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Benzimidazole 5-sulfonamide derivatives as cannabinoid 1 (CB1) receptor ligands

A halogen, compound technology, applied in the field of therapeutic compounds, can solve the problems of psychobehavioral side effects, abuse potential drug dependence and tolerance, etc.

Inactive Publication Date: 2009-07-01
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although CB 1 Agonists such as Δ 9 - THC (Δ 9 -THC) and arachidonic acid (anadamide), which can be used in animal antinociception models, but they often produce unwanted CNS side effects, such as side effects affecting psychobehavior, abuse potential, drug dependence and tolerance, etc.

Method used

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  • Benzimidazole 5-sulfonamide derivatives as cannabinoid 1 (CB1) receptor ligands
  • Benzimidazole 5-sulfonamide derivatives as cannabinoid 1 (CB1) receptor ligands
  • Benzimidazole 5-sulfonamide derivatives as cannabinoid 1 (CB1) receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] 2-tert-butyl-N, N-diethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonamide

[0164]

[0165] Step A: 2-tert-Butyl-N,N-diethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonamide

[0166]

[0167] 2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61.2 mg, 0.165 mmol) (for preparation see Step B below , C, D, E, F, G and H) were added to a solution of diethylamine (0.2 mL, 1.93 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (60 mL), washed with NH 4 Cl (2x5mL), NaCl (2x5mL) washed, and washed with Na 2 SO 4 dry. The crude product was purified by MPLC (silica gel, eluting with hexane / ethyl acetate (1:1)) to afford 20.5 mg (30%) of the title compound as a white solid. 1 H NMR (400MHz, methanol-D 4 )δ 1.13(t, J=7.13Hz, 6H), 1.46-1.63(m, 4H), 1.66(s, 9H), 2.25-2.48(m, 1H), 3.22-3.29(m, 4H), 3.31- 3.41(m, ...

Embodiment 2

[0190] 2-tert-butyl-5-(piperidin-1-ylsulfonyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole

[0191]

[0192] According to the same operation as in Example 1, step A, 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61 mg, 0.17 mmol), piperidine (0.2 mL, 2.0 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The crude product was purified by MPLC (silica gel, eluting with hexane / ethyl acetate (1:1)) to afford 31 mg (45%) of the title compound as a white solid. 1 H NMR (400MHz, methanol-D 4 )δ 1.40(m, 2H), 1.47-1.64(m, 8H), 1.65(s, 9H), 2.25-2.48(m, 1H), 2.92-3.05(m, 4H), 3.29-3.39(m, 2H ), 3.88-3.98(m, 2H), 4.50(d, J=7.62Hz, 2H), 7.82(dd, J=8.69, 1.66Hz, 1H), 8.01(d, J=8.79Hz, 1H), 8.06 (d, J=1.56Hz, 1H); MS(ESI)(M+H) + = 420.0; C 22 h 33 N 3 o 3 S+1.10 TFA+0.50 H 2 O+0.10CH 3 Theoretical for OH (557.23): C, 52.38; H, 6.42; N, 7.54; Found: C, 52.38; H, 6.43; N, 7.58.

Embodiment 3

[0194] 2-tert-butyl-5-(isoxazolidin-2-ylsulfonyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole

[0195]

[0196] According to the same operation as in Example 1, step A, 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61 mg, 0.17 mmol), isoxazolidine hydrochloride (44 mg, 0.40 mmol), DIPEA (0.2 mL, 149 mg, 1.15 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The crude product was purified by MPLC (silica gel, eluting with hexane / ethyl acetate (1:1)) to afford 24 mg (36%) of the title compound as a white solid. 1 HNMR (400MHz, methanol-D 4 )δ 1.43-1.61(m, 4H), 1.63(s, 9H), 2.02-2.19(m, 2H), 2.25-2.42(m, 1H), 3.29-3.38(m, 2H), 3.64-3.73(m , 2H), 3.86(t, J=7.13Hz, 2H), 3.88-3.96(m, 2H), 4.49(d, J=7.42Hz, 2H), 7.98(d, J=1.56Hz, 1H), 7.99 (s, 1H), 8.24 (d, J=0.78Hz, 1H); MS (ESI) (M+H) + = 408.0; C 20 h 29 N 3 o 4 Calcd for S+1.20TFA+0.20 EtOAc (561.99): C, 49.58; H, 5.70; N, 7.48; Found: C, 49.74; H, 5.53; N, 7.46.

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Abstract

Compounds of formula I or pharmaceutically acceptable salts thereof, wherein R1, R2, R3 and R4 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

technical field [0001] The present invention relates to therapeutic compounds, pharmaceutical compositions comprising these compounds, processes for their preparation and uses. In particular, the present invention relates to being a CB 1 Agonist compounds. More specifically, the present invention relates to the effective treatment of pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease (Alzheimer's disease), anxiety disorders, gastrointestinal disorders and / or cardiovascular disorders. Background technique [0002] Pain management has been an important area of ​​research for many years. It is well known that cannabinoid receptors (such as CB 1 receptor, CB 2 receptor) ligands, including agonists, antagonists and inverse agonists, by interacting with CB 1 and / or CB 2 Receptor interactions to reduce pain in various animal models. Usually, CB 1 Receptors are predominantly located in the central nervous system, while CB 2 Rec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06A61P25/28A61K31/4184A61P35/00A61K31/454A61P9/00A61P1/04C07D235/06A61P25/04C07D403/12A61P25/16C07D405/14A61P25/22C07D413/14
CPCC07D401/12C07D413/14C07D405/14C07D403/12C07D405/06C07D413/12A61P1/00A61P1/04A61P1/06A61P1/08A61P25/00A61P25/04A61P25/14A61P25/16A61P25/22A61P25/28A61P35/00A61P43/00A61P9/00A61P9/10A61K31/4184
Inventor 威廉·布朗刘自平丹尼尔·佩奇泽纳·卡杜米桑杰伊·斯里瓦斯塔瓦马克西姆·特伦布莱克里斯托弗·沃波尔魏中勇杨华
Owner ASTRAZENECA AB