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Substituted bicyclic heterocyclic compounds as nadph oxidase inhibitors

A compound, heterocyclic group technology, applied in the field of substituted bicyclic heterocyclic compounds as NADPH oxidase inhibitors, can solve problems such as destroying and changing the function of target molecules

Inactive Publication Date: 2020-03-24
GLENMARK PHARMACEUTICALS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite the importance of ROS in the regulation of fundamental physiological processes, ROS production may also irreversibly destroy or alter the function of target molecules

Method used

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  • Substituted bicyclic heterocyclic compounds as nadph oxidase inhibitors
  • Substituted bicyclic heterocyclic compounds as nadph oxidase inhibitors
  • Substituted bicyclic heterocyclic compounds as nadph oxidase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1770] Synthesis of 6-(2-chlorophenyl)-5-hydroxy-1,3-dimethyl-1,7-dihydro-4H-pyrazolo[3,4-b]pyridin-4-one

[1771]

[1772] 5-Amino-1,3-dimethyl-1H-pyrazole-4-carboxylic acid 2-(2-chlorophenyl)-2-oxoethyl ester (590mg, 1.91mmol) and polyphosphoric acid (6.0mL ) mixture was heated to 120°C for 3h. The reaction mixture was cooled to RT and neutralized with 1N sodium hydroxide. The reaction mixture was extracted with ethyl acetate (3 x 100 mL), and the organic layer was washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to afford 112 mg of the title product as a solid. 1 H NMR (300MHz, DMSO-d 6 ): δ2.52(s, 3H), 3.80(s, 3H), 7.45-7.60(m, 4H), 7.89(s, 1H), 11.62(br s, 1H); APCI(m / z) 290( M+H) + .

[1773] Method B:

Embodiment 2

[1775] 6-(2-Chlorophenyl)-5-hydroxy-3-methyl-1-(2-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridine-4(7H)- Ketone synthesis

[1776]

[1777] 5-amino-3-methyl-1-(2-morpholinoethyl)-1H-pyrazole-4-carboxylic acid 2-(2-chlorophenyl)-2-oxoethyl ester (intermediate -91, 4.0 g, 9.85 mmol) in concentrated sulfuric acid (30 mL) was stirred at 80 °C for 2 h. The reaction mixture was cooled to RT and quenched with ice-cold water (35 mL). The precipitated solid was filtered and dried well to give 1.56 g of the desired product. 1 HNMR (300MHz, DMSO-d 6 ): δ2.39-2.52(m, 7H), 2.69(t, J=7.0Hz, 2H), 3.16-3.41(m, 4H), 4.27(s, 2H), 7.49-7.63(m, 4H), 7.91 (br s, 1H), 11.89 (br s, 1H); ESI (m / z) 389 (M+H) + .

[1778] The preparations of Examples 3-190, 193-194, 198, 200, 202-213, 215 and 217-218 given in Table 1 were carried out according to any of the procedures mentioned above. The structural formula, chemical name, 1 H NMR and MS data.

[1779] Table 1 : structure, chemical name, 1 H...

Embodiment 191

[1822] 6-(2,6-difluorophenyl)-5-hydroxy-1-methyl-3-(morpholinomethyl)-1H-pyrazolo[3,4-b]pyridine-4(7H) -ketone

[1823]

[1824] To a solution of morpholine (28.3 mg, 0.325 mmol) in anhydrous THF (2 mL) was added (6-(2,6-difluorophenyl)-5-hydroxy-3-(hydroxymethyl)-1- Methyl-1H-pyrazolo[3,4-b]pyridin-4(7H)-one) (50 mg, 0.162 mmol) and triphenylphosphine (61.8 mg, 0.23 mmol). The reaction was then cooled at 0° C., and diisopropyl azodicarboxylate (DIAD) (46.8 μL, 0.236 mmol) was added dropwise thereto. The reaction mixture was stirred at RT for 18 h. The mixture was quenched with water (2 drops), then evaporated and purified by column to give 18 mg of the title product. 1 H NMR (400MHz, DMSO-d6 ): δ2.77-2.81(m, 4H), 3.72-3.76(m, 4H), 3.80(s, 3H), 4.00(s, 2H), 7.14-7.20(m, 2H), 7.47-7.53(m , 1H), 8.58 (brs, 1H); ESI (m / z) 377 (M+H) + .

[1825] The preparation of Examples 192, 195-197, 199, 201, 214, 216 and 219-224 given in Table 2 was carried out according to any of th...

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Abstract

The present application relates to substituted fused heteroaryl and heterocyclic compounds, useful as nicotinamide adenine dinucleotide phosphate oxidase inhibitors (NADPH oxidase inhibitors), processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and / or disorders mediated by NADPH oxidase. (Formula I)

Description

[0001] related application [0002] This application claims the benefit of Indian Provisional Application No. 201721015787 filed on May 4, 2017; the content of which application is hereby incorporated by reference in its entirety. technical field [0003] The present application relates to substituted fused heteroaryl and heterocyclic compounds useful as nicotinamide adenine dinucleotide phosphate oxidase inhibitors (NADPH oxidase inhibitors), processes for their preparation, pharmaceutical combinations comprising said compounds and the use of the compound or the composition in the treatment or prevention of various diseases, diseases and / or conditions mediated by NADPH oxidase. Background technique [0004] The NOX family of NADPH oxidases (nicotinamide adenine dinucleotide phosphate oxidases) comprises a family of enzymes that generate reactive oxygen species (ROS), which are increasingly recognized as a source of oxidative stress in many disease settings. Although NOX2 (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D491/052C07D495/04C07D498/04C07D513/04A61P11/00A61P35/00A61K31/437A61K31/5377A61K31/444A61K31/496A61K31/4545
CPCA61P11/00A61P35/00C07D471/04C07D491/052C07D495/04C07D498/04C07D513/04A61K31/437A61K31/496
Inventor S·库马尔A·托马斯S·S·乔杜里L·A·加拉特N·凯拉特卡尔-裘西D·M·沙阿I·穆霍帕迪亚
Owner GLENMARK PHARMACEUTICALS LTD
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