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Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia

A technology for medicinal salts and enantiomers is applied in the field of agonists of muscarinic receptors, and can solve the problems that muscarinic agonists and ACHE-Is are not widely used in clinical practice.

Inactive Publication Date: 2009-08-05
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Muscarinic agonists and ACHE-Is are not widely used clinically due to their propensity to induce a plethora of adverse events when administered to humans

Method used

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  • Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia
  • Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia
  • Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Example 1: 1-(1-{[5-(methoxymethyl)furan-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazole- 2-keto

[0168]

[0169]To 1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one (684mg, 3.15mmol), 5-(methoxymethyl)-2-furancarbaldehyde ( 440mg, 3.14mmol) and NaBH (OAc) 3 (680 mg, 3.22 mmol) in dichloromethane (20 mL) was added acetic acid (0.6 mL) dropwise. The mixture was stirred at room temperature for 48 hours. Usual work-up and purification on preparative HPLC gave the title compound which was converted to its HCl salt (620 mg). MS (M+1): 342.08. 1 H NMR (400MHz, methanol-D4): δppm 2.07 (d, J = 13.28Hz, 2H), 2.69-2.92 (m, 2H), 3.19-3.32 (m, 3H), 3.35 (s, 3H), 3.66 (d, J=12.30Hz, 2H), 4.42(s, 2H), 4.46(s, 2H), 4.50-4.62(m, 1H), 6.49(d, J=3.13Hz, 1H), 6.74(d, J=3.13Hz, 1H), 7.01-7.11(m, 3H), 7.29-7.37(m, 1H).

Embodiment 2

[0170] Example 2: 1-{1-[2-(2-methoxyethoxy)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one

[0171]

[0172] 1-Bromo-2-(2-methoxyethoxy)ethane (2.4mmol), 1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazole-2- A mixture of ketone (2.00 mmol) and sodium carbonate (5 mmol) in acetonitrile (10 mL) was heated at reflux overnight under nitrogen. The reaction mixture was cooled to room temperature, then diluted with diethyl ether (20 mL). The solid was filtered off and the solvent was concentrated. The residue was redissolved in ether (30 mL) and treated with 2N HCl in ether. The precipitate was collected and dried to give the title compound. MS (M+1): 320.05. 1 HNMR (400MHz, DMSO-D6): δ ppm 1.82(d, J=12.50Hz, 2H), 2.80(d, J=12.50Hz, 2H), 3.04-3.31(m, 4H), 3.37-3.71(m, 8H), 3.82(s, 2H), 4.51(t, J=12.11Hz, 1H), 6.96(s, 3H), 7.57(s, 1H), 10.39-11.20(m, 1H), 10.93(s, 1H ).

Embodiment 3

[0173] Example 3: 1-{1-[2-(2-ethoxyethoxy)ethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one

[0174]

[0175] 1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one (100mg, 0.46mmol), potassium carbonate (250mg, 1.81mmol) and 1-bromo-2- A mixture of (2-ethoxyethoxy)ethane (0.1 mL, 0.64 mmol) in acetonitrile (15 mL) was heated at 50 °C for 48 hours. The mixture was concentrated under reduced pressure. The residue was diluted in dichloromethane, washed with water and dried. The crude product was purified by preparative LCMS (acetonitrile / water) to afford the pure compound as its TFA (trifluoroacetic acid) salt (39%). 1 HNMR (400MHz, chloroform-D): δ ppm 1.16(t, J=7.03Hz, 3H), 1.95(d, J=13.28Hz, 2H), 2.83-3.09(m, 4H), 3.26-3.39(m, 2H), 3.49(q, J=7.03Hz, 2H), 3.52-3.59(m, 2H), 3.58-3.68(m, 2H), 3.78-4.02(m, 4H), 4.52-4.75(m, 1H) , 6.84-7.15 (m, 3H), 7.41 (d, J=7.03Hz, 1H), 10.16 (s, 1H). MS: 334.0 (M+1).

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Abstract

Compounds of Formulae I, or pharmaceutically acceptable salts thereof: wherein R, R, R, R, R, R, R, m and n 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 agonists of muscarinic receptors. The invention also provides compositions containing said agonists and methods of using said agonists for treating diseases mediated by muscarinic receptors. In particular, the invention relates to compounds which are effective in the treatment of pain, Alzheimer's disease and / or schizophrenia. Background technique [0002] The neurotransmitter acetylcholine binds two types of cholinergic receptors: the ionotropic family of nicotinic receptors and the metabotropic family of muscarinic receptors. Muscarinic receptors belong to the large superfamily of plasma membrane-bound G protein-coupled receptors (GPCRs) and show a remarkably high degree of homology between species and between receptor subtypes. These M1-M5 muscarinic receptors are predominantly expressed in the parasympathetic nervous system, which exerts stimulatory and inhibitory control of central and peripheral tissues and is i...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4184A61K31/454A61P25/04A61P25/18A61P25/28C07D403/04C07D405/14
CPCC07D403/04C07D405/14C07D401/04A61P11/00A61P19/02A61P25/00A61P25/04A61P25/06A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/32A61P25/34A61P25/36A61P29/00A61P3/04A61P31/12A61P35/00A61P37/06A61P37/08A61P41/00A61P43/00A61P9/10A61P9/12
Inventor 程云兴米洛斯劳·托马斯泽夫斯基
Owner ASTRAZENECA AB
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