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Pyrimidone compounds as chymase inhibitors and their applications

A compound and pharmaceutical technology, applied in the fields of drug combination, organic chemistry, medical preparations containing active ingredients, etc., can solve the problem that the PK property needs to be further improved.

Active Publication Date: 2022-07-19
MEDSHINE DISCOVERY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The reported data of BAY-1142524 show that its in vitro activity is good, but the PK properties need to be further improved

Method used

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  • Pyrimidone compounds as chymase inhibitors and their applications
  • Pyrimidone compounds as chymase inhibitors and their applications
  • Pyrimidone compounds as chymase inhibitors and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109]

[0110] Step A: Compound 1-a (20g, 224.48mmol, 1eq) and monoethyl malonate (29.66g, 224.48mmol, 1eq) were dissolved in Ac at 75°C 2 O (400 mL) mixture was stirred for 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (100-200 mesh, PE / EtOAc=20 / 1-3 / 1) to obtain 1-b.

[0111] Step B: Compound 1-b (21 g, 103.35 mmol, 1 eq) and triethyl orthoformate (15.32 g, 103.35 mmol, 17.19 mL, 1 eq) were dissolved in Ac at 140 °C 2 The O (25 mL) solution was stirred for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography (100-200 mesh, PE / EtOAc=10 / 1-1 / 1) to obtain 1-c.

[0112]

[0113] Step A: Chlorosulfonic acid (210.00 g, 1.80 mol, 120.00 mL, 13.11 eq) was added dropwise to compound 1-d (3-[2-(trifluoromethyl)phenyl]propionic acid) at 0°C ...

Embodiment 2

[0125]

[0126]

[0127] Aqueous HCl (2M, 27.08 mL, 4.46 eq) was added to AcOH (60 mL) in which compound 1 (6.5 g, 12.14 mmol, 1 eq) was dissolved at 15 °C, and the mixture was heated to 120 °C and stirred for 4 h. The mixture was cooled to room temperature and poured into H 2 O (200 mL), extract with EtOAc (100 mL×3), combine the organic phases and wash with saturated brine (300 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of compound 2, which is then prepared by HPLC (column: Phenomenexluna c18 250 mm×100 mm×10 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile %: 35%-65%, 20 min) and SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10μm); mobile phase: [neutral-methanol]; methanol %: 35%-35%, 4.6min; 170min) purification to obtain compound 2-I (retention time: 2.780min) and compound 2-II (retention time: 3.718 min).

[0128] 2-I: 1 H NMR (400MHz, DMSO-d 6 ): δ=8.52(br...

Embodiment 3

[0131]

[0132] Step A: To a solution of compound 3-a (8g, 37.33mmol, 1eq) in DMF (80.00mL) at 15°C was added DIEA (4.82g, 37.33mmol, 6.50mL, 1eq) and 1-h (11.85g) , 37.33mmol, 1eq), the reaction solution was stirred for 12 hours. The reaction solution was poured into 600 mL of water, then diluted with 400 mL of EtOAc, the resulting mixture was extracted with EtOAc (400 mL×2), the organic phases were combined and washed with 400 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound 3-b.

[0133] Step B: To a solution of compound 3-b (13.3 g, 31.92 mmol, 1 eq) in THF (60.00 mL) at 15 °C, a solution of tetrabutylammonium fluoride in THF (1 M, 63.85 mL, 2 eq) was added to react The solution was stirred at 15°C for 2 hours. The reaction solution was diluted with 50 mL of water and extracted with EtOAc (50 mL×2). The organic phases were combined and washed with 50 mL of satura...

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Abstract

A class of compounds having a pyrimidone structure as a chymase inhibitor drug, specifically discloses the compound represented by formula (I), its pharmaceutically acceptable salts and isomers thereof, and pharmaceutical compositions containing them .

Description

[0001] This application claims the following priority: [0002] CN201910597205.5, application date July 3, 2019; [0003] CN202010402394.9, application date May 13, 2020. technical field [0004] The present invention relates to novel pyrimidone compounds as chymase inhibitor drugs, in particular to compounds represented by formula (I), pharmaceutically acceptable salts and isomers thereof, and pharmaceutical compositions containing them . Background technique [0005] Chymase is a glycoprotein belonging to the serine protease family, mainly present in mast cells, endothelial cells and mesenchymal cells. When stimulated by inflammation, mast cells are degranulated, and chymase is released outside the cell and activated. The role of chymase in vivo is mainly to convert Ang I (angiotensin I) to AngII (angiotensin II), induce activation of TGF-β and activate matrix metalloproteinase 9 (MMP-9). TGF-β can promote the production of collagen and promote tissue fibrosis; MMP-9 i...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D239/557C07D413/08A61K31/513A61P11/06A61P13/12A61P9/00
CPCA61K31/513A61P11/06A61P13/12A61P9/00C07D239/557C07D413/08C07D413/14
Inventor 颜小兵丁照中蔡亚仙陈曙辉
Owner MEDSHINE DISCOVERY INC
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