Novel benzimidazole compound and pharmaceutical use of same

A compound and pharmaceutical technology, applied in the field of new benzimidazole compounds and their medical uses, can solve the problems of no disclosure and the like

Active Publication Date: 2018-04-17
SUMITOMO DAINIPPON PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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Method used

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  • Novel benzimidazole compound and pharmaceutical use of same
  • Novel benzimidazole compound and pharmaceutical use of same
  • Novel benzimidazole compound and pharmaceutical use of same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0613] Example 1: Preparation of 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-alcohol (compound 1)

[0614]

[0615] Step (i): Preparation of 1-[(5-fluoro-2-nitrophenyl)amino]-2-methylpropan-2-ol (Compound 62)

[0616] A mixture of compound 61 (1.59 g), 1-amino-2-methylpropan-2-ol (0.98 g), diisopropylethylamine (5.22 mL) and DMF (50 mL) was stirred at 60 °C for 2 hours . A mixture of water and ethyl acetate / hexane (=1 / 1) was added to the reaction mixture, and the target product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain Compound 62 as a crude product.

[0617] Step (ii): Preparation of 1-[(5-(4-fluorophenoxy)-2-nitrophenyl]amino)-2-methylpropan-2-ol (compound 63)

[0618] A mixture of the crude product of compound 62 prepared in step (i), 4-fluorophenol (1.68 g), cesium carbonate (6.52 g) and NMP (25 mL) was stirred at 100 °C for 2 hours. ...

Embodiment 2

[0625] Example 2: Preparation of 6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole (compound 2)

[0626]

[0627] Compound 2 (0.26 g) was prepared according to the method of Example 1 by using the starting material (tetrahydrofuran-2-yl)methanol (0.607 g) instead of 1-amino-2-methylpropan-2-ol.

[0628] 1 H-NMR (DMSO-d6) δ: 1.49 (1H, m), 1.75 (2H, m), 1.94 (1H, m), 3.63 (2H, m), 4.07-4.34 (3H, m), 6.87-6.90 (1H, m), 6.97-7.02 (2H, m), 7.19 (2H, m), 7.35 (1H, m), 7.62 (1H, m), 8.14 (1H, s).

Embodiment 3

[0629] Example 3: Preparation of 6-(4-fluorophenoxy)-1-[2-(prop-2-yloxy)ethyl]-1H-benzimidazole (compound3)

[0630]

[0631] A mixture of compound 65 (0.050 g), sodium hydride (0.011 g) and DMF (1.0 mL), prepared according to Example 1 using appropriate starting materials, was stirred at 0 °C for 30 minutes. To the reaction solution was added 2-bromopropane (0.045 g) and the mixture was further stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous ammonium chloride and ethyl acetate, and the target product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 99 / 1) to obtain Compound 3 (9 mg).

[0632] 1 H-NMR (DMSO-d6) δ: 0.94 (6H, d, J = 6.1 Hz), 3.44 (1H, m), 3.64 (2H, t, J = 5.0 Hz), 4.30 (2H, t, J = 5.0 Hz), 6.87-7.02 (3H, m), 7.18 (2H, m), 7.32...

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Abstract

To provide a therapeutic agent for diseases associated with Nav 1.7, specifically diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, urination disorders and multiple sclerosis. Provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, each of R1a,R1b, R1c and R1d represents a hydrogen atom, a halogen atom, a cyano group, a C1-4 alkyl group, a C1-4 alkoxy group or the like, provided that at least one of the R1a, R1b, R1c and R1d moieties represents a C6-10 aryl group, a C6-10 aryloxy group or the like; each of R2 and R3 represents a hydrogen atom, a C1-6 alkyl group, a C3-10 cycloalkyl group or the like; R4 represents a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group or the like; m represents 1, 2 or 3; L represents a CR7R8 group; and each of R7 and R8 represents a hydrogen atom, a hydroxyl group, a C1-4 alkyl group, a C1-4 alkoxy group or the like.)

Description

technical field [0001] The present invention may relate to a medicament for treating or preventing diseases involving Na channels, especially SCN9A (Nav 1.7), comprising a novel compound having a benzimidazole skeleton or a pharmaceutically acceptable salt thereof as an active ingredient. In more detail, it relates to a medicine for treating or preventing diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal excruciating pain, dysuria and multiple sclerosis drug. Background technique [0002] There are 9 known pore-forming α subunits of voltage-dependent Na channels. Recently, it has been shown that this subunit, Nav 1.7 in particular, is broadly involved in the signaling of acute and chronic pain. [0003] SCN9A (Nav 1.7) is a tetrodotoxin (TTX)-sensitive Na channel located in peripheral sensory or sympathetic nerves, which is also known as NENA or PN1. Physiologically, Nav 1.7 channels function to amp...

Claims

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Application Information

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IPC IPC(8): C07D235/06A61K31/4184A61K31/423A61K31/4439A61K31/497A61K31/501A61K31/506A61K31/5375A61P13/00A61P25/00A61P25/04C07D401/04C07D401/12C07D403/06C07D403/12C07D405/06C07D407/14C07D413/04
CPCC07D403/12C07D401/12C07D405/06C07D235/06A61P25/00A61P25/04A61P13/00C07D401/04C07D405/04C07D413/04C07D413/14C07D417/14C07D405/14C07D235/04A61K31/4184A61P25/08A61P25/24A61P29/00C07D235/08C07D401/10C07D413/10
Inventor 小宫正文岩本浩平金井利夫水岛真吾足立圭司浦岛久仁子
Owner SUMITOMO DAINIPPON PHARMA CO LTD
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