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Leukotriene synthesis inhibitors

A kind of compound and solvate technology, applied in the field of leukotriene synthesis inhibitors

Pending Publication Date: 2021-12-10
纳吉斯制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its clinical application is limited by the need to monitor liver enzyme levels and multiple daily doses
FLAP was originally discovered as the target of MK886, and many compounds targeting FLAP have since entered the clinic to treat respiratory and cardiovascular diseases, but none of them entered the market (D. Petterson et al., Bioorg. Med. ChemmLett. (2015) , v25 (13) pp. 2607-2612)

Method used

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  • Leukotriene synthesis inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0597] Preparation of Compound 101

[0598] To stirred 4-hydroxy-3-methoxybenzaldehyde (10 g, 65.8 mmol) in MeOH (85 mL) / H 2 To a solution of O (13 mL) was added 2-butanone (50 mL, 556 mmol), followed by KOH (15 g, 214 mmol). The mixture was stirred at room temperature for 7 days. The reaction was quenched by addition of water and aqueous HCl (15 mL cone. HCl in 200 mL water) and extracted with EtOAc (300 mL). The organic layer was washed with water (2×150 mL), washed over anhydrous MgSO 4 Dry, filter, and remove solvent under reduced pressure. The residue was washed with Et 2 O / Hex (1:3) triturated, filtered and washed with Et 2 O / Hex (1:3) wash gave 5.2 g of 1-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one as a yellow solid.

[0599] To a stirred solution of 1-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one (5.0 g, 24 mmol) in MeOH (75 mL) was added 10% Pd / C (250 mg). The reaction mixture was stirred under hydrogen for 1 h before additional 10% Pd / C (250 mg) was added. Stirri...

Embodiment 2

[0603] Preparation of Compound 102

[0604]

[0605] At 83°C, 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (170 mg, 0.82 mmol, prepared as described in Example 1), K 2 CO 3 (130 mg, 0.94 mmol) and 2-chlorobenzoxazole (100 μL, 0.87 mmol) in DMF (3 mL) were stirred in a sealed tube for 16 h. The mixture was allowed to cool to room temperature and water (10 mL), brine (10 mL) and EtOAc (20 mL) were added. The layers were separated, the aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with brine (10 mL), washed over anhydrous MgSO 4 Dry, filter, and remove solvent under reduced pressure. The residue was purified by flash chromatography (30% EtOAc in Hex) to afford 130 mg of compound 102 as an oil.

Embodiment 3

[0607] Preparation of compound 103

[0608]

[0609] Under argon, to stirred compound 101 (1.50 g, 3.98 mmol) and K 2 CO 3 (60mg, 0.434mmol) in DMF (20mL) was added CF 3 TMS (1.30 mL, 8.80 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc (40 mL) and water (10 mL) and washed with brine (3 x 40 mL). The organic layer was washed with anhydrous MgSO 4 Dry, filter, and remove solvent under reduced pressure. The residue was taken up in MeOH (20 mL), mixed with concentrated HCl (2 mL) and stirred for 1 h. The solvent was removed under reduced pressure, the residue was taken up in EtOAc (40 mL) and washed with water (2 x 40 mL), then brine (40 mL). The organic layer was washed with anhydrous MgSO 4 Dry, filter, and remove solvent under reduced pressure. The residue was purified by flash chromatography (25% EtOAc in Hex) to afford 1.54 g of compound 103 as a yellow oil.

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Abstract

Provided are specific leukotriene synthesis inhibitor compounds and pharmaceutical compositions comprising the compounds and methods of using the compounds and the pharmaceutical compositions in treating, for example, inflammatory diseases or conditions.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit under 35 U.S.C.§ of U.S. Provisional Patent Application No. 62 / 791,641 filed January 11, 2019, which is hereby incorporated by reference in its entirety for all purposes. [0003] field of invention [0004] The present disclosure relates to specific leukotriene synthesis inhibitor compounds and pharmaceutical compositions comprising the compounds, as well as methods of using the compounds and pharmaceutical compositions to treat, for example, inflammatory diseases or disorders. [0005] Background of the invention [0006] 5-Lipoxygenase (5-LO) is a key enzyme in the production of leukotrienes, pro-inflammatory mediators of disease. With the assistance of 5-lipoxygenase-activating protein (FLAP), 5-LO oxidizes the substrate arachidonic acid to HPETE, and this transient intermediate is degraded to leukotriene A 4 (LTA 4 , the immediate precursor of bioactive molecules), leukotrienes ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/428A61K31/12A61K31/426C07D277/62C07D277/68
CPCC07D277/68C07D215/14A61K31/428A61K31/423A61K31/4184C07D263/58C07D235/22
Inventor D.L.伯戈因E.德布鲁因J.福纳雷夫J.G.K.伊J.M.朗兰兹
Owner 纳吉斯制药股份有限公司
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