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Compounds, compositions and methods comprising pyridazine sulfonamide derivatives

A compound, animal technology, applied in the direction of drug combination, active ingredients of heterocyclic compounds, digestive system, etc., can solve the problem of lack of specific blockers of channels, etc.

Inactive Publication Date: 2013-04-24
寰宇一家健康研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Despite the fact that CaCC and VRAC are ubiquitously expressed in cells and perform such important functions, understanding of these channels has been limited by the lack of specific blockers (or blockers, blockers)

Method used

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  • Compounds, compositions and methods comprising pyridazine sulfonamide derivatives
  • Compounds, compositions and methods comprising pyridazine sulfonamide derivatives
  • Compounds, compositions and methods comprising pyridazine sulfonamide derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0464] N-(3-(6-(4-chlorophenethoxy)pyridazin-3-yl)phenyl)-4-cyanobenzenesulfonamide (compound 3) and N-(3-(6-(benzyl Synthesis of (ethyl)amino)pyridazin-3-yl)phenyl)methanesulfonamide (Compound 7)

[0465]

[0466] Step 1: 3-(4-Chlorophenethoxy)-6-iodopyridazine (compound A)

[0467]To a stirred mixture of 60% sodium hydride mineral oil (0.96 g, 25.0 mmol) in anhydrous THF (30 mL) was added dropwise 4-chlorophenethyl alcohol (3.10 mL) under nitrogen in an ice-water bath at 2 °C , 22.9 mmol). After 30 min a solution of 3-chloro-6-iodopyridazine (5.00 g, 20.8 mmol) in THF (70 mL) was added. The cooling bath was removed and stirring was continued at room temperature for 0.5 h, then at 60 °C for 1.5 h. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate (250 mL) and water (150 mL). The combined organic layers were washed with aqueous sodium chloride (150 mL) and dried over a hydrophobic frit...

Embodiment 2

[0477] Preparation of N-(3-(6-(benzyl(ethyl)amino)pyridazin-3-yl)phenyl)-1,1,1-trifluoromethanesulfonamide (compound 10)

[0478]

[0479] Step 1: 6-(3-Aminophenyl)-N-benzyl-N-ethylpyridazin-3-amine (compound D)

[0480] N-benzyl-N-ethyl-6-iodopyridazin-3-amine (100mg, 0.29mmol), 3-aminophenylboronic acid (55.3mg, 0.32mmol), potassium carbonate (0.12g , 0.83 mmol) to a stirred mixture of degassed toluene (2 mL), absolute ethanol (2 mL) and water was added polymer-bound tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.03 mmol, 0.5-0.9 mmol / g load). The mixture was stirred at room temperature for 15 minutes under nitrogen, then heated at 90 °C for 18 h. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was purified by column chromatography (eluent 9:1 to 2:1, hexane:ethyl acetate) to afford 52 mg (49%) of the title compound as a light yellow solid. The crude product was used directly in the next step without further purif...

Embodiment 3

[0488] Preparation of 3-(6-(4-chlorophenethoxy)pyridazin-3-yl)-N-(4-fluorophenylsulfonyl)benzamide (compound 12)

[0489]

[0490] Step 1: 3-(6-(4-chlorophenethoxy)pyridazin-3-yl)benzoic acid (Compound E)

[0491]3-(4-Chlorophenethoxy)-6-iodopyridazine (1.00g, 2.78mmol), 3-carboxyphenylboronic acid (0.51g, 3.06mmol), anhydrous sodium carbonate (1.15 g, 8.34 mmol) To a stirred mixture of degassed toluene (20 mL), absolute ethanol (20 mL) and water (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.33 g, 0.28 mmol). The mixture was stirred at room temperature for 15 minutes under nitrogen, then heated at 80 °C for 3 h. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was partitioned between dichloromethane (30 mL) and saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was washed successively with dichloromethane (3 x 30 mL), then acidified to pH 1 (10M HCl, 5 mL). The precipitated solid was dissolved...

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Abstract

The present invention relates to methods for treating a disease in an animal, which disease is responsive to blocking of chloride channel by administering to a mammal in need thereof an effective amount of a compound defined herein (including those compounds set forth in Tables 1-3 or encompassed by formula I-III) or compositions thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 61 / 326,179, filed April 20, 2010, the entire contents of which are incorporated into this disclosure by reference. technical field [0003] The present application and invention disclose compounds containing pyridazine sulfonamides that inhibit ion (eg chloride) transport across cell membranes containing chloride channels such as calcium-activated chloride channels (CaCC) and / or bulk Modulatory anion channels (or volume-regulated anion conduction or swell-activated chloride conduction or volume-activated chloride channels, VRACs). The structures of the compounds and their derivatives, as well as pharmaceutical formulations and methods of use are described in more detail below. Background technique [0004] Ion channels are not only essential to normal cellular function, but also play key roles in many disease states. For exam...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/50A61P1/12A61P11/00
CPCA61K31/50A61P1/12A61P9/10A61P9/12A61P11/00A61P13/12A61P15/08A61P19/08A61P29/00
Inventor 欧金尼奥·德奥斯托斯图·H.·尼古恩
Owner 寰宇一家健康研究所
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