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Novel S-nitrosoglutathione reductase inhibitors

A hydroxyl and alkyl technology, applied in the field of new compounds, can solve problems such as unstable reactivity and short lifetime of NO

Inactive Publication Date: 2013-01-09
NIVALIS THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] NO is a free radical gas, which makes it reactive and unstable, so NO has a short lifetime in the body, with a half-life of 3-5 seconds under physiological conditions

Method used

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  • Novel S-nitrosoglutathione reductase inhibitors
  • Novel S-nitrosoglutathione reductase inhibitors
  • Novel S-nitrosoglutathione reductase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0211] Example 1: 3-(4-(1H-tetrazol-5-yl)phenyl)-7-hydroxy-2-(trifluoromethyl)-4H-benzopyran-4-one

[0212]

[0213] synthesis:

[0214] Step 1: Synthesis of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)benzonitrile

[0215] At 0°C, to 4-(2-(2,4-dihydroxyphenyl)-2-oxoethyl)benzamide (Intermediate A) (300mg, 1.08mmol) and triethylamine (TEA ) (0.6ml, 4.32mmol) in DCM (6ml) was added TFAA (1.2ml, 8.64mmol) dropwise. The mixture was stirred at room temperature for 2 hours. Then mix the mixture with 1N HCl solution (5ml), saturated NaHCO 3 (5ml) and brine (5ml) wash. Use Na for organic phase 2 SO 4 It was dried, concentrated, and purified by prep-TLC (PE (petroleum ether): EtOAc=3:1) to obtain a yellow oily product (66 mg, 19.5%). MS(ESI): m / z 332.1[M+1] + .

[0216] Step 2: Synthesis of 3-(4-(1H-tetrazol-5-yl)phenyl)-7-hydroxy-2-(trifluoromethyl)-4H-benzopyran-4-one

[0217] At room temperature, add 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)benzonitrile (5...

Embodiment 2

[0219] Example 2: 5-(7-Hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)thiophene-2-carboxylic acid

[0220]

[0221] synthesis:

[0222] Step 1: Synthesis of methyl 5-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)thiophene-2-carboxylate

[0223] Follow the method described in Step 1 of Example 1, starting with Intermediate B. MS(ESI): m / z371.0[M+1] + .

[0224] Step 2: Synthesis of 5-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)thiophene-2-carboxylic acid

[0225] To 5-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)thiophene-2-carboxylic acid methyl ester (295mg, 0.80mmol) in dioxane Concentrated HCl (1.5ml) was added to the solution in alkane (1.5ml). The reaction mixture was stirred at 70°C for 24 hours, cooled to room temperature and centrifuged. The precipitate was rinsed with water (2ml×2), DCM (2ml×2), and dried in vacuum to obtain the desired product of Example 2 (216.1 mg, 76.3%) as a gray powder.

[0226] data: 1 H NMR(MeOD-d 4 500MHz TMS)...

Embodiment 3

[0227] Example 3: (trans)-4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)cyclohexanecarboxylic acid

[0228]

[0229] synthesis:

[0230] Step 1: Synthesis of ethyl 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)cyclohexanecarboxylate

[0231] The method of step 1 of Example 1 was followed, starting with Intermediate C, where the crude product was directly applied without post-treatment or purification. MS(ESI): m / z 385.1[M+1] + .

[0232] Step 2: To 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-benzopyran-3-yl)cyclohexane carboxyacetate (450 mg, 1.1 mmol) The solution in dioxane (3ml) was added with concentrated HCl (3ml). The solution was stirred at 75°C overnight. The mixture was concentrated in vacuo to obtain a yellow solid, which was purified by prep-HPLC to obtain the pure trans isomer of the desired product of Example 3 (100 mg, 24%).

[0233] data: 1 H NMR(MeOH-d4 500MHz TMS): δ7.97(d,J=9.0Hz,2H), 6.97(dd,J=2.0,8.5Hz,1H), 6.84(d,J=2.5Hz,1H), 2.71(t,J=12.0...

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Abstract

The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.

Description

Technical field [0001] The present invention relates to new compounds, pharmaceutical compositions containing such compounds, and methods for preparing and using the compounds. These compounds can be used as inhibitors of S-nitrosoglutathione reductase (GSNOR). Background technique [0002] The compound nitric oxide is a gas with the molecular formula NO. NO is one of the few known gas signal molecules in biological systems and plays an important role in the control of various biological events. For example, the endothelium uses NO to transmit signals around the smooth muscles of the arteriole walls to relax, causing vasodilation and increasing blood flow to hypoxic tissues. NO is also involved in the regulation of smooth muscle proliferation, platelet function and neurotransmission, and plays a role in host defense. Although NO is highly reactive and has a lifetime of several seconds, it can not only diffuse freely across the membrane, but also bind to many molecular targets....

Claims

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Application Information

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IPC IPC(8): A01N43/16
CPCC07D409/04C07D417/10C07D335/06C07D311/36C07D407/08C07D405/10C07D413/10C07D311/22C07D409/10C07D311/58A61K31/352A61K31/381A61K31/382A61K31/41A61K31/4245A61K31/433A61P1/00A61P1/04A61P7/02A61P9/10A61P9/12A61P11/00A61P11/06A61P11/14A61P29/00A61P35/00A61P43/00
Inventor 孙喜成邱键
Owner NIVALIS THERAPEUTICS
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