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Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof

A compound, phenyl technology, applied in the field of therapeutic compounds, which can solve problems such as side effects

Inactive Publication Date: 2008-12-24
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although CB 1 Agonists such as Δ 9 - THC (Δ 9 -THC) and anadamide, are useful in animal models of anti-nociception, but they are prone to unwanted CNS side effects, such as psychoactive side effects, abuse potential, drug dependence and tolerance Receptivity, etc.

Method used

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  • Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
  • Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
  • Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] 2-tert-butyl-N, N-diethyl-1-{[(2R)-1-methylpiperidin-2-yl]methyl}-1H-benzimidazole-5-carboxamide

[0179]

[0180] Step A. 2-tert-butyl-N,N-diethyl-1-{[(2R)-1-methylpiperidin-2-yl]methyl}-1H-benzimidazole-5-carboxamide

[0181]

[0182] (2R)-tert-butyl 2-[({2-amino-4-[(diethylamino)carbonyl]phenyl}amino)methyl]piperidine-1-carboxylate (75 mg, 0.185 mmol) (for Preparation, see steps B, C and D below) Dissolved in 3 mL of DCE containing TEA (0.058 mL, 0.277 mmol). Trimethylacetyl chloride (0.025 mL, 0.204 mmol) was added dropwise, and the solution was stirred at room temperature for 1 hour. Glacial acetic acid (1 mL) and a few drops of concentrated HCl were added, and the solution was stirred at 75°C for 24 hours. The solvent was concentrated. The residue was dissolved in EtOAc and washed with 2M NaOH, brine, and washed with anhydrous MgSO 4 dry. The solvent was evaporated. The product was dissolved in 5 mL of THF containing a few drops of glacial AcOH. Excess ...

Embodiment 2

[0193] 2-tert-butyl-1-(cyclohexylmethyl)-N,N-diethyl-1H-benzimidazole-5-carboxamide

[0194]

[0195] Step A. 2-tert-butyl-1-(cyclohexylmethyl)-N,N-diethyl-1H-benzimidazole-5-carboxamide

[0196]

[0197] 3-Amino-4-[(cyclohexylmethyl)amino]-N,N-diethylbenzamide (124 mg, 0.409 mmol) (for preparation, see steps B and C below) was dissolved in 3 mL of TEA containing (0.085 mL, 0.614 mmol) in DCE. Trimethylacetyl chloride (0.055 mL, 0.450 mmol) was added dropwise, and the solution was stirred at room temperature for 1 hour. Glacial AcOH (1 mL) and a few drops of concentrated HCl were added, and the solution was stirred at 75°C for 48 hours. The solvent was concentrated. The residue was dissolved in EtOAc and washed with 2M aqueous NaOH, brine, and washed with anhydrous MgSO 4 dry. The solvent was evaporated. The product was obtained by using 20-80% CH 3 CN / H 2 Reverse phase HPLC purification of O and then lyophilization afforded the desired title compound as the corr...

Embodiment 3

[0205] 2-tert-butyl-1-(cyclohexylmethyl)-N-methoxy-N-methyl-1H-benzimidazole-5-carboxamide

[0206]

[0207] Step A. 2-tert-Butyl-1-(cyclohexylmethyl)-N-methoxy-N-methyl-1H-benzimidazole-5-carboxamide

[0208]

[0209] 2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazole-5-carboxylic acid (58 mg, 0.184 mmol) (for preparation see steps B-F below), N,O-dimethylhydroxy Amine hydrochloride (25 mg, 0.276 mmol) and HATU (77 mg, 0.202 mmol) were stirred in 2 mL of DIPEA (0.080 mL, 0.460 mmol) in DMF at room temperature for 3 hours. The solvent was concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO 3 solution, brine, and anhydrous MgSO 4 dry. The solvent was evaporated. Pass the product on a C-18 column by using 20-80% CH 3 CN / H 2 Reverse phase HPLC purification of O and then lyophilization afforded the desired title compound as the corresponding TFA salt. Yield: 29 mg (33%). 1 H NMR (400MHz, methanol-D 4 )δ1.23(m, 5H), 1.62(s, 2H), 1.65(s, ...

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PUM

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Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof: wherein R1, R2, R3, R4 and Z are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

[0001] This application is a Chinese invention application (name of invention: benzimidazole derivatives, compositions containing them, their preparation and their use; filing date: June 9, 2004; application number: 200480016327.2 (international application number: PCT / GB2004 / 002427)) divisional application. technical field [0002] The present invention relates to CB 1 Therapeutic compounds of receptor ligands, pharmaceutical compositions containing these compounds, their preparation methods and their uses, more particularly, the present invention relates to CB 1 Agonist compounds. More particularly, the present invention relates to compounds that are effective in the treatment of pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, anxiety, gastrointestinal disorders and cardiovascular diseases. Background technique [0003] Pain management has been an important area of ​​research for many years. Cannabinoid receptors includ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/08C07D401/06C07D405/06A61K31/4184A61P25/00C07DC07D413/06
CPCC07D235/08C07D401/06C07D405/06C07D413/06A61P1/00A61P1/10A61P1/12A61P1/14A61P13/10A61P15/10A61P23/00A61P25/00A61P25/04A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/32A61P25/34A61P25/36A61P29/00A61P31/12A61P35/00A61P37/02A61P37/08A61P43/00A61P9/00A61K31/4184
Inventor 刘自平丹尼尔·佩奇克里斯托弗·沃尔波尔杨华
Owner ASTRAZENECA AB
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