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Isoquinolone compound and application thereof

A compound and selected technology, applied in the direction of active ingredients of heterocyclic compounds, organic chemistry, drug combination, etc., can solve the problems of undisclosed compound regulation, unsatisfactory therapeutic effect, and restrictions on widespread use

Inactive Publication Date: 2018-07-31
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the prior art such as WO2004108681A1 discloses isoquinoline compounds for regulating HIF and / or EPO, its therapeutic effect is still not very satisfactory, which greatly limits its widespread use in clinical applications
In addition, WO2016123028A1 discloses 4-hydroxy-1-methyl-N-((5-oxo-4,5-dihydro-1H-tetrazol-1-yl)methyl)-7-exyloxy Tetrazolium compounds including isoquinoline-3-carboxamide, but it does not disclose the modulation effect of the compound on HIF

Method used

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  • Isoquinolone compound and application thereof
  • Isoquinolone compound and application thereof
  • Isoquinolone compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] Example 1: 2-(7-(4-chloro-2-fluorobenzyl)-4-hydroxyl-1-methylisoquinoline-3-carboxamide)acetic acid (Compound 1)

[0179]

[0180] The first step: methyl 4-bromo-2-(chloromethyl)benzoate (1b)

[0181] 5-Bromoisobenzofuran-1(3H)-one (10.00g, 47.2mmol), benzyltriethylammonium chloride (2.20g, 9.4mmol), boron trifluoride ether (1.20mL, 9.40mmol ), xylene (50 mL) were added into the reaction flask, and the reaction solution was replaced with nitrogen three times, and then heated to 110° C. for 30 min. Then, thionyl chloride (8.60 mL, 118.0 mmol) was slowly added dropwise into the above reaction solution, and after the drop was completed, the temperature was raised to 130°C for 6 h, then cooled to 40-50°C, and methanol (20 mL) was slowly added dropwise to quench the reaction. The solvent was evaporated from the reaction liquid under reduced pressure, and the title compound 1b (11.40 g, 93.0%) was obtained by separation on a silica gel column.

[0182] The second step: m...

Embodiment 2

[0199] Example 2: N-((2H-tetrazol-5-yl)methyl)-4-hydroxyl-1-methyl-7-phenoxyisoquinoline-3-formamide (compound 2)

[0200]

[0201] The first step: 5-phenoxyisobenzofuran-1(3H)-one (2b)

[0202] Phenol (20.4g, 0.22mol) and DMF 50mL were added to the reaction flask, stirring was started, and 5-bromoisobenzofuran-1(3H)-one (34.0g, 0.16mmol), acetylacetone (3.2 g, 0.03mol), cuprous bromide (3.6g, 0.03mol), potassium carbonate (30.8g, 0.22mol), replaced with nitrogen three times, heated to 90°C and stirred overnight, added 1000mL of purified water to the reaction solution, and suction filtered. Dissolve the filter cake with 800 mL of dichloromethane, wash the organic phase with 800 mL of 1N hydrochloric acid solution, wash with 1000 mL of purified water, dry the organic phase, and concentrate to dryness under reduced pressure to obtain a yellow solid. Title compound 2b (22.5 g, 63%).

[0203] The second step: methyl 2-(chloromethyl)-4-phenoxybenzoate (2c)

[0204] 5-phenoxyi...

Embodiment 3

[0216] Example 3: N-((2H-tetrazol-5-yl)methyl)-4-hydroxyl-1-methyl-7-phenoxyisoquinoline-3-carboxamide (compound 3)

[0217]

[0218] At room temperature, methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (200mg, 0.65mmol), (1H-1,2,3-triazol-4-yl) Methylamine (500mg, 3.68mmol), 2mL of methanol, and 1mL of sodium methoxide in methanol were added to a sealed tube, and the reaction was sealed overnight at 110°C. After suction filtration, the filtrate was added to DCM, and a solid precipitated out. The obtained solid was purified by silica gel column chromatography to obtain the title Compound 3 (75 mg, 30%). MS m / z (ESI): 376 (M+1).

[0219] 1 H NMR (400MHz, CDCl 3 )δ8.44(d, J=9.6Hz, 1H), 7.81(s, 1H), 7.57(d, J=9.6Hz, 2H), 7.23-7.04(m, 3H), 7.12(d, J=8.0 Hz, 2H), 4.83 (s, 2H), 2.89 (s, 3H).

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PUM

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Abstract

The invention relates to an isoquinolone compound and application thereof. The invention in particular relates to an isoquinolone compound used as a HIF prolyl hydroxylase inhibitor (HIF-PHI) and a pharmaceutical composition thereof. Moreover, the present invention provides the application of the isoquinolinone compound or the pharmaceutical composition thereof in the preparation of a medicament for preventing or treating HIF-associated or HIF-mediated diseases as anemia or ischemia, local ischemia or hypoxia.

Description

technical field [0001] The present invention relates to medicaments and methods for regulating or enhancing erythropoiesis and iron metabolism, and treating or preventing iron deficiency and anemia of chronic disease. Background technique [0002] The number of patients with chronic kidney disease (CKD) in China is estimated to be about 120 million, and renal anemia is the most common complication affecting the quality of life of CKD patients. There are about 3.12 million new tumor cases in the country every year, and about 50% of chemotherapy patients will suffer from anemia. [0003] In the case of anemia, trauma, tissue necrosis and defect, etc., tissues or cells are often in a hypoxic state. An early response to tissue hypoxia is the induction of hypoxia inducible factor (HIF). Hypoxia inducible factor (HIF) is a basic helix-loop-helix (bHLH) PAS (Per / Arnt / Sim ) transcriptional activator, whose regulation changes with the gene expression of changes in cellular oxygen c...

Claims

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Application Information

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IPC IPC(8): C07D217/26C07D401/12C07D413/12C07D471/04C07D401/06C07D215/56C07D311/56C07D213/81A61K31/472A61K31/4725A61K31/44A61K31/519A61K31/352A61K31/4375A61P7/02A61P9/10
CPCC07D217/26C07D213/81C07D215/56C07D311/56C07D401/06C07D401/12C07D413/12C07D471/04
Inventor 蔡家强谢益农游泽金宋长伟张继超李路张巧玲汪永强陈兴焦仕虎李友强王涛曾宏宋宏梅叶启军苏东海周信张绍华王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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