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Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy

A technology of sulfonamide and phenyl, applied in the field of heteroarylsulfonamide derivatives

Inactive Publication Date: 2013-07-17
PIERRE FABRE MEDICAMENT SAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the risk of embolism is only partially conditional on the presence of FA alone, since atrial congestion is also associated with increased intraluminal pressure (systolic or diastolic LV dysfunction, valvular heart disease or valve replacement)

Method used

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  • Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy
  • Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy
  • Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0271] Example 1 : N-(2-(4-(6-fluorobenzo[d]oxazol-2-yl)piperazine-1-carbonyl)phenyl)-5-(trifluoromethyl)pyridine-2-sulfonamide (1)

[0272]

[0273] Compound 1 was prepared using Synthetic Method 1: In the presence of 1H-benzo[d][1,3]oxazine-2,4-dione (1.83 g, 11.3 mmol) and DMAP (138 mg, 1.13 mmol), the Intermediate 3a (2.5 g, 11.30 mmol) was taken up in 25 mL THF and 5 mL DMF, and the mixture was stirred at ambient temperature overnight. After concentration to dryness, the residue was taken up in water and extracted with AcOEt. After drying the organic phase and concentrating to dryness, the residue obtained was purified by flash chromatography on silica gel (CH 2 Cl 2 -MeOH, gradient 100-0 to 95-5 over 40 minutes). 0.47 g of solid were obtained (yield: 32%). The obtained solid was then placed in 3 mL of dichloromethane in the presence of 0.119 g (0.48 mmol) of intermediate 4a and 39 μL of pyridine. The mixture was then stirred overnight at ambient temperature, t...

Embodiment 2

[0277] Example 2 : N-(2-(4-(6-fluorobenzo[d]thiazol-2-yl)piperazine-1-carbonyl)phenyl)-pyridine-2-sulfonamide (2)

[0278]

[0279] Compound 2 was prepared using Synthetic Method 1 using Intermediate 3e (yield: 87%) for the first step and Intermediate 4b (yield: 30%) for the second step.

[0280] TLC silica gel 60F254Merck, CH 2 Cl 2 -MeOH:95-5, Rf=0.58.

[0281] NMR 1 H(CDCl 3 ) ppm: 8.65(d,1H), 8.58(s,1H), 8.03(d,1H), 7.89(t,1H), 7.77(d,1H), 7.50(m,1H), 7.39(m,3H ),7.12(m,3H),3.62(m,8H).

[0282] MS(+ESI)m / z498(MH+)

Embodiment 3

[0283] Example 3 : N-(2-(4-(6-bromobenzo[d]thiazol-2-yl)piperazine-1-carbonyl)phenyl)-pyridine-2-sulfonamide (3)

[0284]

[0285] Compound 3 was prepared using Synthetic Method 1 using intermediate 3f for the first step (quantitative yield) and intermediate 4b for the second step (yield: 80%).

[0286] TLC silica gel 60F254Merck, CH 2 Cl 2 -MeOH:95-5, Rf=0.60.

[0287] mp=102℃

[0288] NMR 1 H(CDCl 3 )ppm:8.66(d,1H),8.56(s,1H),8.03(d,1H),7.88(t,1H),7.75(m,2H),7.41(m,4H),7.16(m,2H ),3.64(m,8H).

[0289] MS(+ESI)m / z558(MH+)

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Abstract

The present invention concerns derivatives of heteroarylsulfonamides, notably as blockers of Kv potassium channels, and more particularly of channels Kv1.5, Kv4.3 or Kv11.1, their application in clinical therapy and their preparation methods. These compounds correspond to the following general formula (I): where R1 represents one or more substituents of the phenyl core X such as: hydrogen, halogen, trifluoromethyl, trifluoromethoxy, linear or branched C1-C4 alkyl, or linear or branched C1-C4 alkoxy, A represents oxygen or sulphur, B represents nitrogen when n=1 or 2 and D represents -C(=O)-, or B represents CH when n=0 and D represents -CH2O- or when n=1 and D represents -O-, R2 represents a hydrogen, a methyl, a fluorine or chlorine atom or a methoxy, HetAr represents a pyridyl or quinolyl group, possibly substituted by a group such as a linear or branched C1-C4 alkyl, a linear or branched C1-C4 alkoxy, a halogen, or a trifluoromethyl, and to their pharmaceutically acceptable salts.

Description

technical field [0001] The present invention relates to heteroaryl sulfonamide derivatives, their preparation method and their application in human therapy, which are used as blockers of Kv potassium channels, especially channels Kv1.5, Kv4.3 and Kv11.1. Background technique [0002] Potassium channels represent the largest family of ion channels in the human genome, with approximately 80 genes (Tamargo et al., Cardiovasc. Res. 2004, 62:9-33). These potassium channels can be subdivided into 3 subfamilies: by potential or voltage (K v channel) and calcium (K Ca channel) activated channel, inwardly rectifying channel (K ir ) and two-pore potassium channels (K 2p ). The voltage-activated channel subfamily is the most representative one in the human body, in excitable cells (cardiomyocytes, neurons, striated muscle or smooth muscle cells) and non-excitable cells such as pancreatic cells, prostate cells, parathyroid cells, etc. Has a nearly ubiquitous distribution (for revie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D417/12A61K31/423A61K31/428
CPCC07D417/14C07D413/14C07D413/12C07D417/12A61P29/00A61P3/12A61P35/00A61P43/00A61P9/00A61P9/04A61P9/10A61K31/496A61K31/4439A61K31/444A61K31/4709
Inventor E·杜邦-帕斯莱格I·勒罗伊C·皮尼耶
Owner PIERRE FABRE MEDICAMENT SAS
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