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Imidazole derivatives as aldosterone synthase inhibitors

Technology of a compound, alkyl, applied in the field of imidazole derivatives as aldosterone synthase inhibitors

Inactive Publication Date: 2012-09-12
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, significant side effects such as gynecomastia and impotence were observed in male patients receiving spironolactone, while hyperkalemia was observed in patients taking either drug

Method used

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  • Imidazole derivatives as aldosterone synthase inhibitors
  • Imidazole derivatives as aldosterone synthase inhibitors
  • Imidazole derivatives as aldosterone synthase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0350] Example 1-1: 3-fluoro-4-((5R,7S)-7-hydroxy-7-vinyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5- base) benzonitrile

[0351]

[0352] Stirred 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5- To a solution of benzonitrile (0.6 g, 2.5 mmol) in THF (20 mL) was added via syringe a solution of vinylmagnesium bromide (0.7 M) in THF (4.3 mL, 3.0 mmol). The crude product was warmed to room temperature over 3 hrs. use NH 4 Aq. Cl quenched the crude product. The crude product was diluted with EtOAc. with MgSO 4 The organic layer was dried, filtered and concentrated. By preparing plates, using 5% (2M NH 3 MeOH solution) / CH 2 Cl 2Purify the crude product twice and then use RPHPLC using 10%-40% MeCN / H 2 O was purified to give 142 mg of the title product as the major diastereomer. MS 270.2 (M+H); LCMS condition A, retention time 0.99min. 1H NMR (400MHz, CDCl 3 -d) δppm 2.56(br.s., 1H), 2.68(dd, 1H), 3.22(dd, 1H), 5.24(d, 1H), 5.41(d, 1H), 5.59-5.73(m, 1H) ...

Embodiment 1-2

[0354] Example 1-2: 4-((5R,7S)-7-(3-cyclopropylphenyl)-7-hydroxyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole -5-yl)-3-fluorobenzonitrile

[0355]

[0356] To a solution of 1-bromo-3-cyclopropyl-benzene (0.018ml, 0.124mmol) in THF (0.2ml) cooled to -78°C was added 1.6M t-BuLi (0.155ml, 0.249mmol). The crude product was stirred at -78 °C for 2 hrs. To this solution was added 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (20 mg , 0.083 mmol) in THF (0.2 ml). The crude product was stirred at -78°C for 1 hr, then at 0°C for 1 hr, and at room temperature for 1 hr. The reaction was quenched with water and CH 2 Cl 2 Aqueous extraction. use Na 2 SO 4 The organic layer was dried, filtered and concentrated. By preparing plates, using 10% (2M NH 3 MeOH solution) / CH 2 Cl 2 The crude product was purified. The title product (4 mg) was isolated as the major diastereomer. MS 360.1 (M+H); LCMS condition B, retention time 1.16min. 1H NMR (400MHz, CD...

Embodiment 1

[0358] Example 1: 34-((5R,7S)-7-(4-(1,1-difluoroethyl)phenyl)-7-hydroxyl-6,7-dihydro-5H-pyrrolo[1, 2-c]imidazol-5-yl)-3-fluorobenzonitrile

[0359]

[0360] To a solution of 1-(1,1-difluoro-ethyl)-4-iodo-benzene (167 mg, 0.62 mmol) in THF (2 mL) cooled to -40 °C was added dropwise a 2M solution of i-PrMgCl in THF ( 0.42 mL, 0.83 mmol). The crude product was stirred at -40°C for 1 hr. Add 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (125 mg, 0.52 mmol) solution in THF (2 mL). The crude product was slowly warmed to room temperature over 3 hrs. use NH 4 Aq. Cl quenched the crude product. The crude product was diluted with EtOAc. The organic layer was washed with brine, MgSO 4 Dry, filter and concentrate. Use 2M NH by prepping the plate 3 MeOH / CH 2 Cl 2 Solution The crude product was purified twice to give 37 mgs of the title product. MS 384.3 (M+H); LCMS condition A, retention time 1.31 min. 1H NMR (400MHz, CDCl 3 )δppm 1.83(t, ...

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Abstract

The present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof, wherein the variables R1, R2, R3, R4, R5, R7 and p are defined herein. The invention also relates to a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Description

Background of the invention [0001] The mineralocorticoid aldosterone is produced by the adrenal glands and acts on the distal tubules and collecting ducts of the kidney to increase ion and water reabsorption in the kidney. Aldosterone causes sodium retention, potassium secretion, increased water retention, and increased blood pressure. [0002] Aldosterone has been implicated in the pathogenesis of cardiovascular diseases such as hypertension and heart failure. In clinical trials, treatment with the nonselective mineralocorticoid receptor antagonist (MRA) spironolactone or the selective MRA eplerenone significantly reduced the risk of heart failure or myocardial infarction in patients who had been taking an angiotensin-converting enzyme inhibitor or Morbidity and mortality in patients on beta-blockers. However, significant side effects such as gynecomastia and impotence were observed in male patients treated with spironolactone, while hyperkalemia was observed in patients ta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04A61K31/4184A61P1/00A61P9/00
CPCA61P1/00A61P1/16A61P3/04A61P3/08A61P5/48A61P5/50A61P7/00A61P7/10A61P9/00A61P9/04A61P9/06A61P9/10A61P9/12A61P13/12A61P25/00A61P25/04A61P25/06A61P27/00A61P27/02A61P43/00C07D471/04C07D487/04
Inventor R·孙L·G·莫诺维奇S·沙穆安J·韦斯特布鲁克
Owner NOVARTIS AG
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