1H),8.52–8.44(m,1H),7.94–7.83(m,1H), 4.56(t,J=6.1Hz,2H),4.24(t,J=6.1Hz,2H),4.01–3.85(m,3H),3.44–...

Embodiment 2

[0078] (S)-2-(nitrooxy)ethyl-4-((4-fluoroisoquinolin-5yl)sulfonyl)-3-methyl-1,4-azepane-1-methanol Ester (I 2 )

[0079]

[0080] Dissolve 2-hydroxyethyl nitrate (42mg, 0.39mmol) in 5ml of anhydrous THF, add bis(pentafluorophenyl)carbonate (200mg, 0.51mmol), tetrabutylammonium fluoride (117μl, 0.117mmol ) and stirred at room temperature for 2 h, added TEA (113 μl, 0.78 mmol) to the free compound V ripasudil (154.1 mg, 0.39 mmol) and stirred overnight at room temperature. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50 mL), and washed three times with saturated sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain I 2 (50 mg, 32%).

[0081] 1 H NMR (300MHz, CD 3 OD)δ9.25(s,1H),8.73–8.62(m,1H),8.59–8.52(m,1H),8.52–8.44(m,1H),7.88(t,J=7.9Hz,1H), 4.85–4.74(m,2H),4.58–4.34(m,2H),4.30–4.11(m,1H),4.00–3.86(m,2H),3.43–3.31(m,2H)...

Embodiment 3

[0083] (S)-3-(nitrooxy)propyl-4-((4-fluoroisoquinolin-5yl)sulfonyl)-3-methyl-1,4-azepane-1-methanol Ester (I 3 )

[0084]

[0085] Dissolve 3-hydroxypropyl nitrate (47mg, 0.39mmol) in 5ml of anhydrous THF, add bis(pentafluorophenyl)carbonate (200mg, 0.51mmol), tetrabutylammonium fluoride (117μl, 0.117mmol ) and stirred at room temperature for 2 h, added TEA (113 μl, 0.78 mmol) to the free compound V ripasudil (154.1 mg, 0.39 mmol) and stirred overnight at room temperature. The reaction solution was diluted by adding an appropriate amount of dichloromethane (50 mL), and washed three times with saturated sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain I 3 (50 mg, 32%).

[0086] 1 H NMR (300MHz, CD 3 OD)δ9.25(s,1H),8.69–8.60(m,1H),8.60–8.52(m,1H),8.52–8.44(m,1H),7.88(t,J=7.9Hz,1H), 4.74–4.57(m,2H),4.35–4.22(m,2H),4.04–3.88(m,3H),3.45–3.31(m,2H),3.12–2.89(m,2...

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Abstract

The invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a nitric oxide (NO) donor type ripasudil derivative as well as a preparation method and an application thereof. The derivative reserves relatively strong ROCK inhibitory activity, inhibits myosin light chain phosphorylation of trabecular meshwork cells, and relaxes a trabecular meshwork aqueous humor efflux pathway; the released NO can relax a trabecular meshy aqueous humor drainage pathway and inhibit aqueous humor generation, and the NO and the aqueous humor cooperate to reduce intraocular pressure and protect retinal ganglion cells of a high intraocular pressure model mouse. The invention relates to NO donor type rivasdil derivatives or pharmaceutically acceptable salts thereof, preparation methods of the NO donor type rivasdil derivatives and the pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds and medical application of the compounds,in particular to application of the compounds in preparation of medicines for preventing and / or treating ophthalmic diseases such as glaucoma and ocular hypertension.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a nitric oxide (NO) donor type ripasudil derivative, a preparation method and application thereof. Such derivatives retain strong ROCK inhibitory activity, inhibit the phosphorylation of myosin light chain in trabecular meshwork cells, and relax the trabecular meshwork water efflux pathway; the released NO can relax the trabecular meshwork water efflux pathway and Inhibit the production of aqueous humor, and the two synergistically reduce intraocular pressure and protect retinal ganglion cells in high intraocular pressure model mice. The present invention relates to such NO donor type ripasudil derivatives, or pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these compounds and their medical uses, especially in the preparation of prevention and / or treatment of glaucoma , high intraocular pressu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/22C07D493/04A61K31/551A61P27/02A61P27/06A61P3/10
CPCC07D217/22C07D493/04A61P27/02A61P27/06A61P3/10
Inventor 黄张建赵凌杨泽秋张奕华吴建兵吴克玲
Owner CHINA PHARM UNIV
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