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Isoindoline derivatives for the treatment of arrhythmias

A compound and alkyl technology, applied in the field of novel medicinal 3-oxoisoindoline-1-carboxamide compounds, can solve the problems of not giving references and the like

Inactive Publication Date: 2009-09-09
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Additionally, the following compounds are known compounds in Chemical Abstracts, but no references are given: 3-Oxo-N,2-diphenylisoindoline-1-carboxamide

Method used

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  • Isoindoline derivatives for the treatment of arrhythmias
  • Isoindoline derivatives for the treatment of arrhythmias
  • Isoindoline derivatives for the treatment of arrhythmias

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0975] 2-[2-(4-Chlorophenyl)propyl]-N-[(5-methylisoxazol-3-yl)methyl]-3-oxoisoindoline-1-carboxamide

[0976] A solution of 2-formylbenzoic acid (1.23g, 8.2mmol) in methanol (15ml) was treated with 2-(4-chloro-phenyl)-propylamine hydrochloride (16.9g, 8.2mmol) and triethylamine (1.14ml). The mixture was stirred at room temperature for 30 minutes. A solution of 3-isocyanomethyl-5-methyl-isoxazole from Preparation L was added and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated, dissolved in 50 ml of dichloromethane and washed with 100 ml of saturated NaHCO 3 Solution wash. The organic phase was separated, dried over magnesium sulfate and evaporated. The remaining oil was purified using preparative HPLC to afford the title compound (0.903 g, 26% yield).

[0977] [M+1](ES)424.10

[0978] 1 H NMR (500MHz, CDCl 3 )δ7.46-7.61(m, 3H); 7.35-7.44(m, 1H); 7.07-7.27(m, 5H); 5.81(s, 1H); 4.78(s, 1H); 1H); 4.31-4.39 (m, 1H); 4.12-4.27 (m, 1H); ...

Embodiment 2

[0980] 2-(biphenyl-2-ylmethyl)-N-(tert-butyl)-5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamide

[0981] (i) N-(biphenyl-2-ylmethyl)-N-[2-(tert-butylamino)-1-(2-furyl)-2-oxoethyl]but-2-yne amide

[0982] (Biphenyl-2-ylmethyl)amine (23.78mmol, 4.36g) was dissolved in methanol, 2-furfural (23.78mmol, 2.29g) and but-2-ynoic acid (23.78mmol, 2.00g) were added. The mixture was stirred at room temperature for 30 minutes. Isocyano-tert-butane (23.7g, 1.98g) was added and the mixture was stirred at room temperature overnight. The solvent was removed by evaporation. The product was used in the next step without further purification.

[0983] (ii) 2-(biphenyl-2-ylmethyl)-N-(tert-butyl)-5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamide

[0984] N-(biphenyl-2-ylmethyl)-N-[2-(tert-butylamino)-1-(2-furyl)-2-oxoethyl]butyl from step (i) above -2-Ynamide (23.0mmol, 9.87g) was dissolved in xylene (200ml), and ytterbium(III) trifluoromethanesulfonate (2.30mmol, 1.43g) was added. The mixtu...

Embodiment 3

[0988] (R or S) 2-(biphenyl-2-ylmethyl)-N-(tert-butyl)-5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamide

[0989] (S or R) 2-(biphenyl-2-ylmethyl)-N-(tert-butyl)-5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamide

[0990] Separation of 2-(biphenyl-2-ylmethyl)-N-(tert-butyl)-5-hydroxyl by preparative HPLC using Reprosil 20×250 mm chiral column with 40% isopropanol in heptane as mobile phase - Enantiomer of 4-methyl-3-oxoisoindoline-1-carboxamide (Example 2) (0.20 g, 0.47 mmol) to give the (+) enantiomer of the title compound (0.10 g) (E1 ) and (-) enantiomer (0.10 g) (E2).

[0991] (+) Enantiomers:

[0992] HRMS: Yes (C 27 h 28 N 2 o 3 +H) + Calculated: 429.2178; found (ES[M+H]+): 429.2166.

[0993] (-) enantiomer:

[0994] HRMS: Yes (C 27 h 28 N 2 o 3 +H) + Calculated: 429.2178; found (ES [M+H]+): 429.2147.

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Abstract

The present invention provides compounds of formula I, wherein R to R have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

Description

field of invention [0001] The present invention relates to novel pharmaceutically useful 3-oxoisoindoline-1-carboxamide compounds, especially compounds useful in the treatment of cardiac arrhythmias. Background technique [0002] Cardiac arrhythmia can be defined as an abnormality in the rate, rhythm or onset of the heart's beating, or as a conduction disturbance that causes abnormal activity. Arrhythmias can be defined by origin (i.e., supraventricular, including atrial, atrioventricular, arrhythmia, ventricular arrhythmias) and / or by rate (i.e., bradyarrhythmias (slow) and tachyarrhythmias (fast)) for clinical classification. [0003] Negative clinical results with "traditional" antiarrhythmic drugs (Class I antiarrhythmic drugs) that act by slowing conduction velocity in the treatment of cardiac arrhythmias (see, e.g., New England Journal of Medicine 321, 406 (1998 ) reported results of the Arrhythmia Suppression Test (CAST) suggest that compounds that selectively delay...

Claims

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Application Information

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IPC IPC(8): C07D209/46A61K31/40A61K31/4035A61K31/41A61K31/435A61K31/495A61P9/04A61P9/06C07D403/00C07D413/00C07D401/00
Inventor A·比约J·博斯特伦O·戴维森H·埃姆特纳斯U·格兰T·伊利夫斯基J·卡贾纽斯R·奥尔森L·桑德伯格G·斯特兰德伦J·森德尔Z·-Q·袁Z·－Q·袁
Owner ASTRAZENECA AB
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